WO2007043418A1 - Method for prediction of postoperative prognosis for patient with pulmonary adenocarcinoma, and composition for use in the prediction - Google Patents

Abstract

Disclosed is a method for prediction of the prognosis for a patient with pulmonary adenocarcinoma, which comprises the steps of: distinguishing whether the pulmonary adenocarcinoma belongs to the TRU-type subfamily or the non-TRU-type subfamily using a specific gene set; when the pulmonary adenocarcinoma is determined as belonging to the TRU-type subfamily, further distinguishing whether the TRU-type pulmonary adenocarcinoma belongs to the TRU-a-type subfamily or the TRU-b-type subfamily; and predicting the prognosis for the patient in vitro based on the correlation between postoperative prognosis and subtype in pulmonary adenocarcinoma. Also disclosed is a method for categorizing pulmonary adenocarcinoma into any one of the subtypes mentioned above. Further disclosed is a composition for use in these methods.

Description

 Methods and compositions for predicting postoperative prognosis in patients with lung adenocarcinoma

 Technical field

 [0001] The present invention relates to a method and a composition for predicting the postoperative prognosis of a lung adenocarcinoma patient.

[0002] The present invention also relates to a method for classifying lung adenocarcinoma into its subtypes.

 Background art

 [0003] Lung cancer is the leading cause of cancer-related death in developed countries (Non-patent Documents 1 and 2). Currently, tumor classification is based on histological features from large microscopic observations, but on the other hand, significant changes in clinical judgment are sometimes evident even within certain tissue types, and adenocarcinoma is It is known to exhibit the highest degree of morphological and clinical diversity (Non-patent Document 3). Therefore, a more detailed and accurate means to classify non-small cell lung cancer (NSCLC), especially adenocarcinoma, has improved today's inappropriate diagnostic capabilities as well as a better understanding of the etiology. There are great expectations for enabling more effective treatments.

 [0004] Recent development of microarray technology has made it possible to correlate various clinical parameters with gene expression profiles of individual cases (Non-Patent Documents 4 to 9). To date, various other group force expression profiles, including our group, have been reported to reproduce the morphological classification of NSCLC, and several studies have shown that adenocarcinoma is further It has been shown that subclassification is possible (Non-Patent Documents 10 to 13).

 [0005] However, the results of these sub-classifications reported so far are inconsistent with each other, and it is difficult to simply adapt to those findings, and it is also difficult to draw some clear conclusions. It should also be pointed out that conventional expression profiling studies provide very little information about the relationship between expression profiles and basic genetic changes (Non-Patent Document 14). Such information is inherently known to be important in clarifying the pathogenesis of lung cancer.

[0006] By the way, the discovery of an activating mutation of epidermal growth factor receptor (EGFR) is one of the most noteworthy findings in the field of lung cancer research today (Non-patent Documents 15 and 16). EGF R mutations are present in a subset of lung adenocarcinoma (Non-Patent Documents 15-20), and tumors with this mutation are highly gefitinib (selective EGFR tyrosine kinase inhibitors; such as Ire _SSa ^™ ). (Non-Patent Documents 15 to 17, 19). A good clinical response to gefitinib has been observed most frequently in non-smoking adenocarcinoma patients of Japanese and other Asian women (Non-Patent Documents 21 and 22). The present inventors also detected EGFR mutations frequently in lung adenocarcinoma, which is considered to be morphologically derived from peripheral airway epithelial cells, so-called terminal respiratory unit (TRU) type adenocarcinoma. (Non-Patent Documents 23 and 24).

Non-Patent Document 1: Minna JD et al. (Edit), Harrison's Principals of Internal Medicine (16th edition), McGraw-Hill, 2001, pp 506—516

Non-Patent Document 2: Statistics and Information Department, Minister's Seer etariat: Vital Statistics of Japan 2001 Vol. 3, Ministry of Healt h, Labor and Welfare, Japan, 2003, pp384— 411

Non-Patent Document 3: Travis WD et al., Pathology and genetics of tumors of the lung, pleura, thymus and heart, World Health Organization clas sification of tumors, Lyon, I ARC press, 2004

Non-Patent Document 4: Perou CM et al., Nature 406: 747— 52, 2000

Non-Patent Document 5: Alizadeh AA et al., Nature 403: 503— 11, 2000

Non-Patent Document 6: Shipp MA et al., Nat Med 8: 68—74, 2002

Non-Patent Document 7: Singh D et al., Cancer Cell 1: 203— 9, 2002

Non-Patent Document 8: van, t Veer LJ et al., Nature 415: 530— 6, 2002

Non-Patent Document 9: Hedenfalk I et al., Proc Natl Acad Sci USA 100: 2532— 7, 2003

Non-Patent Document 10: Garber ME et al., Proc Natl Acad Sci USA 98: 13784—9, 2001

Non-Patent Document ll: Bhattacharjee A et al., Proc Natl Acad Sci USA 98: 1379 0-5, 2001

Non-Patent Document 12: Beer DG et al., Nat Med 8: 816—24, 2002 Non-patent literature 13: Tomida S et al., Oncogene 23: 5360-70, 2004 Non-patent literature 14: Meyerson M et al., J Clin Oncol 23: 3219— 26, 2005 Non-patent literature 15: Paez JG et al., Science 304: 1497- 500, 2004

 Non-patent document 16: Lynch TJ et al., N Engl J Med 350: 2129—39, 2004 Non-patent document 17: Pao W et al., Proc Natl Acad Sci USA 101: 13306— 11,

2004

 Non-Patent Document 18: Kosaka T et al., Cancer Res 64: 8919-23, 2004

 Non-patent document 19: Mitsudomi T et al., J clin Oncol 23: 2513— 20, 2005 Non-patent document 20: Shigematsu H et al., J Natl Cancer Inst 97: 339-46, 20

05

 Non-patent document 21: Fukuoka M et al., J Clin Oncol 21: 2237-46, 2003 Non-patent document 22: Kris MG et al., Jama 290: 2149—58, 2003

 Non-Patent Document 23: Yatabe Y et al., Am J Surg Pathol 29: 633— 639, 2005 Non-Patent Document 24: Yatabe Y et al., Am J Surg Pathol 26: 767-73, 2002 Disclosure of the Invention

 [0007] Conventionally, in an actual clinical setting, human lung cancer has been diagnosed based on clinical and pathological classification. In other words, the conventional diagnosis relies on morphological diagnosis by microscopic observation, and thus lacks objectivity and information on the prognosis of the patient is extremely limited. Diagnosis based on comprehensive and systematic expression profiles is also useful for diagnosis in a useful form by analyzing information that should have genetic abnormalities closely related to the development and progression of lung cancer in an integrated manner with the expression profile. I was unable to capture it.

 [0008] In this situation, the present inventors simultaneously analyzed a wide range of expression profiles and EGFR, p53 and K ras mutation status in 149 NSCLC cases, including 90 adenocarcinomas, The aim was to establish a taxonomy defined by both genetic and clinicopathologically relevant expression profiles.

[0009] Furthermore, we have used this taxonomy to significantly increase morbidity and EGFR mutations in one of the two major subtypes identified in lung adenocarcinoma (TRU type). The purpose of this study was to clarify the impact on the prognosis. Summary of the Invention

 [0010] In the present application, the present inventors found four gene sets identified by comprehensive gene analysis of human lung cancer, and by using these sets, based on the expression profile of lung adenocarcinoma force. We found that there were two main groups that were objectively clinically and molecularly meaningful, and that one group was divided into two subgroups.

 [0011] As a result of further research based on these findings, the use of these gene sets enables prediction of postoperative prognosis in patients with lung adenocarcinoma and the occurrence of lung cancer. We succeeded in detecting the association between EGFR mutations, which play an important role in progress, and prognosis. These new findings have made it possible to provide important information for deciding how to treat NSCLC, especially lung adenocarcinoma.

Therefore, in summary, the present invention has the following features.

 [0013] In the first aspect, the present invention provides a method for predicting the postoperative prognosis of a patient having lung adenocarcinoma in vitro, wherein the method is a TRU type, which is a subtype of lung adenocarcinoma. Or non-TRU type, and if it is identified as TRU type, further identify TRU-type lung adenocarcinoma as TRU-a type or TRU-b type. This includes determining that the prognosis is good for type b, or that the postoperative prognosis is poor for TRU-a type or non-TRU type, where the TRU type and non-TRU type Type, TRU-a type, and TRU-b type are TRU-type adenocarcinoma and non-TRU-type adenocarcinoma for one or more genes of the following corresponding gene set in the biological sample of the patient. Or by measuring the difference in relative expression levels between TRU-a adenocarcinoma and TRU-b adenocarcinoma, and

The gene set belonging to the TRU type is the following UniGene registration number: Hs.512690, Hs.153322, Hs.218366, Hs.220629, Hs.436996, Hs.435759, Hs.10455 5, Hs .247824, Hs.127821, Hs.480281, Hs.529117, Hs.545862, Hs.391561, Hs.479 372, Hs.533055, Hs.550526, Hs.322854, Hs.465720, Hs.356664, Hs. 26630, Hs.53 4496, Hs.85962, Hs.211267, Hs.128041, Hs.534458, Hs.495774, Hs.437806, Hs.l 33062, Hs.501758, Hs.444535, Hs.444480, Hs. 326561, Hs.483906, Hs.169943, Hs.271285, Hs.158339, Hs.62604, Hs.469359, Hs.436657, Hs.8417, Hs.155538, Hs. 533526, Hs.512756, Hs.87191, Hs.463079, Hs.513779, Hs.476209, Hs.279580, Hs.351544, Hs.269408, Hs.134807, Hs.482417, Hs.176626, Hs.465643, Hs.183390, Hs.411299, Hs.234027, Hs.109358, Hs.103983, Hs.26216, Hs.534352, Hs.240457, Hs.516036, Hs.144875, Hs.411312, Hs.l03989, Hs. 537722, Hs.333130, Hs.5179 62, Hs.90250, Hs.478930, Hs.121629, Hs.l94061, Hs.520627, Hs.348012, Hs.522 836, Hs.l376, Hs.520049, Hs. 512856, Hs.355236, Hs.349470, Hs.476231, Hs.137 556, Hs.390567, Hs.368353, Hs.412792, Hs.449207, Hs.527095, Hs.118722, Hs.3 77090, Hs. 232696, Hs.447544, Hs.372773, Hs.222055, Hs.511839, Hs.153299, Hs .434374, Hs.287729, Hs.553740, Hs.l27189, Hs.497723,

 Hs.l81973, Hs.173656, Hs.451956, Hs.184507, Hs.532492, Hs.370904, Hs.46046 8, Hs.520612, Hs.436667, Hs.l25116, Hs.459391, Hs.450320, Hs .149769, Hs.32 5890, Hs.356820, Hs.289319, Hs.73893, Hs.129493, Hs.515069, Hs.34560, Hs.47 7278, Hs.351571, Hs.112087, Hs.154224, Hs l25950, Hs.438016, Hs.367956, Hs. 553778, Hs.329266, Hs.479658, Hs.458713, Hs.249196, Hs.467529, Hs.145061, Hs.49653, Hs.129227, Hs.313343 , Hs.194554, Hs.l23114, Hs.126561, Hs.42091, Hs.369385, Hs.98661, Hs.458306, Hs.148584, Hs.501684, Hs.422466, Hs.523732, Hs.525557, Hs .l372, Hs.379097, Hs.208124, Hs.389311, Hs.2561, Hs.117545, Hs.446388, Hs.2813, Hs.473894, Hs.502092, Hs.524479, Hs.314261, Hs.382306 , Hs.458252, Hs.380222, Hs.379636, Hs.302034, Hs.253495, Hs.345877, Hs.25956 3, Hs.528569, Hs.152337, Hs.436317, Hs.546408, Hs.46700, Hs.l027, Hs.151219, Hs.279611, Hs.310456, Hs.520319, H s.406976, Hs.181245, Hs.449621, Hs.5154 65, Hs.310540, Hs.554891, Hs.449601, Hs.355394, Hs.380710, Hs.171995, Hs.44 9585, Hs.522484, A gene having Hs.298023, Hs.520339, Hs.121443, or a variant, homologue or derivative thereof,

 The gene set belonging to the non-TRU type has the following UniGene registration number:

Hs.62661, Hs.200804, Hs.533185, Hs.461329, Hs.479270, Hs.446201, Hs.35086, Hs.500761, Hs.44298, Hs.469030, Hs.309767, Hs.441047, Hs. 98309, Hs.31409, Hs.518299, Hs.532870, Hs.196534, Hs.108106, Hs.289319, Hs.69771, Hs.374378, Hs.369422, Hs.368641, Hs.302963, Hs.530461, Hs.l955, Hs.513726, Hs.148767, Hs.523220, Hs.525796, Hs.271264, Hs.69321, Hs.231367, Hs. 500761, Hs.528304, Hs.148685, Hs.87417, Hs.164060, Hs.514843, Hs.418416, Hs.126521, Hs.51983 9, Hs.103834, Hs.279840, Hs.497741, Hs.531457 , Hs.226390, Hs.480143, Hs.473 721, Hs.369762, Hs.514527, Hs.204238, Hs.3104, Hs.519873, Hs.519909, Hs.179 718, Hs.l03183, Hs.520210 , Hs.444683, Hs.234545, Hs.80976, Hs.311187, Hs.89 497, Hs.444118, Hs.541635, Hs.477898, Hs.511776, Hs.434886, Hs.117299, Hs.2 52451 , Hs.468058, Hs.21554, Hs.165904, Hs.445244, Hs.413924, Hs.99120, Hs.5 21171, Hs.462379, Hs.481860, Hs.489207, Hs.414407, Hs.505575, Hs.516826, Hs.62180, Hs.368934, Hs.530509, Hs.278906, Hs.511987, Hs.444082, Hs.471873, Hs.24583, or a variant, homologue or derivative thereof is there,

 The gene set belonging to the TRU-a type has the following UniGene registration number:

Hs.220629, Hs.153322, Hs.127821, Hs.218366, Hs.436996, Hs.247824, Hs.55052 6, Hs.62604, Hs.104555, Hs.465720, Hs.480281, Hs.495480, Hs .545862, Hs.1051, Hs.l33062, Hs.115263, Hs.349470, Hs.495774, Hs.155538, Hs.435759, Hs.1280 41, Hs.465643, Hs.169943, Hs.534496, Hs. 379010, Hs.184507, Hs.469359, Hs.20 12, Hs.l09358, Hs.438016, Hs.326561, Hs.367956, Hs.271285, Hs.176626, Hs.13 7556, Hs.437806, Hs. 240457, Hs.533055, Hs.532492, Hs.85962, Hs.268698, Hs.5 20627, Hs.524479, Hs.449585, Hs.158339, Hs.522836, Hs.279580, Hs.444535, Hs .446388 , Hs.149769, Hs.513779, Hs.l03983, Hs.512756, Hs.348012, Hs.467529, Hs.434374, Hs.389311, Hs.49653, Hs.424542, Hs.436667, Hs.516036, Hs .533526, Hs.463079, Hs.310456, Hs.125950, Hs.351571, Hs.478930, Hs.483906, Hs.2595 63, Hs.249196, Hs.412792, Hs.183390, Hs.87191, Hs. 171995, Hs.117545, Hs.554 891, Hs.351544, Hs.368353, Hs.482417 Hs.l26561, Hs.154224, Hs.232696, Hs.5 20319, Hs.l53299, Hs.449621, Hs.502092, Hs.537722, Hs.127189, Hs.525589, Hs.476231, Hs.527095, Hs .511839, Hs.372773, Hs.112087, Hs.458252, Hs.181973, Hs.289319, Hs.25333, Hs.513075, Hs.356820, Hs.549577

, Hs.380222, Hs.46700, Hs.129227, Hs.l00431, Hs.129493, Hs.173656, Hs.9613, Hs.301478, Hs.553740, Hs.151219, Hs.369385, Hs.525383, Hs.473721, Hs.37562 4, Hs.355236, Hs.116724, Hs.9613, Hs.418055, or a gene thereof A variant, homologue or derivative, and

 The gene set belonging to the TRU-b type has the following UniGene registration number:

 Hs.334873, Hs.180878, Hs.126521, Hs.519033, Hs.l87636, Hs.518448, Hs.32276 1, Hs.31409, Hs.524513, Hs.253495, Hs.436437, Hs.148989, Hs .279575, Hs.7566 8, Hs.470791, Hs.104476, Hs.494496, Hs.517549, Hs.278906, Hs.498586, Hs.183 617, Hs.499758, Hs.350065, Hs.511138, Hs l50793, Hs.129174, Hs.212606, Hs.2 75775, Hs.279611, Hs.496414, Hs.436142, Hs.282984, Hs.32417, Hs.69321, Hs.4 14629, Hs.502618, Hs .405755, Hs.480143, Hs.90250, Hs.436317, Hs.60371, Hs.2 83683, Hs.208093, Hs.336768, Hs.1116459, Hs.l31673, Hs.42091, Hs.32417, Hs. 7 5812, a gene having Hs.355394, or a variant, homologue or derivative thereof.

 [0014] In the present specification, TRU (terminal respiratory unit) is a unit composed of airway epithelium located in the periphery, particularly in the lung, and its structural unit force is also generated or similar to them. Adenocarcinoma with character is called TRU adenocarcinoma. Non-TRU adenocarcinoma refers to a subtype other than TRU.

 [0015] In the present specification, the postoperative prognosis means that the prognosis of a patient after surgery for lung adenocarcinoma is typically determined by the survival rate at 5 years after the operation. Prognosis is closely related to cancer metastasis, and poor prognosis means high invasiveness, metastasis, or high degree of cancer, while good prognosis or good prognosis is such invasion. Means less metastatic, metastatic or advanced.

 [0016] In the present specification, the gene variants include, for example, variants that arise due to biological events such as mutation, gene polymorphism, alternative splicing, and the degeneracy of the genetic code. To do. The mutant has one or more substitutions, deletions, additions, insertions and the like mutations on the original nucleotide sequence of the gene.

[0017] In this specification, a homologue is the same because it has the same biological function or action as the gene, although the sequence is partially different from that of the gene for reasons such as different species. It refers to a nucleic acid belonging to one family. [0018] Mutants and homologues are 70% or more, preferably 80% or more, more preferably 90% or more, 95% or more, 97% or more, 98% or more with each of the corresponding genes at the nucleotide level. Or 99% or more identity. Here, the identity (%) can be determined using a known BLAST program in which a gap is introduced. In general, identity (%) can be calculated as a percentage of the number of matched bases relative to the total number of bases.

 [0019] In the present specification, the derivative refers to the gene containing a chemical modification of a base. Examples of such chemical modification include methylation, acetylation, thiolation, carboxymethylation, and methoxylation. Etc. are included.

 [0020] In the present specification, patients refer to mammals including humans, dogs and cats, and preferred mammals are humans.

 [0021] In one embodiment of the present invention, the UniGene registration number:

 Hs.512690, Hs.153322, Hs.218366, Hs.220629, Hs.436996, Hs.435759, Hs.10455 5, Hs.247824, Hs.127821, Hs.480281, Hs.529117, Hs.545862, Hs .391561, Hs.479 372, Hs.533055, Hs.550526, Hs.322854, Hs.465720, Hs.356664, Hs.26630, Hs.53 4496, Hs.85962, Hs.211267, Hs.128041, Hs .534458, Hs.495774, Hs.437806, Hs.l 33062, Hs.501758, Hs.444535, Hs.495480, Hs.326561, Hs.483906, Hs.169943, Hs.271285, Hs.158339, Hs. 62604, Hs.469359, Hs.436657, Hs.8417, Hs.155538, Hs. 533526, Hs.512756, Hs.87191, Hs.463079, Hs.513779, Hs.476209, Hs.279580, Hs.351544, Hs.269408, Hs.134807, Hs.482417, Hs.176626, Hs.465643, Hs.183390, Hs.411299, Hs.234027, Hs.109358, Hs.103983, Hs.26216, Hs.534352, Hs. 240457, Hs.516036, Hs.144875, Hs.411312, Hs.l03989, Hs.537722, Hs.333130, Hs.5179 62, Hs.90250, Hs.478930, Hs.121629, Hs.l94061, Hs.520627 , Hs.348012, Hs.522 836, Hs.l376, Hs.520049, Hs.51 2856, Hs.355236, Hs.349470, Hs.476231, Hs.137 556, Hs.390567, Hs.368353, Hs.412792, Hs.449207, Hs.527095, Hs.118722, Hs.3 77090, Hs. 232696, Hs.447544, Hs.372773, Hs.222055, Hs.511839, Hs.153299, Hs .434374, Hs.287729, Hs.553740, Hs.l27189, Hs.497723,

Hs.l81973, Hs.173656, Hs.451956, Hs.184507, Hs.532492, Hs.370904, Hs.46046 8, Hs.520612, Hs.436667, Hs.l25116, Hs.459391, Hs.450320, Hs .149769, Hs.32 ^{• S H, 8 IOS 's} H ST96 "S H, ISW) Or s H ZS6' S HS OSTS" SH, SSSSS 'S H 68SS2S • S H ^ Z ^ ZV SS96 ^ "S H, 86989S' S H 2T02 ^{"S H 0I06ZS 'S H S92Sn} " SH, ISOI' s H

^{H ^ Z LV 280W S H 86nS} "SH, 9068W S H 60S0SS" SH, S689S 'S HH

SH 9289TS "SH S SSOS" SH 0 I ' ^S H 0268 ^ " ^S H 098T8 ^" ^S H ^ LZZW "ILUZ S'sH 02T66" ^S H

, W) 6S9r ^s H, SSIS ' ^S H, 8S089' ^S H l Z Z ' ^S H 662 n "SH, 988' ^S H 9 US" SH, 868 ^S H, SS9I ' ^S H 8UW ^S H L6 68'SH 8inS " ^S H 9Z608" ^S H, SS; S ' ^S H S89W ^S H, OHS'SH, S8IS0I' ^S H, 8U 6 FSH, 6066IS'sH S 86TS "SH, rain S ' ^S H, 8SSW) S' ^S H SSWS'sH 29Z69S " ^S H" IZL UV e ^ T08 ^ " ^s H 06S922" ^S H USS'sH lfLL6V ^s H, 0 86 ' ^S H S8S0r ^s H, 6 S86TS "SH T2S92r ^s H, 9I 8I' ^S H, S IS'sH, 090 9I ' ^S H ^ Z8' ^S H, S898 I ' ^S H

0S8SS'sH T9Z00S "SH Z9STS2" ^S H T2S69 " ^S H 9SIW ^S H 96 S2S" SH 022S2S "SH

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6T2TSrsH 20r ^s H 00Z9 ^ " ^S H, 80 9 ' ^S H TS9SF ^S H SSSSI'sH 69S82S" SH S 9S6S2 "SH Z8S TSH S020S" ^S H 9S96 S "SH 22208S" ^S H

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26020S "SH f6S £ LV ^s H ST82" ^S H, 88S9W ^S H, S m ' ^s H, I9SS' ^S H US68S " ^S H H80S ' ^S H Z606ZS" SH ZL £ V ^S H SSSSS'SH

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6 .686TC / 900Zdf / X3d 8 o / OOZ OAV 553740, Hs.525383, Hs.473721, Hs.375624, Hs.ll6724, Hs.9613, Hs.418055, Hs.334873, Hs.180878, Hs.126521, Hs.519033, Hs.l87636, Hs.518448, Hs.32276 1, Hs.31409, Hs.524513, Hs.436437, Hs.148989, Hs.279575, Hs.75668, Hs.47079 1, Hs.104476, Hs.494496, Hs.517549, Hs.278906, Hs.498586, Hs.183617, Hs.499 758, Hs.350065, Hs.511138, Hs.150793, Hs.l29174, Hs.212606, Hs.275775, Hs.4 96414, Hs.436142, Hs.282984, Hs.32417, Hs.69321, Hs.414629, Hs.502618, Hs.4 05755, Hs.480143, Hs.60371, Hs.283683, Hs.208093, Hs.336768, Hs.1116459, Hs.131673, Hs .32417, Hs.75812

 Each of the genes having the sequence is characterized by including the sequence shown in SEQ ID NOs: 1 to 351 or a complementary sequence thereof.

[0022] In another embodiment, the differential level S of the expression level of the gene belonging to the TRU-type or non-TRU-type adenocarcinoma, and the difference in the expression level of the gene belonging to the non-TRU-type or TRU-type adenocarcinoma respectively. When it is relatively large, the adenocarcinoma is determined as TRU adenocarcinoma or non-TRU adenocarcinoma, respectively.

 [0023] Alternatively, the difference in the expression level of the gene belonging to the TRU-a type or TRU-b adenocarcinoma is relative to the difference in the expression level of the gene belonging to the TRU-b type or TRU-a adenocarcinoma, respectively. When it is large, the adenocarcinoma is determined as TRU-a type adenocarcinoma or non-TRU type-b adenocarcinoma, respectively.

 [0024] Because the difference in expression level is a relative difference between TRU adenocarcinoma and non-TRU adenocarcinoma, or between TRU-a adenocarcinoma and TRU-b adenocarcinoma , One is determined by the power vj, which is greater than the other. Preferably, such a difference is 1.5 times or more, more preferably 2.0 times or more.

 [0025] In another embodiment, the expression level of the gene is determined by measuring the presence or amount of a nucleic acid or protein corresponding to the gene.

 [0026] In the present specification, the nucleic acid is either DNA or RNA, and includes, for example, a transcription product (mRNA), cDNA, cRNA and the like of each gene.

[0027] The protein means a protein encoded by each gene, a variant thereof, or a fragment thereof. Variants include splicing variants based on polymorphisms. fragment Is a protein fragment spontaneously generated by the action of proteaase-peptidase in vivo and includes any size fragment as long as it can be identified as a fragment of the target protein. . The preferred size of the fragment is 20 or more amino acids, more preferably 30 or more amino acids, and even more preferably 50 or more amino acids.

[0028] In still another embodiment, the expression level of the gene can be measured by a hybridization method or a gene amplification method.

[0029] The hybridization method includes, for example, a microarray method, a blotting method such as a Northern blot or a Southern blotting method, a Northern or Southern hybridization method, an in situ hybridization method, and the like. . Preferred hybridization methods are microarray methods such as DNA microarrays, oligonucleotide microarrays and protein microarrays. Gene amplification methods include the polymerase chain reaction (PCR) method, ICAN method, LAMP method, and PAL SAR method. Preferable! / The gene amplification method is the PCR method.

 [0030] In another embodiment, the expression level of the gene can alternatively be measured by an immunological method.

 [0031] The immunological method includes detecting an immunological complex of a specific antibody against a protein encoded by the gene or a fragment thereof and a target protein. Here, the protein or a fragment thereof can be preferably obtained by a conventional cDNA cloning method based on a sequence registered in a gene bank and a protein synthesis method using an expression vector / host system. Immunological methods include enzyme immunoassays (EIA, ELISA, etc.), fluorescent antibody methods, radioimmunoassays, agglutination methods, and turbidimetric methods. In addition, the antigen-antibody reaction is preferably a homogeneous or heterogeneous reaction, or a reaction by a force solid phase method which can be performed under either solid phase or non-solid phase conditions. Furthermore, a sandwich method using a labeled secondary antibody is also preferably used.

[0032] In still another embodiment, the prognostic method of the present invention includes the wild-type EG FR gene when the epidermal growth factor receptor (EGFR) gene contains a mutation in the TRU-type lung adenocarcinoma. It can further include predicting that the patient's postoperative prognosis is poor compared to lung adenocarcinoma, including [0033] Whether the EGFR gene contains a mutation can be determined by, for example, Kosaka T et al., Cancer.

Res 64: 8919—23, 2004 (Non-patent Document 18), Mitsudomi T et al., J clin Oncol 23: 2513-20, 2005 (Non-patent Document 19), and the like. Briefly, in such a method, the gene region can be amplified using PCR, and the mutation can be detected using gel electrophoresis or determination of the nucleotide sequence.

 [0034] In the second aspect, the present invention also classifies the lung adenocarcinoma into either a TRU-type or non-TRU-type subtype, and next !, the TRU-type adenocarcinoma is classified into TRU-a type or TRU type. -b classification method, wherein the method comprises a TRU adenocarcinoma and a non-TRU adenocarcinoma for one or more genes of the corresponding gene set below in a patient biological sample. Or the relative expression level difference between TRU-a type adenocarcinoma and TRU-b type adenocarcinoma, and the gene showing the difference in expression level is

 (a) The following UniGene registration numbers:

Hs.512690, Hs.153322, Hs.218366, Hs.220629, Hs.436996, Hs.435759, Hs.10455 5, Hs.247824, Hs.127821, Hs.480281, Hs.529117, Hs.545862, Hs .391561, Hs.479 372, Hs.533055, Hs.550526, Hs.322854, Hs.465720, Hs.356664, Hs.26630, Hs.53 4496, Hs.85962, Hs.211267, Hs.128041, Hs .534458, Hs.495774, Hs.437806, Hs.l 33062, Hs.501758, Hs.444535, Hs.495480, Hs.326561, Hs.483906, Hs.169943, Hs.271285, Hs.158339, Hs. 62604, Hs.469359, Hs.436657, Hs.8417, Hs.155538, Hs. 533526, Hs.512756, Hs.87191, Hs.463079, Hs.513779, Hs.476209, Hs.279580, Hs.351544, Hs.269408, Hs.134807, Hs.482417, Hs.176626, Hs.465643, Hs.183390, Hs.411299, Hs.234027, Hs.109358, Hs.103983, Hs.26216, Hs.534352, Hs. 240457, Hs.516036, Hs.144875, Hs.411312, Hs.l03989, Hs.537722, Hs.333130, Hs.5179 62, Hs.90250, Hs.478930, Hs.121629, Hs.l94061, Hs.520627 , Hs.348012, Hs.522 836, Hs.l376, Hs.520049, Hs.51285 6, Hs.355236, Hs.349470, Hs.476231, Hs.137 556, Hs.390567, Hs.368353, Hs.412792, Hs.449207, Hs.527095, Hs.118722, Hs.3 77090, Hs. 232696, Hs.447544, Hs.372773, Hs.222055, Hs.511839, Hs.153299, Hs .434374, Hs.287729, Hs.553740, Hs.l27189, Hs.497723, Hs.l81973, Hs.173656, Hs.451956, Hs.184507, Hs.532492, Hs.370904, Hs.46046

8, Hs.520612, Hs.436667, Hs.l25116, Hs.459391, Hs.450320, Hs.149769, Hs.32 5890, Hs.356820, Hs.289319, Hs.73893, Hs.129493, Hs.515069 , Hs.34560, Hs.47 7278, Hs.351571, Hs.112087, Hs.154224, Hs.l25950, Hs.438016, Hs.367956, Hs.553778, Hs.329266, Hs.479658, Hs.458713, Hs.249196, Hs.467529, Hs.145061, Hs.49653, Hs.129227, Hs.313343, Hs.194554, Hs.l23114, Hs.126561, Hs.42091, Hs.369385, Hs.98661, Hs. 458306, Hs.148584, Hs.501684, Hs.422466, Hs.523732, Hs.525557, Hs.l372, Hs.379097, Hs.208124, Hs.389311, Hs.2561, Hs.117545, Hs.446388, Hs.2813, Hs.473894, Hs.502092, Hs.524479, Hs.314261, Hs.382306, Hs.458252, Hs.380222, Hs.379636, Hs.302034, Hs.253495, Hs.345877, Hs. 25956 3, Hs.528569, Hs.152337, Hs.436317, Hs.546408, Hs.46700, Hs.l027, Hs.151219, Hs.279611, Hs.310456, Hs.520319, Hs.406976, Hs.181245 , Hs.449621, Hs.5154 65, Hs.310540, Hs.554891, Hs.44960 1, Hs.355394, Hs.380710, Hs.171995, Hs.44 9585, Hs.522484, Hs.298023, Hs.520339, Hs.121443, or a variant, homologue or derivative thereof If it is a gene in the set, the lung adenocarcinoma is determined to be TRU type, or

 (b) The following UniGene registration numbers:

Hs.62661, Hs.200804, Hs.533185, Hs.461329, Hs.479270, Hs.446201, Hs.35086, Hs.500761, Hs.44298, Hs.469030, Hs.309767, Hs.441047, Hs. 98309, Hs.31409, Hs.518299, Hs.532870, Hs.196534, Hs.108106, Hs.289319, Hs.69771, Hs.374378, Hs.369422, Hs.368641, Hs.302963, Hs.530461 , Hs.l955, Hs.513726, Hs.148767, Hs.523220, Hs.525796, Hs.271264, Hs.69321, Hs.231367, Hs.500761, Hs.528304, Hs.148685, Hs.87417, Hs .164060, Hs.514843, Hs.418416, Hs.126521, Hs.51983

9, Hs.103834, Hs.279840, Hs.497741, Hs.531457, Hs.226390, Hs.480143, Hs.473 721, Hs.369762, Hs.514527, Hs.204238, Hs.3104, Hs.519873 , Hs.519909, Hs.179 718, Hs.l03183, Hs.520210, Hs.444683, Hs.234545, Hs.80976, Hs.311187, Hs.89 497, Hs.444118, Hs.541635, Hs.477898 , Hs.511776, Hs.434886, Hs.117299, Hs.2 52451, Hs.468058, Hs.21554, Hs.165904, Hs.445244, Hs.413924, Hs.99120, Hs.5 21171, Hs.462379, Hs.481860, Hs.489207, Hs.414407, Hs.505575, Hs.516826, Hs .62180, Hs.368934, Hs.530509, Hs.278906, Hs.511987, Hs.444082, If it is a gene in a gene set comprising Hs.471873, Hs.24583, or a variant, homologue or derivative thereof, the lung adenocarcinoma is determined to be non-TRU type, or

(c) UniGene registration number:

 Hs.220629, Hs.153322, Hs.127821, Hs.218366, Hs.436996, Hs.247824, Hs.55052 6, Hs.62604, Hs.104555, Hs.465720, Hs.480281, Hs.495480, Hs .545862, Hs.1051, Hs.l33062, Hs.115263, Hs.349470, Hs.495774, Hs.155538, Hs.435759, Hs.1280 41, Hs.465643, Hs.169943, Hs.534496, Hs. 379010, Hs.184507, Hs.469359, Hs.20 12, Hs.l09358, Hs.438016, Hs.326561, Hs.367956, Hs.271285, Hs.176626, Hs.13 7556, Hs.437806, Hs. 240457, Hs.533055, Hs.532492, Hs.85962, Hs.268698, Hs.5 20627, Hs.524479, Hs.449585, Hs.158339, Hs.522836, Hs.279580, Hs.444535, Hs .446388 , Hs.149769, Hs.513779, Hs.l03983, Hs.512756, Hs.348012, Hs.467529, Hs.434374, Hs.389311, Hs.49653, Hs.424542, Hs.436667, Hs.516036, Hs .533526, Hs.463079, Hs.310456, Hs.125950, Hs.351571, Hs.478930, Hs.483906, Hs.2595 63, Hs.249196, Hs.412792, Hs.183390, Hs.87191, Hs. 171995, Hs.117545, Hs.554 891, Hs.351544, Hs.368353, Hs.482417 Hs.l26561, Hs.154224, Hs.232696, Hs.5 20319, Hs.l53299, Hs.449621, Hs.502092, Hs.537722, Hs.127189, Hs.525589, Hs.476231, Hs.527095, Hs .511839, Hs.372773, Hs.112087, Hs.458252, Hs.181973, Hs.289319, Hs.25333, Hs.513075, Hs.356820, Hs.549577

 , Hs.380222, Hs.46700, Hs.129227, Hs.l00431, Hs.129493, Hs.173656, Hs.9613, Hs.301478, Hs.553740, Hs.151219, Hs.369385, Hs.525383, Hs 473721, Hs.37562 4, Hs.355236, Hs.116724, Hs.9613, Hs.418055, or a gene in a gene set comprising a variant, homologue or derivative thereof, the lung gland Determine that the cancer is TR Ua type, or

 (d) UniGene registration number:

Hs.334873, Hs.180878, Hs.126521, Hs.519033, Hs.l87636, Hs.518448, Hs.32276 1, Hs.31409, Hs.524513, Hs.253495, Hs.436437, Hs.148989, Hs .279575, Hs.7566 8, Hs.470791, Hs.104476, Hs.494496, Hs.517549, Hs.278906, Hs.498586, Hs.183 617, Hs.499758, Hs.350065, Hs.511138, Hs.l50793, Hs.129174 , Hs.212606, Hs.2 75775, Hs.279611, Hs.496414, Hs.436142, Hs.282984, Hs.32417, Hs.69321, Hs.4 14629, Hs.502618, Hs.405755, Hs.480143 , Hs.90250, Hs.436317, Hs.60371, Hs.2 83683, Hs.208093, Hs.336768, Hs.1116459, Hs.l31673, Hs.42091, Hs.32417, Hs.7 5812, Hs.355394 And determining whether the lung adenocarcinoma is TRU-b type when the gene is a gene in a gene set consisting of a gene having the above or a variant, homologue or derivative thereof.

Here, TRU, non-TRU, mutant, homologue and derivative have the same meaning as described above.

[0036] Here, the difference in the expression level of the gene belonging to the TRU-type or non-TRU-type adenocarcinoma is relatively larger than the difference in the expression level of the gene belonging to the non-TRU-type or TRU-type adenocarcinoma, respectively. Sometimes, the adenocarcinoma is determined as TRU-type adenocarcinoma or non-TRU-type adenocarcinoma, respectively.

 [0037] Furthermore, the difference in the expression level of the gene belonging to the TRU-a type or TRU-b adenocarcinoma is different from the difference in the expression level of the gene belonging to the TRU-b type or TRU-a adenocarcinoma, respectively. When relatively large, the adenocarcinoma is determined as TRU-a type adenocarcinoma or non-TRU type-b adenocarcinoma, respectively.

 [0038] In one embodiment thereof, the UniGene registration number:

Hs.512690, Hs.153322, Hs.218366, Hs.220629, Hs.436996, Hs.435759, Hs.10455 5, Hs.247824, Hs.127821, Hs.480281, Hs.529117, Hs.545862, Hs .391561, Hs.479 372, Hs.533055, Hs.550526, Hs.322854, Hs.465720, Hs.356664, Hs.26630, Hs.53 4496, Hs.85962, Hs.211267, Hs.128041, Hs .534458, Hs.495774, Hs.437806, Hs.l 33062, Hs.501758, Hs.444535, Hs.495480, Hs.326561, Hs.483906, Hs.169943, Hs.271285, Hs.158339, Hs. 62604, Hs.469359, Hs.436657, Hs.8417, Hs.155538, Hs. 533526, Hs.512756, Hs.87191, Hs.463079, Hs.513779, Hs.476209, Hs.279580, Hs.351544, Hs.269408, Hs.134807, Hs.482417, Hs.176626, Hs.465643, Hs.183390, Hs.411299, Hs.234027, Hs.109358, Hs.103983, Hs.26216, Hs.534352, Hs. 240457, Hs.516036, Hs.144875, Hs.411312, Hs.l03989, Hs.537722, Hs.333130, Hs.5179 68'SH 8inS " ^S H 9Z608" ^S H, SS; S ' ^S H S89W ^S H, OHS'SH, S8IS0I' ^S H, 8U 6 FSH, 6066IS'sH S 86TS "SH, rain S ' ^S H, 8SSW ) S ' ^S H SSWS'sH 29Z69S " ^S H" IZL UV e ^ T08 ^ " ^s H 06S922" ^S H USS'sH lfLL6V ^s H, 0 86' ^S H S8S0r ^s H, 6 S86TS "SH T2S92r ^s H, 9I 8I ' ^S H, S IS'sH, 090 9I' ^S H ^ Z8 ' ^S H, S898 I' ^S H

0S8SS'sH T9Z00S "SH Z9STS2" ^S H T2S69 " ^S H 9SIW ^S H 96 S2S" SH 022S2S "SH

Z9Z8 ^ F ^S H 92 STS "SH, SS6I ' ^S H, 19 S'sH, S96 ^S H, I 989S' ^S H, SS 69S ' ^S H SL £ L £' ^s H TZZ69" ^S H 6TS682 " ^S H , 90I80I ' ^S H SS96r ^s H 0 82SS "SH 6628TS" s H, 60WS' ^S H 60S86 " ^S H WH„ ' ^S H Z9Z60S " ^S H 0S069 ^" ^S H 862 ^ " ^S H T9Z00S" SH

^{, 980SS 'S H, I0S9'} S H 0LZ6LV S H, 6SSI9 'S H S8TSSS "SH, W) 800S' S H, I99S9 'S H

S8S6

^{, I68 SS'sH O½OTS "s H,} S9 ½TS" SH T296 ^ "S H 3 ^ ΐ8Γ δ Η, 9 690 'S H 6TS02S" SH, 9S rain ^S' S H U96 2 "SH

6T2TSrsH 20r ^s H 00Z9 ^ " ^S H, 80 9 ' ^S H TS9SF ^S H SSSSI'sH 69S82S" SH S 9S6S2 "SH Z8S TSH S020S" ^S H 9S96 S "SH 22208S" ^S H

90S28S " ^S H, I9 S ' ^S

^{26020S "SH, 68S 'S H} ST82" S H, 88S9W S H

, S m ' ^s H, I9SS' ^S H US68S " ^S H H80S ' ^S H Z606ZS" SH ZL £ V ^S H SSSSS'SH

T9986 " ^S H S8S69S" ^S H

^{, 160 'S H T9S92r s H} , IISSI' S H ½S½r s H

^{, I90S I'SH 6Z L9V S H,} 96I6 S H ST 8SF S H, 8S96 'S H 99262S "S H 8ZZSSS • SH 9S6Z9S" S H 9T08S ^ "S H, 0S6SS S H"SI'sH Z802ir s H, IZSISS ' ^S H 8Z2Z LfSH 690STS "SH S6½2r ^S H S68S" SH 6TS682 " ^S H 0289SS" SH 068S

^{Z £ 'S H, 69 6} I' S H, 0SS0S 'SH, I6S6S' sH, 9IISSI 'S H Z999S ^ "S H 2T902S" SH, 8 9W) 9f s H 060 S "SH

9S9S FSH SZ6T8r ^s H

£ ZLL6V ^S H 68T SrsH 2ZZ82 " ^S HL ££ V SH 662SSrsH 6S8nS" SH SS0222 " ^S H £ LLZL £ ' ^S

9692S2 " ^S H 060ZZ S ' ^S H 22 8ir ^s H S60 2S" SH 026 ^ " ^S H 26 2TF ^S H SSS89S" ^S H Z9S06S " ^S H, 9SS SrsH TS29 F ^S H

, 9ZS ^S H 9S8

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91 ·

.686TC / 900Zdf / X3d 8 o / OOZ OAV 497, Hs.444118, Hs.541635, Hs.477898, Hs.511776, Hs.434886, Hs.117299, Hs.2 52451, Hs.468058, Hs.21554, Hs.165904, Hs.445244, Hs.413924 , Hs.99120, Hs.5 21171, Hs.462379, Hs.481860, Hs.489207, Hs.414407, Hs.505575, Hs.516826, Hs .62180, Hs.368934, Hs.530509, Hs.278906, Hs. 511987, Hs. 444082, Hs. 471873, H s. 24583,

 Hs.l051, Hs.115263, Hs.379010, Hs.2012, Hs.268698, Hs.49653, Hs.424542, Hs.525589, Hs.25333, Hs.513075, Hs.549577, Hs.l00431, Hs. 9613, Hs.301478, Hs.5 53740, Hs.525383, Hs.473721, Hs.375624, Hs.l l6724, Hs.9613, Hs.418055, Hs.334873, Hs.180878, Hs.126521, Hs. 519033, Hs.l87636, Hs.518448, Hs.32276 1, Hs.31409, Hs.524513, Hs.436437, Hs.148989, Hs.279575, Hs.75668, Hs.47079 1, Hs.104476, Hs. 494496, Hs.517549, Hs.278906, Hs.498586, Hs.183617, Hs.499 758, Hs.350065, Hs.511138, Hs.150793, Hs.l29174, Hs.212606, Hs.275775, Hs.4 96414, Hs.436142, Hs.282984, Hs.32417, Hs.69321, Hs.414629, Hs.502618, Hs.4 05755, Hs.480143, Hs.60371, Hs.283683, Hs.208093, Hs.336768 , Hs.1116459, Hs.131673, Hs.32417, Hs.75812

 Each of the genes having the sequence includes a sequence shown in SEQ ID NOs: 1 to 351 or a complementary sequence thereof.

 [0039] In another embodiment, the gene expression level can be determined by a hybridization method.

[0040] The hybridization method can be exemplified by the same method as described above, for example, a microarray method, or a plotting method such as Northern blot or Southern blot. For this purpose, a microarray can be preferably used.

[0041] In the third aspect, the present invention provides the following UniGene registration number:

Hs.512690, Hs.153322, Hs.218366, Hs.220629, Hs.436996, Hs.435759, Hs.10455 5, Hs.247824, Hs.127821, Hs.480281, Hs.529117, Hs.545862, Hs .391561, Hs.479 372, Hs.533055, Hs.550526, Hs.322854, Hs.465720, Hs.356664, Hs.26630, Hs.53 4496, Hs.85962, Hs.211267, Hs.128041, Hs .534458, Hs.495774, Hs.437806, Hs.l 33062, Hs.501758, Hs.444535, Hs.495480, Hs.326561, Hs.483906, Hs.169943, Hs Z9Z8 ^ F ^S H 92 STS "SH, SS6I ' ^S H, 19 S'sH, S96 ^S H, I 989S' ^S H, SS 69S ' ^S H SL £ L £' ^s H TZZ69" ^S H 6TS682 " ^S H , 90I80I ' ^S H SS96r ^s H 0 82SS "SH 6628TS" s H, 60WS' ^S H 60S86 " ^S H WH„ ' ^S H Z9Z60S " ^S H 0S069 ^" ^S H 862 ^ " ^S H T9Z00S" SH, 980SS' ^S H, I0S9 ' ^S H 0LZ6LV ^S H, 6SSI9' ^S H S8TSSS "SH, W) 800S ' ^S H, I99S9' ^S H

S8S6

, I68 SS'sH O½OTS " ^s H, S9 ½TS" SH T296 ^ " ^S H 3 ^ ΐ8Γ ^δ Η, 9 690 ' ^S H 6TS02S" SH, 9S rain S' ^S H U96 2 "SH 6T2TSrsH 20r ^s H 00Z9 ^ " ^S H, 80 9 ' ^S H TS9SF ^S H SSSSI'sH 69S82S" SH S 9S6S2 "SH Z8S TSH S020S" ^S H 9S96 S "SH 22208S" ^S H

90S28S " ^S H, I9 S ' ^s

^{26020S "SH, 68S 'S H} ST82" S H, 88S9W S H, S m' s H, I9SS 'S H US68S "S H H80S' S H Z606ZS" SH ZL £ V S H SSSSS'SH

^{T9986 "S H S8S69S" S H} , 160 'S H T9S92r s H, IISSI' S H ½S½r s H

^{, I90S I'SH 6Z L9V S H,} 96I6 S H ST 8SF S H, 8S96 'S H 99262S "S H 8ZZSSS • SH 9S6Z9S" S H 9T08S ^ "S H, 0S6SS S H"SI'sH Z802ir s H, ^{IZSISS 'S H 8Z2Z LfSH 690STS "} SH S6½2r S H S68S" SH 6TS682 "S H 0289SS" SH 068S Z £' S H, 69 6 I 'S H, 0SS0S' SH, I6S6S 'sH, 9IISSI' S H Z999S ^ ^{"S H 2T902S" SH, 8} 9W) 9f s H 060 S "SH

9S9S FSH SZ6T8r ^s H

£ ZLL6V ^S H 68T SrsH 2ZZ82 " ^S HL ££ V SH 662SSrsH 6S8nS" SH SS0222 " ^S H £ LLZL £ ' ^S

9692S2 " ^S H 060ZZ S ' ^S H 22 8ir ^s H S60 2S" SH 026 ^ " ^S H 26 2TF ^S H SSS89S" ^S H Z9S06S " ^S H, 9SS SrsH TS29 F ^S H

, 9ZS ^S H 9S8 S'sH I08 T ^S H 2902S "SH, I90 6I ' ^S H 629ΐ2Γ ^δ Η, 0S68' ^S H 0S206" ^S H 29 6 TS "SH, 0SISSS ' ^S H ^ S SS ^ H, 686S0I ' ^S H 2ISnr ^S H, SZ8' ^S H, 9S09IS'SH ZSW) W ^S H

06SS8F ^S HS ^ 9S9 ^ " ^S H, 9S99 I ' ^S HT ^ 8 ^" ^S H 08 ^ F ^S H, 80 69S' ^S H ISS 'SH 08S6 2 "SH, 60S ^S H 6 STS" SH, 6 0S9 ' ^S H T6TZ8 " ^S H 9S 2TS" SH 92SSSS "SH 8SSeersH T ^ 8" ^S H ZS99S ^ " ^S H, 6SS69 H, Lake S9' ^S H 6SS8SrsH S82T 2"

81 · 686TC / 900Zdf / X3d 8 o / OOZ OAV Hs.523220, Hs.525796, Hs.271264, Hs.69321, Hs.231367, Hs.500761, Hs.528304, Hs.l48685, Hs.87417, Hs.164060, Hs.514843, Hs.418416, Hs. 126521, Hs.51983 9, Hs.103834, Hs.279840, Hs.497741, Hs.531457, Hs.226390, Hs.480143, Hs.473 721, Hs.369762, Hs.514527, Hs.204238, Hs. 3104, Hs.519873, Hs.519909, Hs.179 718, Hs.l03183, Hs.520210, Hs.444683, Hs.234545, Hs.80976, Hs.311187, Hs.89 497, Hs.444118, Hs. 541635, Hs.477898, Hs.511776, Hs.434886, Hs.117299, Hs.2 52451, Hs.468058, Hs.21554, Hs.165904, Hs.445244, Hs.413924, Hs.99120, Hs.5 21171, Hs.462379, Hs.481860, Hs.489207, Hs.414407, Hs.505575, Hs.516826, Hs .62180, Hs.368934, Hs.530509, Hs.278906, Hs.511987, Hs.444082, Hs.471873, H s.24583,

 Hs.l051, Hs.115263, Hs.379010, Hs.2012, Hs.268698, Hs.49653, Hs.424542, Hs.525589, Hs.25333, Hs.513075, Hs.549577, Hs.l00431, Hs. 9613, Hs.301478, Hs.5 53740, Hs.525383, Hs.473721, Hs.375624, Hs.l l6724, Hs.9613, Hs.418055, Hs.334873, Hs.180878, Hs.126521, Hs. 519033, Hs.l87636, Hs.518448, Hs.32276 1, Hs.31409, Hs.524513, Hs.436437, Hs.148989, Hs.279575, Hs.75668, Hs.47079 1, Hs.104476, Hs. 494496, Hs.517549, Hs.278906, Hs.498586, Hs.183617, Hs.499 758, Hs.350065, Hs.511138, Hs.150793, Hs.l29174, Hs.212606, Hs.275775, Hs.4 96414, Hs.436142, Hs.282984, Hs.32417, Hs.69321, Hs.414629, Hs.502618, Hs.4 05755, Hs.480143, Hs.60371, Hs.283683, Hs.208093, Hs.336768 , Hs.1116459, Hs.131673, Hs.32417, Hs.75812

A nucleic acid capable of detecting the expression of a gene having the above, or a variant, homologue or derivative thereof,

 (1) a nucleotide sequence represented by SEQ ID NOs: 1-351,

 (2) a nucleotide sequence comprising the nucleotide sequence shown in SEQ ID NOs: 1-351,

(3) a nucleotide sequence complementary to the nucleotide sequence of (1) or (2),

 (4) The nucleotide sequence that is hybridized under stringent conditions with any one of the sequences (1), (2), or (3), and

(5) The portion of the nucleotide sequence of (1), (3) or (4) above from 15 bases to less than the total number of bases Array,

 An operation for a patient with lung adenocarcinoma comprising a nucleic acid having a sequence selected from the group consisting of: an antibody against a protein or fragment encoded by the gene, or a variant, homologue or derivative thereof, or a fragment thereof. Threads and adults for predicting prognosis in vitro or for classifying lung adenocarcinoma as either TRU, non-TRU, TRU-a or TRU-b subtypes

 I will provide a.

 [0042] The composition of the present invention can be used for in vitro prediction of postoperative prognosis in patients with lung adenocarcinoma as described above, and as described above, to classify lung adenocarcinoma into four types .

 [0043] In the present specification, the stringent condition means a condition in which nucleotide sequences having at least 80%, preferably at least 95% identity, hybridize to each other, such as a microarray. The analysis, hybridization and washing conditions were 60 in 1M sodium chloride ZO. 5% (WZV) sarkosyl Z30% formamide. C, 17 hours of noise hybridization, then 6 X SSCZ 0.005% (WZV) in Triton X-102 solution at room temperature, once for 10 minutes, then 0.1 X SSC / 0.005% (W / V) Triton X-102 solution should be washed at a temperature of 0-4 ° C once for 5 minutes. Here, 1 X SSC is 150 mM sodium chloride and 15 mM sodium citrate aqueous solution (PH7.2). Hybridization is described in Ausbel FM et al., Short Protocols in Molecular Biology (3rd edition) A Compendium of Methods from Current Protocols in Molecular Biology, 1995, John Wiley & Sons, Inc. (USA). Has been.

 [0044] In another embodiment, the composition of the present invention is in the form of a kit or a DNA microarray (also called a DNA chip) or a protein array.

From the present invention, lung adenocarcinoma is classified into its subtypes (TRU, non-TRU type, TRU-a and TRU-b), the relationship between each subtype and the postoperative prognosis, and the TRU type. The relationship between EGFR gene mutation and postoperative prognosis in lung adenocarcinoma in Japan was revealed. By using the method of the present invention, it is possible to select a patient who has a high possibility of recurrence after surgery and to make a treatment plan for improving the survival rate, or to be clinically used as a molecular target drug for lung cancer. Gehuichi- It is possible to select patients with particularly poor prognosis from patients with EGFR mutations that are known to be involved in the reactivity of Iressa (trade name) and select them as subjects for postoperative treatment with EGFR inhibitors. Become.

Brief Description of Drawings

[Figure 1] Shows unsupervised classification systematic clustering and analysis results of four major gene changes in 149 NSCLC cases. The boxes in the histology row (“Hist”) are squamous cell carcinoma (blue; SQ), large cell carcinoma (red, LA), adenocarcinoma (orange, AD), squamous adenocarcinoma (grey), and large Represents cell endocrine cancer (yellow). Black boxes indicate the presence of EGFR, p53 and Kms mutations in their individual rows. The expression index of the transcript sequence (row) in the sample (column) is indicated by the color code (see expression index in the bottom bar in the figure).

 [Figure 2] Unsupervised classification systematic clustering (TRU, non-TRU, TRU-a, TRU-b) and analysis results of four major gene changes in 90 lung adenocarcinoma cases . Figure 2A shows the results of classification systematic clustering and search for mutations. The expression index is the same as in Figure 1. FIG. 2B is a graph showing the frequency of EGFR, p53 and K ras mutations (Frequencies of mutations) (%). Black boxes indicate the presence of EGFR, p53 and K ras mutations in their individual rows. Prominent invasive growth is indicated by a black box, localized invasive growth is indicated by a gray box, and negative or negligible invasive growth is indicated by a white box.

 [Figure 3] Profiling identified using non-TRU, TRU-a or TRU-b, and Stanford data sets (Garber ME et al., Proc Natl Acad Sci USA 98: 13784-9, 2001) The results of unsupervised classification systematic clustering based on the expression profiles of the 30 genes ranked higher in terms of differential expression in the lung adenocarcinoma subset identified in. The expression index is the same as in Figure 1. This figure shows that adenocarcinoma cases are systematically classified into TRU and non-TRU types, and cases identified as TRU types are further classified as TRU-a or TRU-b. .

FIG. 4 shows a Kaplan-Meier survival curve for lung adenocarcinoma subtypes identified by expression profile. The horizontal axis shows the number of months after surgery (Months after surgery), and the vertical axis shows the survival rate (Survaival). Also The number of risk patients classified into non-TRU type, TRU-a type, and TRU-b type in each postoperative observation month is also shown. From the figure, TRU-b adenocarcinoma had a significantly better prognosis than non-TRU type, but the prognosis of TRU-a type was similar to that of non-TRU type.

 FIG. 5 shows Kaplan-Meier survival curves for the presence or absence of EGFR mutations in all cases of lung adenocarcinoma and TRU-type lung adenocarcinoma. FIG. 5A shows postoperative survival curves for adenocarcinoma cases with or without EGFR gene mutation. FIG. 5B shows a postoperative survival curve for the presence or absence of EG FR gene mutation in TRU adenocarcinoma. The horizontal axis shows the number of months after surgery (Months after surgery), and the vertical axis shows the survival rate (Survaival). The number of risk patients with wild-type or mutant EGFR (wt-EGFR and mut-EGFR, respectively) in each postoperative observation month is also shown.

 [Figure 6] Shows the formula for calculating the weight (S).

 [Fig.7] Shows the weighted-voting formula and its meaning.

 [Fig.8] Shows discrimination model by weighted-voting.

 Detailed Description of the Invention

 [0047] Of the cases diagnosed as non-small cell lung cancer (NSCLC) at the Aichi Cancer Center (Nagoya), 90 were adenocarcinoma, 35 squamous cell carcinoma, 18 large cell carcinoma, 4 We prepared 149 cases of tumor specimens including 2 cases of squamous adenocarcinoma and 2 cases of large cell neuroendocrine cancer, and then prepared a double-stranded cDNA and then a cRNA and combined a microarray containing 18,175 unique genes. Were used to obtain an exhaustive and systematic expression profile. Sarakuko, clustering genes and cases using the CLUSTER program and displaying the results with TREEVIEW (Eisen MB et al., Proc Natl Acad Sci USA 95: 14863-8, 1998). (SAM) was used to score genes specific to each of the patient subtypes (Tusher VG et al., Proc Natl Acad Sci USA 98: 5116-21, 2001).

 [0048] Analyzes using gene ontology (GO) (Ashburner M et al., Nat Genet 2 5: 25-9, 2000) revealed functionally distinct organisms of gene sets specific to each patient subtype. Clarified the anatomical features.

[0049] In addition, various clinical parameters and the expression of the subtypes defined by the expression profile To investigate the relationship, multivariate logistic regression analysis was performed, and postoperative survival was assessed using the Kaplan-Meier method.

 [0050] As a result, it was found that lung adenocarcinoma cases could be classified into two main sub-clusters, which were referred to as TRU type and non-TRU type. Taxonomic clustering performed with 4,138 transcripts most variably expressed in adenocarcinoma, resulting in two major stagnation figures (TRU and non-TRU) and right stagnation The existence of two additional subclusters (TRU-a type and TRU-b type) became clear in the figure (Fig. 2A).

 [0051] To gain further insight into the phenotypes and biological properties of lung adenocarcinoma subtypes defined by these two major expression profiles, namely non-TRU and TRU types, SAM analysis was performed and 1,657 differentially expressed genes were extracted in prefiltering at a significance level of less than 0.1% false positive rate. Of these genes, 286 genes showed a difference in expression level at a magnification of 2 times or more between TRU and non-TRU types. The 286 genes found this time also had 194 genes with higher expression in the TRU type and 92 genes with higher expression in the non-TRU type. As a result of investigating basic functional differences between TRU and non-TRU types, TRU type showed a clear relationship with normal lung function, whereas non-TRU type showed cell cycle and proliferation. It was found to show the relationship.

 [0052] Furthermore, as a result of investigating the prognosis after surgery, TRU-a showed poor prognosis similar to that of non-TRU, whereas TRU-b had a non-TRU prognosis. It was found to be significantly better than that (Figure 4). SAM analysis was performed using the same criteria (false positive rate of less than 0.1%), and 169 genes showing differences in expression levels between TRU a type and TRU-b type at a factor of 2 or more were extracted. did. These 169 genes are higher in TRU-a type! It consisted of 119 genes with sputum expression and 50 genes with higher sputum expression in TRU-b type! /.

[0053] Tables 1 to 4 show gene sets belonging to adenocarcinoma subtypes of TRU type, non-TRU type, TRU_a, and TRU_b, respectively. In the table, Uni-Gen symbol and UnilD are the registration number of the symbol and sequence of the gene registered in the Uni Gene data bank, respectively, and GBI D represents the registration number of the sequence of the gene registered in GenBank. At the same time, heredity The child name (or protein name or feature) is also displayed.

[table 1]

.686lC / 900Zdf / X3d

[] 0057

οε

3d 8 ο / Ζ · ΟΟΖ OAV

.686TC / 900Zdf / X3d 8 o / OOZ OAV 222 A 23 P74290 NM 052942 Hs.51 3726 GBP5 Guanylate Dinding protein 5

 223 A 23 P5464 NM 005444 Hs.148767 RQCD1 RCD1 required for cell differentiation 1 homolog

224 A 23 P741 1 5 NM 003579 Hs.523220 RAD54L RAD54-like

 225 A_23_P 140705 NM— 033286 Hs.525796 C1 5orf23 Chromosome 1 5 open reading frame 23

226 A 23 P1451 14 NM 001498 Hs.271264 GCLC Gluta mate— cysteine ligase, catalytic subunit

227 A 23 P92222 NM 1 52673 Hs.69321 MUC20 Mucin 20

 228 A 23 P127288 NM 00041 7 Hs.231 367 IL2RA Interleukin 2 receptor, alpha

 229 A 23 P158725 NM 004207 Hs.500761 SLC16A3 Solute carrier family 1 6, member 3

 230 A_23_P 1 70362 NM 014 265 Hs.528 304 ADAM28 A disintegrin and metalloproteinase domain 28

231 NM 01 6235 2777 NM 01 6235 Hs.148685 GPRC5B G protein-coupled receptor, family C

 232 A 23 P146456 NM 001333 Hs.8741 7 CTSL2 Cathepsin L2

 233 A 23 P122863 NM 001001 555 Hs.164060 GRB10 Growth factor receptor-bound protein 10

234 AK02381 7 4258 NM 020964 Hs.514843 KIAA1 632 KIAA1632 protein

 235 A 23 P 108871 NM 032494 Hs.41 8416 ZC3H8 Zinc finger CCCH type domain containing 8

236 A 23 P 102801 NM 0021 10 Hs.1 26521 HCK Hemopoietic cell kinase

 237 A 23 P160427 024 024709 Hs.51 9839 C1 orf1 1 5 Hypothetical protein FLJ 14146

 238 A 23 P481 75 NM 024056 Hs.103834 MGC5576 Hypothetical protein MGC5576

 239 A 23 P21 8516 NM 01 3360 Hs.279840 ZNF222 Zinc finger protein 222

 240 A 23 P401 NM 01 6343 Hs.497741 CENPF Centromere protein F, 350 / 400ka (mitosin)

241 A_23_P43444 AK094914 Hs.531457 IMAGE: 531 1 1 29 cDNA DKFZp667B1 718

 242 A 23 P1 36222 NM— 001 034 Hs.226390 RR 2 Ribonucleotide reductase M2 polypeptide

243 A 23 P1 39682 002864 Hs.480143 PZP Pregnancy-zone protein

 244 A 23 P571 NM— 006516 Hs.473721 SLC2A1 Solute carrier family 2, member 1

 245 A 23 P50096 NM— 001071 Hs.369762 TYMS Thymidylate synthetase

 246 A 23 P1 1 881 5 NM 001 1 68 Hs.514527 B1RC5 Baculoviral IAP repeat-containing 5

 247 A 23 P1 69437 NM— 005564 Hs.204238 LCN2 Lipocalin 2 (oncogene 24p3)

 248 AW183154 r 1 74 NM— 014875 Hs.3104 KIF14 Kinesin family member 14

249 A 23 P31031 NM 00441 5 Hs.519873 DSP Desmoplakin

tu0061

006

o

SEQ ID NO: Probe name GBiD UnilD Uni-Gene symbol Gene name

 308 A_23_P 162668 NM.001874 Hs.334873 CPM Carb oxyp e pti da se M

 309 A 23 P146233 N 000237 Hs. 180878 LPL Lipoprotein lipase

 310 A 23 P102801 NM 0021 10 Hs.126521 HCK Hemopoietic cell kinase

 31 1 A_23_P92499 N .003264 Hs.519033 TLR2 To] Hike receptor 2

 31 2 A 23 P 128447 AY792511 Hs.187636 LRR 2 and eu cine-rich repeat kinase 2

 31 3 A 23 P29773 NM.014398 Hs.518448 LAMP3 Lysosomal-associated membrane protein 3

 314 A 23 P84475 BC03021 1 Hs.322761 NO DATA clone IMAGE: 5199989

 31 5 A_23_P1 16173 AL831866 Hs.31409 LOC120376 Hypothetical protein LOC 120376

 31 6 A 23 P25030 N J03725 Hs.524513 HSD17B6 3 ~ hy droxysteroi d epim erase

 168 A 23 P46785 NM 003019 Hs.253495 SFTPD Surfactant, pulmonary-associated protein D

 31 7 A 23 P36745 NM 000690 Hs.436437 ALDH2 Aldehyde dehydrogenase 2 family

 318 A 23 P163306 NM 032866 Hs.148989 CGNL1 junction-associated coiled-coil protein

 319 A 23 P69171 NM 033050 Hs.279575 SUCNR1 Succinate receptor 1

 320 A 23 P43817 NM 032793 Hs.75668 MFSD2 Hypothetical protein FLJ 14490

 321 AK096822 2646 NM 152520 Hs.470791 ZNF533 Zinc finger protein 533

 322 A 23 P115022 NM 144626 Hs.104476 MGC17299 Hypothetical protein GC17299

 323 A 23 P2571 1 1 NM 000507 Hs.494496 FBP1 Fructose-1, 6-bisphosphatase 1

 324 A 23 P91669 NM 014422 Hs.517549 P1B5PA Phosphatidylinositol (4,5) bisphosphate 5-phosphatase

325 A 23 P252572 NM 001001888 Hs.278906 vcx-c Variably charged X-C

 326 A 23 P104252 NM 030569 Hs.498586 IT! H5 Inter-alpha (globulin) inhibitor H5

 327 A— 23— P134854 NM 194284 Hs.183617 CLDN23 Claudin 23

 328 A 23 P26854 NM 014859 Hs.499758 K1AA0672 KIAA0672 gene product

 329 NM_153014.2705 AK125154 Hs.350065 PLXNA2 Plexin A2

 330 A 23 P88710 NM 015497 Hs.511138 DKFZP564G2022 DKFZP564G2022 protein

 331 A 23 P14595 NM.001275 Hs.150793 CHGA Chromogranin A

 332 A 23 P143068 NM 024726 Hs.129174 IQCA IQ motif containing with AAA domain

 333 A 23 P36416 NM 013267 Hs.212606 GLS2 Glutaminase 2

334 A 23 P121926 NM 005410 Hs.275775 SEPP1 Selenoprotein P

Therefore, according to one aspect of the present invention, the lung adenocarcinoma is identified and classified as TRU type or non-TRU type, and then the TRU type adenocarcinoma is identified and classified as TRU-a type or TRU-b type. Provide law.

 [0068] This method involves the use of one or more genes in each of the above gene sets in a biological sample of a patient between a TRU-type adenocarcinoma and a non-TRU-type adenocarcinoma, or a TRU-a type gland. When the relative expression level difference between cancer and TRU-b type adenocarcinoma is measured and the gene showing the difference in expression level is one of the genes listed in Table 1, If the cancer is determined to be TRU type and is one of the genes listed in Table 2, it is determined that the lung adenocarcinoma is non-TRU type. Furthermore, if the adenocarcinoma determined as TRU type is one of the genes listed in Table 3, the lung adenocarcinoma was determined to be TRU-a type and listed in Table 4. If it is any of the gene group, it includes determining that the lung adenocarcinoma is TRU-b type.

 [0069] More specifically, the difference in the expression level of the gene belonging to the TRU type or non-TRU type adenocarcinoma as compared with the difference in the expression level of the gene belonging to the non-TRU type or TRU type adenocarcinoma, respectively. When relatively large, the adenocarcinoma is determined as TRU-type adenocarcinoma or non-TRU-type adenocarcinoma, respectively.

 [0070] Furthermore, the difference in the expression level of the gene belonging to the TRU-a type or TRU-b adenocarcinoma is different from the difference in the expression level of the gene belonging to the TRU-b type or TRU-a adenocarcinoma, respectively. When relatively large, the adenocarcinoma is determined as TRU-a type adenocarcinoma or non-TRU type-b adenocarcinoma, respectively.

 [0071] For example, for genes A, B, and C belonging to TRU-type adenocarcinoma and genes X, Υ, and Z belonging to non-TRU-type adenocarcinoma, the expression levels of gene A in adenocarcinoma sample 1 and sample 2 are 130 respectively. 80 (arbitrary unit), the expression level of gene B in adenocarcinoma sample 1 and sample 2 is 25 and 20 (arbitrary unit), respectively, and gene C in adenocarcinoma sample 1 and sample 2 Expression levels of 1050 and 950 (arbitrary units), respectively, and gene X expression levels in adenocarcinoma sample 1 and sample 2 are 600 and 650 (arbitrary units), respectively, and adenocarcinoma sample 1 and sample When the expression level of gene Y in sample 2 is 350 and 450 (arbitrary units), respectively, and the expression level of gene Z in sample 1 and sample 2 is 25 and 50 (arbitrary units), respectively, Identify 1 as a TRU adenocarcinoma and Sample 2 as a non-TRU adenocarcinoma.

[0072] The present invention further provides a TRU type, non-TRU type, TRU-a type or TRU-b type of lung adenocarcinoma according to another embodiment in Tables 1 to 4 above in a biological sample of a patient. The corresponding gene set listed In the same manner as in the above classification method, one or more genes of a gene, or mutants, homologues or derivatives thereof, between TRU type adenocarcinoma and non-TRU type adenocarcinoma, or TRU-a type adenocarcinoma Provide a method for predicting the postoperative prognosis of a patient, including identifying by measuring the difference in relative expression levels between TRU-b type adenocarcinoma.

 [0073] According to this method, lung adenocarcinoma is first identified as TRU-type or non-TRU-type, and then TRU-type adenocarcinoma is further determined as TRU-type or TRU- If the lung adenocarcinoma subtype is TRU-b type, the postoperative prognosis is good, or if it is TRU-a type or non-TRU type, the postoperative prognosis is poor. It is determined that it is.

 [0074] Furthermore, the present inventors found that the presence of EGFR mutations was significantly higher in TRU-type adenocarcinoma than in non-TRU-type adenocarcinoma (45.3% vs. 21.6%), and EGFR An interesting finding was obtained that the postoperative prognosis of patients with TRU-type adenocarcinoma containing mutations was poorer than that of patients with TRU adenocarcinoma containing wild-type non-mutated EGFR. Lung cancers with EGFR gene mutations, especially NSCLC, are known to be highly sensitive to gefitib (EGFR tyrosine kinase inhibitor), so the selection of patients for such molecular targeted drug therapy Therefore, the above knowledge can be used.

 [0075] That is, the present invention relates to the above-mentioned prognosis prediction method, particularly when the EGFR gene contains a mutation in TRU-type lung adenocarcinoma, and the postoperative prognosis of the patient is poor compared to lung adenocarcinoma containing the wild-type EGFR gene Further predicting that Such prediction in TRU-type lung adenocarcinoma can be combined with prediction based on the relationship between the above-mentioned subtypes and prognosis to enable diagnosis or determination with higher accuracy and higher clinical application value.

 [0076] Also, in all adenocarcinomas, there are five genes having EGFR mutation and at least twice up-regulation in adenocarcinoma, Eleven genes that show up-regulation of 2 times were identified, and the genes that were differentially and differentially expressed in TRU adenocarcinoma with high-frequency EGFR mutation were searched, and EGFR mutation In the presence of GAMPLA4 gene having an upregulation of 2 times or more, and RAMP1, APOH, PEX3, EST and DHRS7 genes showing 1.5 to 2 times upregulation were identified.

[0077] Furthermore, non-TRU adenocarcinoma cases have the highest percentage of p53 and / or K — Includes tumors with ras mutations (41% for p53; 16% for K-ras), followed by TRU-a (29% and 12%, respectively), TRU-b (21% and 0%, respectively) It was in order. This indicates that non-TRU adenocarcinoma contains relatively high p53 and / or K ras mutations compared to other subtypes, particularly TRU-a and TRU-b adenocarcinoma. ing.

 [0078] These findings are also considered to be useful for prognosis determination when used in combination with determination of postoperative prognosis of lung adenocarcinoma patients as well.

[0079] In the method of the present invention, first, a nucleic acid for measuring the expression of a gene included in each gene set listed in Tables 1 to 4, or a mutant, homologue or derivative thereof is prepared.

 [0080] Such nucleic acids have the following UniGene accession numbers:

 Hs.512690, Hs.153322, Hs.218366, Hs.220629, Hs.436996, Hs.435759, Hs.10455 5, Hs.247824, Hs.127821, Hs.480281, Hs.529117, Hs.545862, Hs .391561, Hs.479 372, Hs.533055, Hs.550526, Hs.322854, Hs.465720, Hs.356664, Hs.26630, Hs.53 4496, Hs.85962, Hs.211267, Hs.128041, Hs .534458, Hs.495774, Hs.437806, Hs.l 33062, Hs.501758, Hs.444535, Hs.495480, Hs.326561, Hs.483906, Hs.169943, Hs.271285, Hs.158339, Hs. 62604, Hs.469359, Hs.436657, Hs.8417, Hs.155538, Hs. 533526, Hs.512756, Hs.87191, Hs.463079, Hs.513779, Hs.476209, Hs.279580, Hs.351544, Hs.269408, Hs.134807, Hs.482417, Hs.176626, Hs.465643, Hs.183390, Hs.411299, Hs.234027, Hs.109358, Hs.103983, Hs.26216, Hs.534352, Hs. 240457, Hs.516036, Hs.144875, Hs.411312, Hs.l03989, Hs.537722, Hs.333130, Hs.5179 62, Hs.90250, Hs.478930, Hs.121629, Hs.l94061, Hs.520627 , Hs.348012, Hs.522 836, Hs.l376, Hs.520049, Hs.51285 6, Hs.355236, Hs.349470, Hs.476231, Hs.137 556, Hs.390567, Hs.368353, Hs.412792, Hs.449207, Hs.527095, Hs.118722, Hs.3 77090, Hs. 232696, Hs.447544, Hs.372773, Hs.222055, Hs.511839, Hs.153299, Hs.434374, Hs.287729, Hs.553740, Hs.l27189, Hs.497723,

Hs.l81973, Hs.173656, Hs.451956, Hs.184507, Hs.532492, Hs.370904, Hs.46046 8, Hs.520612, Hs.436667, Hs.l25116, Hs.459391, Hs.450320, Hs .149769, Hs.32 S "SH 8 ^ T0S" ^S H ST96 " ^S H, ISW) Or ^s H ZS6 ' ^S HS OSTS" SH, SSSSS' ^S H 68SS2S • ^S H ^ Z ^ ZV SS96 ^ " ^S H, 86989S ' ^S H 2T02 ^{"S H 0I06ZS 'S H S92Sn} " SH, ISOI' s H

^{H ^ Z LV 280W S H 86nS} "SH, 9068W S H 60S0SS" SH, S689S 'S HH

SH 9289TS "SH S SSOS" SH 0 I ' ^S H 0268 ^ " ^S H 098T8 ^" ^S H ^ LZZW "ILUZ S'sH 02T66" ^S H

, W) 6S9r ^s H, SSIS ' ^S H, 8S089' ^S H l Z Z ' ^S H 662 n "SH, 988' ^S H 9 US" SH, 868 ^S H, SS9I ' ^S H 8UW ^S H L6 68'SH 8inS " ^S H 9Z608" ^S H, SS; S ' ^S H S89W ^S H, OHS'SH, S8IS0I' ^S H, 8U 6 FSH, 6066IS'sH S 86TS "SH, rain S ' ^S H, 8SSW) S' ^S H SSWS'sH 29Z69S " ^S H" IZL UV e ^ T08 ^ " ^s H 06S922" ^S H USS'sH lfLL6V ^s H, 0 86 ' ^S H S8S0r ^s H, 6 S86TS "SH T2S92r ^s H, 9I 8I' ^S H, S IS'sH, 090 9I ' ^S H ^ Z8' ^S H, S898 I ' ^S H

0S8SS'sH T9Z00S "SH Z9STS2" ^S H T2S69 " ^S H 9SIW ^S H 96 S2S" SH 022S2S "SH

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A nucleic acid capable of detecting the expression of a gene having the above, or a variant, homologue or derivative thereof,

 (1) a nucleotide sequence represented by SEQ ID NOs: 1-351,

 (2) a nucleotide sequence comprising the nucleotide sequence shown in SEQ ID NOs: 1-351,

(3) a nucleotide sequence complementary to the nucleotide sequence of (1) or (2),

 (4) The nucleotide sequence that is hybridized under stringent conditions with any one of the sequences (1), (2), or (3), and

 (5) a partial sequence of less than the total number of bases from 15 bases of the nucleotide sequence of (1), (3) or (4),

Force group power One or more nucleic acids having a selected sequence.

For example, if the nucleic acid is a DNA molecule of about 100 bases or less, it can be synthesized using an automatic DNA synthesizer (for example, Applied Biosystems, USA) using the phosphoramidite method. Alternatively, the nucleic acid can be prepared by cDNA cloning. After obtaining total RNA from the tumor lung tissue and obtaining poly A (+) RNA by oligo dT cellulose column treatment, the cDNA library was prepared by reverse transcriptase-polymerase chain reaction (RT-PCR) method. Hybridization with a probe (15 or more, preferably 30 or more, more preferably 50 to 100 or more base length) prepared in advance from this library based on the sequence registered in the gene bank A cDNA clone can be obtained. The obtained clone is inserted into an appropriate expression vector such as Escherichia coli or Bacillus subtilis after being inserted into a commercially available expression vector, and the host cell is propagated. Alternatively, based on the sequence registered in the gene bank, a primer prepared in advance (usually 15 to 30 bases, preferably 17 to 25 bases long) is used, and the cDNA clone is used as a template. Amplification can be achieved by polymerase chain reaction (PCR). For specific procedures and reagents for cDNA cloning and PCR, commercially available kits, devices, and reagents can be used. For example, Sambrook J et al., Molecular Cloning A Laboratory Manual, 1989, Cold Spring Haroor Laboratory Press (USA); Ausbel FM et al., Short Protocols in Molecular Biology (3rd edition) AC ompendium of Methods from Current Protocols in Molecular Biology, 1995, John Wiley & Sons, Inc. (USA) Yes.

[0082] The nucleic acid comprising the nucleotide sequence that hybridizes under stringent conditions to the nucleic acid of (4) above is a nucleic acid comprising a sequence shown in SEQ ID NOs: 1 to 351 or a complementary sequence thereof. Any nucleic acid that hybridizes with the nucleic acid. Such nucleic acid is DNA or RNA.

 [0083] Stringent conditions include those defined and exemplified above. That is, examples of such conditions are: 1M sodium chloride Z0.5% (WZV) sarkosyl Ζ30% formamide, 60 ° C, 17 hours hybridization, then 6 X SSCZ 0.005% ( (WZV) Triton X-102 solution, once at room temperature for 10 minutes, and further in 0.1 X SSC / 0.005% (W / V) Triton X-102 solution while maintaining at 0-4 ° C Washing is performed once every 5 minutes. Here, 1 X SSC is 150 mM sodium chloride and 15 mM sodium citrate aqueous solution (pH 7.2).

 [0084] Hybridization includes microarray methods, blotting methods such as Northern or Southern blots, Northern or Southern hybridization methods, in situ hybridization methods, quantitative RT-PCR methods, and the like.

[0085] In the nucleic acid (5), the nucleic acid fragment having the nucleotide sequence (1), (3) or (4) has a size of 15 bases to less than the total number of bases. Fragments can have any number of bases within this range, for example, 20 bases or more, 30 bases or more, 50 bases or more, 70 bases or more, 100 bases or more, 150 bases or more, 200 bases or more, 300 bases or more, 400 bases or more, 500 bases The number of bases. [0086] According to the present invention, for one or more genes of each gene set in the above table in a biological sample of a patient, between TRU-type adenocarcinoma and non-TRU-type adenocarcinoma, or TRU-a Measure the relative expression level difference between type A adenocarcinoma and TRU-b adenocarcinoma.

 [0087] Here, the difference in relative expression level means that a certain gene set is present between TRU-type adenocarcinoma and non-TRU-type adenocarcinoma or between TRUa-type adenocarcinoma and TRU-b-type adenocarcinoma. When the expression levels of these genes are compared, it means the difference in the expression level that the gene exhibits between the above-mentioned subtypes. In the present invention, the preferable difference in expression level for a specific gene is 1.5 times or more, more preferably 2.0 times or more.

 [0088] By identifying a gene showing a difference in expression level, the relationship between the gene and a subtype of lung adenocarcinoma (ie, TRU, TRU-a, TRU-b, or non-TRU type) can be clarified. it can. Thus, for example, the postoperative prognosis of a patient can be predicted by identifying a subtype of lung adenocarcinoma, or the above relationship between the gene set containing the identified gene and the subtype can be estimated. Based on this, lung adenocarcinoma can be classified into four types.

 [0089] According to the present invention, the difference in the expression level of a gene can be performed by measuring the presence or amount of a nucleic acid or a protein corresponding to the gene.

 [0090] The biological sample includes a lung cancer tissue or cell of a lung cancer patient, and is a cancer tissue excised by surgery, a tissue or cell obtained by biopsy, and the like.

 [0091] These two different methods will be specifically described below.

 [0092] (Method using nucleic acid)

 In order to detect 351 genetic markers according to the present invention, the above-described nucleic acids that hybridize with each of these markers are used. The number of genes to be detected is 1 or 2 or more for each gene set, preferably 2 or more, 5 or more, 10 or more, 20 or more, 30 or more, 40 or more, 50 or more, or 60 or more. The greater the number of genes, the better the accuracy of identifying lung adenocarcinoma subtypes.

[0093] Hybridization should be performed by a microarray method, blotting method such as Northern or Southern blotting, Northern or Southern hybridization method, in situe hybridization method, quantitative RT-PCR method, etc. Can do. A preferred hybridization method is microarray, quantitative RT-PCR or plotting. Also good In addition, examples of microarrays are DNA microarrays and protein microarrays

[0094] In the DNA microarray method, a DNA chip in which nucleic acid probes that hybridize with the genes (1 to all) listed in Tables 1 to 4 above are bound to a substrate is prepared and used.

 [0095] As the DNA chip, any type of substrate can be used as long as the nucleic acid probe can be immobilized. The solid phase includes, for example, glass, polymer, and the like, and a spacer containing a reactive group for covalently binding a nucleic acid can be introduced. Since such chips are commercially available, it is desirable to use them.

 [0096] The solid phase immobilization of the nucleic acid probe is not particularly limited, but a general method, for example, a method of spotting DNA using a high-density dispenser called a spotter or an arrayer, a droplet is ejected from a nozzle. It can be carried out using a method such as an inkjet method.

 [0097] DNA or RNA in a biological sample, cDNA derived therefrom, cDNA, cRNA or other nucleic acid labeled with a fluorescent substance such as Cy dye (Cr3 or Cy5) is hybridized with the probe on the DNA chip. Let The fluorescence intensity is read using a laser scanning reader, and the data is analyzed by a computer.

[0098] In the plotting method, the nucleic acid probe of the present invention is labeled with a radioisotope (eg, ³² P and ³⁵ S) or a fluorescent substance (rhodamine derivative, Cy dye, etc.) and then transferred to a polymer membrane such as nylon. Hybridization is performed between the DNA or RNA in the biological sample obtained and the nucleic acid such as cDNA or cRNA derived therefrom. The signal is detected using a radiation detector or a fluorescence detector and its intensity is measured.

 [0099] Quantitative RT-PCR is performed by PCR using an RNA primer in a biological sample, annealing the primer with cDNA so that the target gene region can be amplified. Detect double-stranded DNA. The target gene is detected by pre-labeling the primer with a radioactive isotope or fluorescent substance, or by electrophoresis of the PCR product on an agarose gel and staining double-stranded DNA with ethidium bromide. It can be quantified.

[0100] PCR conditions are, for example, denaturation: 92-94 ° C for 30-60 seconds; annealing: 50-55 ° C for 30-60 seconds; extension: 68-72 ° C for 30-60 seconds as one cycle 30-40 cycles of reaction Including. As the reverse transcriptase, commercially available enzymes such as Superscript III (Invitrogen, USA), AMV Reverse Transcriptase (Promega, USA), M-MLV (RNaseH_) (Takara Shuzo, Kyoto) and the like can be used.

[0101] (Protein method)

 An alternative method for measuring the expression level of the gene is an immunological method.

 [0102] In this method, a protein or fragment thereof corresponding to each gene is synthesized using protein synthesis or gene recombination techniques, and the resulting protein or fragment thereof is used as an antigen for rabbit, mouse, rat, Immunize animals such as horses, bushes, goats, and hidges, and produce and purify antibodies against these antigens.

[0103] Antibodies include polyclonal antibodies, monoclonal antibodies, anti-peptide antibodies, and the like.

[0104] Polyclonal antibodies are obtained by immunizing the animals subcutaneously with about 10 to 300 μg of antigen, and further boosting about 2 weeks later, collecting blood about 3 weeks to 1 month after the first immunization, and antiserum. To IgG components containing the desired polyclonal antibody can be prepared by a method including separation using ammonium sulfate fractionation and ion exchange chromatography. In order to increase specificity, the obtained IgG is bound to a column made by binding the target protein to a carrier such as cellulose or agarose, and then eluted with a high salt buffer, followed by dialysis or ultrafiltration. A specific polyclonal antibody can be obtained by desalting by a method such as The antibody titer can be measured by a conventional immunoassay, for example, enzyme immunoassay (EIA, ELISA), radioimmunoassay (RIA), fluorescent antibody method and the like.

[0105] The monoclonal antibody can be prepared, for example, by the following general method.

[0106] The target protein or fragment thereof is administered subcutaneously to mice or rats (for example, BalbZc mice) in the same manner as the production of polyclonal antibodies, and booster immunization is performed about 2 to 4 times at intervals of 1 to 4 weeks. When the antibody titer reaches its peak, the antigen is injected intravenously or intraperitoneally to make the final immunity. Two to five days later, antibody-producing cells (for example, spleen cells or lymph node cells) are collected. The antibody-producing cells are then fused to a myeloma cell line (preferably a hypoxanthine 'guanine' phosphoribosyl 'transferase (HGPRT) deficient cell line) to produce a hyperidoma cell, and HAT (hypoxanthine, aminopterin, thymine) Make a selection. Cell fusion is performed in animal cell culture media such as serum-free DMEM, RPMI-1640 media, The antibody-producing cells and the myeloma cell line are mixed at a ratio of about 1: 1 to 20: 1 and performed in the presence of a cell fusion promoter such as polyethylene dallicol. Confirmation of the target antibody can be performed by the immunoassay described above. In addition, about 10 million hyperidomas are administered into the abdominal cavity of mice to proliferate the hyperidomas, and after the hyperidomas are proliferated, ascites is collected after 1 to 2 weeks. The antibody can be purified by an appropriate combination of methods such as ammonium sulfate fractionation, ion exchange chromatography, affinity chromatography, and gel chromatography.

 [0107] An anti-peptide antibody is an antibody against a linear peptide on the surface of a protein, and can increase immunological specificity. Such peptides include, for example, the estimation of hydrophilic-hydrophobic regions by Kyte-Dool ittle et al., The probability of being located on the surface of a specific peptide site on a protein molecule by Emini et al., The degree of bending of the polypeptide chain, such as Chou —Fasman et al. Can be estimated using a helix, β-sheet, secondary structure prediction of protein displaying turn, etc. alone or in combination. The estimated peptide can then be synthesized using a peptide synthesizer.

[0108] Here, synthesis of the target protein (encoded by the genes shown in Tables 1 to 4 above) is performed by incorporating a cDNA clone into an expression vector and transforming or transfecting a prokaryotic or transformed By culturing a eukaryotic host cell, the cell or culture supernatant can also be obtained. A commercially available expression vector can be used. Host cells include prokaryotic cells such as bacteria (eg, E. coli, Bacillus subtilis, Pseudomonas bacteria), yeast (eg, Saccharomyces, Pichia, etc.), insect cells (eg, sua cells), mammalian cells (eg, CHO, COS, BHK, HEK293, etc.). Vectors consist of plasmids, cosmids, phages, etc., and include DNA encoding the target protein, promoter, enhancer if necessary, polyadenylation signal, ribosome binding site, replication origin, terminator, selection marker, etc. Can be included. In order to facilitate the purification of the polypeptide, a DNA sequence encoding a labeled peptide, such as a histidine tag of 6 to: L0 residue, FLAG, GFP polypeptide, etc. may also be included. The gene recombination techniques are described in Sambrook et al. (Supra) and Ausbel et al. (Supra), and the techniques described therein can be used for the present invention. [0109] The target protein obtained as described above is gel filtration, ion exchange chromatography, affinity chromatography, hydrophobic chromatography, isoelectric focusing, electrophoresis, ultrafiltration, salting out, Purification can be performed by appropriately combining dialysis and the like.

[0110] The sequence of the target protein or fragment thereof can be obtained by accessing the NCBI HomePage based on the GenBank registration numbers described in Tables 1 to 4 above.

[0111] The antibodies described above can be used for the detection of a target protein or fragment thereof in a biological sample. A large number of target proteins can be detected or defined at a time by creating a protein microarray in which a large number of antibodies are bound on a microarray substrate, or by spotting a large number of antibodies in a dot pattern on a filter such as a PVDF membrane. It becomes possible to measure. Or, conventional immunoassays such as enzyme immunoassay (ELISA, EIA), fluorescent antibody method, radioimmunoassay (RIA), luminescence immunoassay, immunoturbidimetric method, latex agglutination, latex turbidimetric The target protein or fragment thereof in a biological sample can be detected or quantified by a method, hemagglutination reaction, particle agglutination reaction, Western plot method, or the like.

[0112] When the reaction is carried out on a solid phase, the solid phase carrier may be a polymer film (filter) such as polystyrene, polycarbonate, or polyethylene, a plate, a tube, a strip, or the like, or a particle such as a latex or magnetic substance. included. The solid phase can be physically or chemically performed. For chemical bonding, the solid phase can be treated with a reagent such as maleylation reagent or cyanogen bromide, and functional groups that react with amino groups of proteins can be introduced into the solid phase.

Labels include enzymes such as horse radish peroxidase and alkaline phosphatase, fluorescent materials such as fluorescein, rhodamine and derivatives thereof, luminescent materials such as luciferase and luminol, and radioisotopes such as ³² ρ and ¹²⁵ ι Etc. are included. Examples of the labeling agent include a dartal aldehyde method, a maleimide method, a pyridyl disulfide method, a chloramine T method, and a Bolton Hunter method.

[0113] The present invention also provides the nucleic acid (1) to (5) for measuring the expression of a gene included in each gene set listed in Tables 1 to 4 above, or a mutant, homologue or derivative thereof. Or a tongue encoded by the gene, or a variant, homologue or derivative thereof For in vitro prediction of postoperative prognosis in patients with lung adenocarcinoma, including antibodies to the antibodies or fragments or fragments thereof, or for lung adenocarcinoma as TRU, non-TRU, TRU-a or TRU Compositions are provided for classification into any sub-type of type -b.

[0114] According to an embodiment of the present invention, the composition is in the form of a kit or a microarray.

[0115] In the kit of the present invention, the nucleic acids shown in (1) to (5) above, from TRU type, non-TRU type, TRUa type and TRU-b gene sets (see Tables 1 to 4, respectively) A nucleic acid capable of detecting the total number of genes from one or more of the above is packaged for each gene set.

[0116] Another kit of the present invention provides an antibody or fragment thereof against a protein or fragment thereof encoded by a gene included in each gene set listed in Tables 1 to 4 above, or a variant, homologue or derivative thereof. Is packaged for each protein set corresponding to each gene set.

 [0117] The antibody contained in the composition of the present invention is not limited to those which are polyclonal antibodies, monoclonal antibodies, anti-peptide antibodies and the like produced by the method described above. The type of antibody may be any type, class, subclass, and includes, for example, IgG, IgM, IgE, IgD, IgA and the like. Antibody fragments include Fab, (Fab '), Fv, etc.

 2

[0118] The kit may further contain reagents for carrying out hybridization, such as a buffer, a reverse transcriptase, and a labeled secondary antibody.

[0119] The microarray of the present invention is a DNA microarray (also referred to as a DNA chip) or a protein microarray.

 [0120] Each of these microarray chips is bound with the above-described nucleic acids (1) to (5) or the above-described antibodies or fragments thereof. That is, on the surface of the chip, nucleic acids that can be hybridized with the genes included in the gene sets listed in Tables 1 to 4 above, or variants, homologues or derivatives thereof, or proteins encoded by these genes. Or an antibody or fragment thereof that reacts immunologically specifically with the protein, or a variant or derivative thereof.

[0121] The mutant is a fully mature sequence of the above gene or protein and 70% or more, preferably 80% or more, more preferably 90% or more, 95% or more at the nucleotide or amino acid level. Or it has 98% or more identity. Here, identity (%) can be determined using a known BLAST or FASTA program with a gap introduced. In general, identity (%) can be calculated as a percentage of the number of matched bases relative to the total number of bases.

 [0122] Derivatives of proteins include chemically modified derivatives such as glycosylation, phosphorylation, sulfation, alkylation, and acylation.

 [0123] As the substrate of the chip, glass or resin (polymer) is usually used, and, for example, poly L-lysine, silane or densified amino groups are introduced on the surface thereof.

 [0124] The binding of the nucleic acid or antibody to the substrate is performed by the spot method or the inkjet method as described above.

 [0125] The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples.

 Example

[0126] A. Materials and Methods

 .

 A series of 149 NSCLC cases, including 90 adenocarcinomas, 35 squamous cell carcinomas, 18 large cell carcinomas, 4 squamous adenocarcinomas and 2 large cell neuroendocrine carcinomas The file power of a patient who successfully performed curative resection between December 1995 and December 1999 at the Center's Thoracic Surgery (Nagoya) was also obtained. 82 post-surgical cases with adenocarcinoma and follow-up range from 6 to 108 months (median 77.0 months; average 65. 1 month) for postoperative survival analysis It was used. The remaining 8 cases were excluded because they were receiving gefitib treatment. All tumor specimens were embedded in OCT composites and stored at 80 ° C after obtaining the required approval from the formal review department and written informed consent from the patient.

[0127] Acquisition of expression profile

The frozen tissue of the tumor specimen was subjected to rough microdissection under the direction of a pathologist using all 10th Giemsa-stained sections. Total RNA was extracted using RNeasy kit (Qiagen, USA) and then treated with DNase I. Large batches of reference RNA were prepared by using 20 lung cell lines, all representing major histological types of lung cancer. From total RNA25 Ong, using poly dT primer and MMLV-RT incorporating T7 promoter, Double-stranded cDNA was synthesized. cRNA was prepared and labeled with Cy3 or Cy5 (Cy dye; Amersham Pharmacia Biotech, USA) using a low RNA Fluorescent Liniear Amplification kit (Agilent Technologies, USA). Cy 5-sample cRN A and Cy 3-normal reference cRN A were hybridized with a custom-made Agilent oligonucleotide microarray containing a total of 21,619 spots corresponding to 18,175 unique genes and Analyzed by focused laser scanning (Agilent Technologies, USA). The fluorescence intensity on the scanned image was quantified, and the value was corrected and normalized to the background value.

 [0128] Bioinformatics analysis

 In order to filter out potential noise during the analysis, powerful genes for which sufficient expression signals could not be obtained in more than 10 samples were eliminated. In addition, the ability to eliminate genes whose expression level has changed by less than 3 fold throughout the sample set of interest. This is also a powerful force that such genes are unlikely to provide useful information. Using the CLU STER program, mean association order clustering of both genes and cases was performed using median centering and normalization, followed by TREEVIEW (Eisen MB et al., Proc Natl Acad Sci USA 95: 14863— 8, 1998 ) To display the results. SAM, a characteristic signal extraction technique, was used to score genes specific to each patient's lung adenocarcinoma subtype (Tusher VG et al., Proc Natl Acad Sci USA 98: 5116-21, 2001 ).

 [0129] Mutation analysis of EGFR, Ό53 and K ras genes

 p53 (Exon 4-10), EGFR (Exon 15-24) and Kras (Exon 1-2) genes were amplified from the same RNA used for microarray analysis. The resulting PCR product was directly sequenced as previously described (Kosaka T et al. Cancer Res 64: 8919-23, 2004;).

 [0130] Identification method based on GO item and other statistical analysis

Analysis using Gene Ontology (GO) (Ashburner M et al., Nat Genet 25: 25-9, 2000) reveals biological features of different functions of the gene set specific to each of the patient's adenocarcinoma subtypes I made it. The database file used for this GO analysis is UniGene ftp site (ftp: ZZftp.ncbi.nih.gov/repository/UniGene/) Power downloaded. Analyzes database files including Hs. Seq. All, His data, and LL-tempi with Unigene ID corresponding to spots on the microarray with the help of a program written in Perl newly developed by the present inventors. To connect to the corresponding GO item via the LocLink ID. Finally, out of 18,175 unique genes on the microarray, 12,745 known genes were associated with approximately 67,000 GO items. Of these items, Fisher's exact test identified the items that occurred significantly more frequently in the target gene set.

[0131] The% ² test or Fisher's exact test was used for frequency analysis. In order to investigate the relationship between various clinical parameters and the expression of the subtypes defined by the expression profile, a multivariate oral dystic regression analysis was performed. Survival was assessed as a function of time using the Kaplan-Meier method, and the difference in survival was analyzed with a log-rank test. The Cox proportional hazards model was used to analyze independent factors affecting survival. All analyzes were performed using Stata software (version 7; Stata Corp, USA), with a two-sided significance level set at P <0.05.

 [0132] B. Results

 / 田 H qflrtf's profile branch

First, all 149 samples were classified using a systematic clustering method without teacher values. At this time, we established a molecular classification method based on the similarity of genome-wide expression patterns in individual tumors using 4,834 most variably expressed transcripts. The resulting cluster accurately reproduced the well-established and widely used NSCLC histological classification (Figure 1). SAM analysis revealed the presence of different gene sets with up-gradation or down-regulation for each cluster, and this gene set was also identified by the inventors (Tomida S et al., Oncogene 23: 5360—70, 20 04) and other researchers (Garber ME et al., Proc Natl Acad Sci USA 98: 13 784-9, 2001; Bhattacharjee A et al., Proc Natl Acad Sci USA 98: 13790-5, 2001) It was found to be similar to the gene set. [0133] In this study, we conducted an extensive search for mutations in the EGFR, p53, and K-ras genes that are strongly thought to be the cause of the development of lung cancer, and found the subtypes defined by the expression profile. We investigated whether it was related to the presence or absence of these genetic changes. Clearly accurate reproduction of the conventional NSCLC histological classification and conventional reporting power on these three genetic changes As predicted, a highly significant relationship was found between the EGFR mutation and the corresponding adenocarcinoma morphology Between the figures (36% vs. 0%; P <0.001), and between the p53 mutation and the saddle figure that is almost squamous cell and large cell carcinoma (67% vs. 33%; P <0. 001).

 [0134] Two adenocarcinoma tumor types identified by expression profile

 During this study, we noticed that there were two major subclusters, while adenocarcinoma cases were clustered together as a large single saddle diagram. This finding was performed in a separate analysis of adenocarcinoma because of the strong features of other NSCLC tissue types that could obscure differences within adenocarcinoma. For this purpose, a systematic clustering performed with the 4,138 transcripts most variable expressed in adenocarcinoma, the two major diagrams, and further in the right diagram The existence of two subclusters was clearly shown (Figure 2A). Morphological analysis indicates that bronchioloalveolar carcinoma is within the right-handed subcluster. Other adenocarcinoma subtypes or variants that follow the WHO classification are clearly clustered in any particular pleatogram. It was shown not to be. However, we found that the features of the cases in the right-side diagram are TRU-type adenocarcinomas, i.e. different adenocarcinoma subsets that we previously proposed based on their different cell morphology ( Yatabe Y et al., Am J Surg Pathol 29: 633-639, 2005; Yatabe Y et al., Am J Surg P athl 26: 767-73, 2002; Yatabe Y, Elsevier Science / Academic Press, 2004, ppl69—179, I noticed something similar to New York). ((Note) For convenience, the tumors on the right and left sides are called TRU adenocarcinoma and non-TRU adenocarcinoma, respectively.)

To gain further insight into the morphological and biological properties of adenocarcinoma subtypes defined by these two major expression profiles, namely non-TRU and TRU, we first performed a SAM analysis and showed differential Expressed genes were selected. For SAM analysis 1,657 genes were extracted by pre-filtering at a significant level with a false positive rate of less than 0.1%, and 286 of these genes had a genetic power of 2 or more and were multiplied by TRU and non-TRU types. There was a difference between their expression levels. These 286 genes consisted of 194 genes with higher expression in the TRU form and 92 genes with higher expression in the non-TRU form (data not shown) . In order to better understand the basic functional differences between TRU and non-TRU, the gene set identified by SAM was analyzed using GO items. This method was developed in our laboratory for this study. Using this identification method, GO items related to 9 biological processes, 6 molecular functions, and 2 cellular components were extracted as significantly more frequent in TRU adenocarcinoma, Clear relationship with normal lung function (Table 5)

[Table 5]

Table 5 Gene Ontology (GO) Items TRU! I Significantly Key to Non-TRU Type

GO mode GO item GO arc session P

 TRU related GO items

 Biology 0¾

 Regulation of fat body surface GO: 0050828 0.002 Sexual differentiation GO: 0007548 0.002 Lipid protein metabolism G0: 0042157 0.013 Congenital immunity GO: 0045087 0.014 Occurrence of moderate GO: 0007498 0.018

GO: 0006817 0.019 Gas in the GO GO: 0007585 0.022 Lipid metabolism GO: 0006629 0.027

 ¾ ^ T (sensu Metazoa) GO: 0007338 0.030 奸 Function:

 娜 Binding GO: 0003823 0.001 劂 Motofuji Activity GO: 0016712 0.002 隨 Bind GO: 0019825 0.003 Phospholipid W¾f ATPase Activity GO: 0004012 0.013 Non-specific Monogenous Xigenase ¾ "GO: 0050381 0.032

 Steroid GO: 0005496 0.037

 Non-key area GO: 0005576 0.011 Microsome GO: 0005792 0.032 Non-TRU type GO items

 biology :

 Nucleated tide biosynthesis GO: 0009165 0.002 Yarn ω¾ϋ GO: 0007049 0.003 Circulation GO: 0008015 0.003 Chromatin and / or moth »GO: 0006325 0.005

 Yarn GO: 0007067 0.014 麵 GO: 0007565 0.021 Yarn MS surface acceptance ί¾¾ ^

 Generation of epidermis GO: 0008544 0.046 Function:

 Polypeptide ァ -Acetinole-Galacto GO: 0004653 0.006 Saminole transferase

 Bonding GO: 0005524 0.038

 Soluble fraction GO: 0005625 0.001

^ fe body, around central body GO: 0000775 0.004 Kinetokoa GO: 0000776 0.005 Nuclear GO: 0005730 0.032 On the other hand, GO items identified as specific to non-TRU type are And those related to proliferation, suggesting the inherent aggressive nature of non-TRU adenocarcinoma.

 [0136] Identification of the subtypes identified by these very robust expression profiles of adenocarcinoma was performed by a similar unsupervised clustering analysis using independent data sets. A Stanford data set consisting of 34 cases of lung adenocarcinoma (Garber ME et al., Proc Natl Acad Sci USA 98: 13784—9, 2001) was analyzed for differential expression in non-TRU, TRU-a and TRU-b types. Based on the expression profiles of the 30 top ranked genes, analysis was performed by unsupervised classification systematic clustering. This analysis resulted in a clear visualization of the two major saddle diagrams with subclusters. The morphogram appeared to correspond well to the adenocarcinoma subtypes identified in the three expression profiles identified in this study (Figure 3).

 [0137] ^ ¾ special relationship in profile,

 Next, we investigated the relationship between various clinicopathological properties and adenocarcinoma subtypes identified by the two expression profiles, namely TRU adenocarcinoma and non-TRU adenocarcinoma (Table 6).

[Table 6]

Acupuncture between pulmonary fistulas identified by expression profile (EP) and vaginal pathological difficulties

 Identified by EP?

 Clinical Acupuncture T U TRU P

 Number of examples 37 53

 Age (M)

 ≤62 years 22 28 0. 67

 > 62 years 15 25

 side

 Male 26 21 0. 005 Female 11 32 Non-aged 8 37 <0. 001 Current and past leaders 27 16

 Ρ Τ

 T1 14 26 0. 72

 Τ2 17 20

 Τ3 4 4

 Τ4 2 3

 ρ Ν

 NO 25 35 1. 0

 Nl 3 5

 N2 9 13

 p stage

 I 22 30 0. 83

 II 6 7

 III 9 16

 Invasive growth

 Positive 35 30 <0. 001

■, Positive 1 14

 Ttx can be S 1 9 隱 17 6 0. 001 Locality 4 4

 Negative 16 43

TRU-type adenocarcinoma was found to be significantly more frequent in women (P = 0.005) and nonsmokers (P-0.001) than in non-TRU types. On the other hand, detailed microscopic examination shows that the presence of invasive growth and necrosis, which are indicators of higher malignancy / appearance and rapid proliferation, is a cell cycle-related GO that is distinguished from non-TRU tumors. According to the item and the dominant growth, it was characteristically widespread among non-TRU types (P <0.001 for both invasive growth and necrosis). Change age, gender, smoking status and pathological stage Multivariate logistic regression analysis with numbers identified non-smoking status as a significantly related variable (P = 0.001). Regarding the prognosis after surgery, we found that cases belonging to the two apparent clusters under the morphological diagram of TRU adenocarcinoma seen in Fig. 2, namely TRU-a and TRU-b, I noticed that there was a difference in prognosis after surgery. TRU-a has a prognosis similar to that of non-TRU, whereas TRU-b adenocarcinoma has a significantly better prognosis than non-TRU (P = 0. 021; (Figure 4). This is consistent with the fact that microscopic examination showed clear invasive growth in TRU-b adenocarcinoma much less frequently than other adenocarcinoma types. (P <0. 001).

 [0139] Engagement of ffi ^ EGFR in profile,

 We examined whether the power of any of the three major genetic changes in NSCLC was significantly associated with adenocarcinoma subtypes identified in the expression profile (Figure 2B). The presence of EGFR mutations was found to be significantly more frequent in TRU adenocarcinoma than in non-TRU adenocarcinoma (45.3% vs 21.6%; P = 0.026). We also found that the two apparent clusters under the morphological diagram of TRU-type adenocarcinoma, namely TRU-a and TRU-b, are slightly different in terms of the frequency of EGFR mutations, We found that TRU-b adenocarcinoma (52.6%) showed a higher EGFR mutation frequency than TRU-a adenocarcinoma (41.2%). In contrast, K-ras and p53 did not correlate with adenocarcinoma subtype (P = 0.33 for p53; P = 0.17 for K-ras), but the mutation frequency was suddenly interesting. An inverse correlation was observed between these genetic changes and EGFR mutations. Non-TRU adenocarcinoma includes the highest percentage of tumors with p53 and / or K-ras mutations (41% for ρ53; 16% for K-ras), followed by TRU-a (29% and 12%) and TRU-b type (21% and 0% respectively).

 [0140] Significant prognosis of EGFR mutation in TRU adenocarcinoma

The present inventors and other researchers have reported that the presence of EGFR mutations does not affect the postoperative prognosis of patients with NSCLC (Kosaka T et al., Cancer Res 64: 8 919-23, 2004; Shigematsu H et al., J Natl Cancer Inst 97: 339-46 , 2005), this was confirmed in this independent data set (Figure 5 Α; Ρ = 0.4 2). Based on the fact that this finding may indicate a more important role for EGFR mutations, especially in the development of TRU adenocarcinoma than in the development of other lung cancer types. The inventors performed a separate analysis of TRU-type adenocarcinoma cases to investigate the potential relationship between EGFR mutations and postoperative prognosis. A significant relationship was detected between poor postoperative prognosis and the presence of EGFR mutations in TRU adenocarcinoma (FIG. 5B; P = 0.024). This relationship was further confirmed by the results of multivariable Cox regression analysis (Table 7).

 [Table 7]

Difficult prognostic factors for TRU 雞 麵 Co o regression analysis

 Variable Poor / Good Risk factor 9 5% C I * P Age> 62 1 <62 1. 09 0. 39-3, 04 0.87 删 Male 1 Female 1. 03 0. 33-3. 23 0.96

 Yes (¾fe and past) / No 1. 28 0. 36-4. 53 0. 70 Stage IHQI 1 I 7. 61 2. 37-24. 5 0. 001 Subcluster 1 TRU-a 1 T Ub 8. 25 1 99-34. 2 0. 004

EGFR status mutation Barbarian 7. 71 2. 02-29. 4 0. 003

* 95% CI: 95% confidence interval

[0141] The presence of EGFR mutations in TRU-type adenocarcinoma is the disease stage (H. R. = 7. 61; P = 0.

 001) and histological subtypes identified in the expression profile (HR = 8.25; P = 0.003), as well as independent prognostic factors (HR = 7.71; P = 0.003) On the other hand, gender, age and smoking status did not show any significant relationship.

[0142] Snooping of genes with significant differential expression in the presence or absence of EGFR

 In all adenocarcinoma cases, a significance level of 5% false-positive rate was used to select genes associated with the presence of EGFR mutations, which was achieved when using a 1% pseudo-positive rate. It is a force that is not selected at all (Table 8).

[Table 8] Table 8

Genes identified as up-regulated fc¾ [^

 Child gd No. UniGene ID difference

ZDHHC11 zinc finger, containing DHHC domain 11 Hs. 3368851 3.0

GGTLA4 * 7-Glutamizoretransferase-like activity 4 Hs. 355394 2.3

LOC 01022 * Supplementary L0C401022 Hs. 98661 2. 1

CPAMD8 C3 and PZP-like, a-2-macroglobulin Hs. 529075 2.1 Domain containing 8

 EST Ψ uncopied locus Hs. 449965 2. 0 哪 41 * GSGL541 Hs. 211 267 1. 9

RGMA RGM domain family, member 1 A Hs. 271277 1. 8

DNALI1 dynein, axone manore, light intermediate Hs. 406050 1. 8 Polypeptide 1

 ESP1 Nakakusoukata 1 Hs. 447531 1. 7

CDKL2 * Cyclin-dependent kinase-like 2 Hs. 310 540 1. 7

EST transcription locus Hs. 553240 1. 7

EST transcription locus Hs. 9S587 1. 6

APOH Apolipoprotein H (β-2-glycoprotein I) Hs. 445358 1. 6

LGALS3BP Lectin, galactoside, soluble, Hs. 514535 1.5

 3-binding protein

 PEX3 Peroxisome biogenesis factor 3 Hs. 7277 1.5

C6orf60 Housing 6 0 F60 Hs. 443789 1.5

TRU 鵜

GGTLA4 * _γ _g gnoretaminoretransferase-like activity 4 Hs. 355 394 2.4

RAMP1 reporter (calcitonin) activity modification Hs. 471783 1. 9 protein

 APOH Apolipoprotein H (_2_glycoprotein I) Hs. 445358 1. 7

PEX3 Peroxisome biogenesis factor 3 Hs. 7277 1. 7

EST transcription locus Hs. 553240 1. 6

DHRS7 Dihydrogenase / Reductase (SDR family) Hs. 59719 1.5 Member 1

* It is also a gene expressed in TU. Identified five genes with EGFR mutations and more than 2-fold upregulation in tumors, while 11 more genes were associated with the presence of EGFR mutations Regulation was shown. We further searched for genes that are differentially and differentially expressed in TRU adenocarcinoma with EGFR mutations that appear significantly more frequently. While it was necessary to use a fairly high pseudo-positive rate (10%) to select genes by SAM, a single gene with more than twice up-regulation in the presence of EGFR mutation, ie GGTLA4 was identified. In addition, 8 genes showed 1.5-2 fold upregulation at the same level of significance (Table 5). [0144] ¾S

 The expression profile in a given tumor can be considered as a result of a complex effect. Such effects are the result of accumulated genetic changes important to the pathogenesis, as well as the promiscuous commitment of progenitor cells. In this study seeking that understanding, we succeeded in establishing a very consistent adenocarcinoma taxonomy identified by its expression profile. Its relevance to the method is clearly supported by the inclusion of various distinct molecular genetic and clinicopathological features. The two main subtypes, TRU and non-TRU, are characterized by differential expression of a large number of genes and thus show significant differences in their gene usage (Yatabe Y et al., Am J Surg Pathol 29: 633 639, 2005). The results obtained using our GO item identification method further support these different properties. TRU-type tumors are characterized by biological processes that are important for the management of peripheral lung function (Veldhuizen EJ et al., Biochim Biophys Acta 1467: 255-70, 2000). Similarly, this seems to reflect the retention of the characteristics of these progenitor cells. In contrast, many non-TRU-type related GO items are related to cell cycle and cell growth and appear to be consistent with high-grade microscopic findings.

 [0145] The striking differences in clinical features between TRU and non-TRU subtypes also support the robustness of the taxonomy identified in the expression profiles of the present invention. A notable clinical feature of the TRU type is a significantly higher proportion of women and non-smokers, whereas multivariate analysis results indicate non-smoking status as an independently related factor. It does not indicate gender. That is, this tumor type appears to produce peripheral lung airway cell forces with much less smoking effects, and retains its ancestral characteristics as demonstrated by GO item-based analysis. It seems to be. The TRU-b type has the most favorable prognosis, has a low frequency of invasive growth, and expresses higher levels of various differentiation markers even when compared to the TRU-a type. This suggests that TRU-b retains the characteristics of normal peripheral lung airway cells better than other types, but may have the potential to progress to TRU-a.

[0146] This study clearly shows that the presence of EGFR mutations is significantly associated with TRU adenocarcinoma It is shown that. In fact, 45.3% of TRU adenocarcinoma cases have EGFR mutations, compared to 21.6% of non-TRU cases. On the other hand, p53 and K-ras did not show a significant difference in the frequency of their mutations, but there was an interesting reverse trend of the highest incidence in non-TRU types. The presence of EGFR mutations was significantly associated with short postoperative survival regardless of disease stage, particularly for TRU adenocarcinoma. In fact, the 5-year survival rate for patients with TRU-type stage IV disease was found to be 25% in the presence of sudden EGFR mutation and 78% in the absence. Based on these findings, possible clinical analyzes of the subtypes identified in the expression profile and the mutation status of EGFR to select candidate drugs for intensive adjuvant therapy with gefitib, if possible It suggests usefulness.

 [0147] In conclusion, this study aims to establish a molecular taxonomy identified by genetic and clinicopathologically relevant expression profiles for the presence of heterogeneity in lung cancer, especially adenocarcinoma. , Hit the light.

 [0148] Examples of C TRI and non-TRI glands

 Signal-to-noise metrics, Golub et al., Science, Vol. 286, pp531 to 537, 1999) were used to classify lung adenocarcinoma into TRU and non-TRU types. When the lung adenocarcinoma cases are defined as class 1 for the TRU type and class 2 for the non-TRU type, the signal noise statistic weight S is calculated by the following formula (Fig. 6).

[0149] S = — μ / ο + σ)

 class 1 class2 class 1 class2

 Here, for each gene, μ represents the mean value of the total expression intensity data of classl, and μ class 1

 Indicates the average value of all expression intensity data of class2, and σ indicates the total expression intensity of class 1 class2 class 1

_Σ indicates the standard deviation of the total expression intensity data of cla _SS 2.

 class 2

 [0150] Next, a weighted vote for gene X is calculated using the following Weighted-Voting formula (Figure 7).

[0151] V = S (G -b)

 Where V is the weighted vote for gene X and S is calculated by the above formula

 X

Indicates the weight, G indicates the expression intensity (or expression level) of gene X, b is b = (μ 1 + μ 2) / 2

 x

 (Where μ 1 and 2 indicate the average of the average values of classl and class2, respectively), and indicate the centers (ie, centroids) of the two groups.

[0152] By adding weight according to the deviation of the center of gravity force, the sum of V in each group is 0

 X

 When larger, adenocarcinoma is classified as classl, and when the sum of V is less than 0, adenocarcinoma is classified as class2.

 X

 Can be classified.

 [0153] For example, for samples 1, 2, 3, 4 and 5 belonging to classl and samples 6, 7, 8, 9 and 10 belonging to class2, genes (Gene) A, B, C (above, TRU characteristic genes) , The expression intensity (or expression level) of genes (Gene) X, Υ, Ζ (and above, non-TRU genes) was measured, and the average expression intensity of each gene in five samples of each group) and standard deviation (σ ), And the weight (S) and centroid (b) are calculated from the above equations. The results are shown in Table 9.

 X

[Table 9]

[0154] For sampleA and sampleB to be classified, measure the expression intensity (or expression level) of each gene, calculate the above expression force weight (S), G-b, find each V, and then add 6 genes

 X

 Find the total sum of V (Fig. 8).

 X

 As a result, sampleA is identified as TRU type because the sum of V is greater than 0. Also s

 X

 ampleB is identified as a non-TRU type because the sum of V is less than zero.

 X

 Industrial applicability

[0156] According to the present invention, the relationship between adenocarcinoma subtype and postoperative prognosis in lung adenocarcinoma patients, and certain subtypes ( It is possible to predict the relationship between EGFR mutation in TRU type and postoperative prognosis, so that a treatment plan suitable for postoperative patients can be made. Thus, the present invention can contribute to the medical industry for the treatment of lung adenocarcinoma.

Claims

The scope of the claims

 A method for predicting the postoperative prognosis of a patient with lung adenocarcinoma in vitro, wherein the method identifies lung adenocarcinoma as one of its subtypes, TRU type or non-TRU type, and then TRU type Is identified as TRU-a type or TRU-b type, and TRU-b type has a good postoperative prognosis, or TRU-a type or non-TRU type includes determining that postoperative prognosis is poor, wherein the TRU type, non-TRU type, TRU-a type and TRU-b type are For the expression of one or more genes in the corresponding set of genes below in a biological sample, between TRU adenocarcinoma and non-TRU adenocarcinoma, or TRU-a adenocarcinoma and TRU-b adenocarcinoma By measuring the difference in relative expression levels between, and

 The gene set belonging to the TRU type has the following UniGene registration number:

Hs.512690, Hs.153322, Hs.218366, Hs.220629, Hs.436996, Hs.435759, Hs.10455 5, Hs.247824, Hs.127821, Hs.480281, Hs.529117, Hs.545862, Hs .391561, Hs.479 372, Hs.533055, Hs.550526, Hs.322854, Hs.465720, Hs.356664, Hs.26630, Hs.53 4496, Hs.85962, Hs.211267, Hs.128041, Hs .534458, Hs.495774, Hs.437806, Hs.l 33062, Hs.501758, Hs.444535, Hs.495480, Hs.326561, Hs.483906, Hs.169943, Hs.271285, Hs.158339, Hs. 62604, Hs.469359, Hs.436657, Hs.8417, Hs.155538, Hs. 533526, Hs.512756, Hs.87191, Hs.463079, Hs.513779, Hs.476209, Hs.279580, Hs.351544, Hs.269408, Hs.134807, Hs.482417, Hs.176626, Hs.465643, Hs.183390, Hs.411299, Hs.234027, Hs.109358, Hs.103983, Hs.26216, Hs.534352, Hs. 240457, Hs.516036, Hs.144875, Hs.411312, Hs.l03989, Hs.537722, Hs.333130, Hs.5179 62, Hs.90250, Hs.478930, Hs.121629, Hs.l94061, Hs.520627 , Hs.348012, Hs.522 836, Hs.l376, Hs.520049, Hs.51285 6, Hs.355236, Hs.349470, Hs.476231, Hs.137 556, Hs.390567, Hs.368353, Hs.412792, Hs.449207, Hs.527095, Hs.118722, Hs.3 77090, Hs. 232696, Hs.447544, Hs.372773, Hs.222055, Hs.511839, Hs.153299, Hs.434374, Hs.287729, Hs.553740, Hs.l27189, Hs.497723,

Hs.l81973, Hs.173656, Hs.451956, Hs.184507, Hs.532492, Hs.370904, Hs.46046 8, Hs.520612, Hs.436667, Hs.l25116, Hs.459391, Hs.450320, Hs .149769, Hs.32 5890, Hs.356820, Hs.289319, Hs.73893, Hs.129493, Hs.515069, Hs.34560, Hs.47 7278, Hs.351571, Hs.112087, Hs.154224, Hs.l25950, Hs.438016 , Hs.367956, Hs.553778, Hs.329266, Hs.479658, Hs.458713, Hs.249196, Hs.467529, Hs.145061, Hs.49653, Hs.129227, Hs.313343, Hs.194554, Hs l23114, Hs.126561, Hs.42091, Hs.369385, Hs.98661, Hs.458306, Hs.148584, Hs.501684, Hs.422466, Hs.523732, Hs.525557, Hs.l372, Hs.379097 , Hs.208124, Hs.389311, Hs.2561, Hs.117545, Hs.446388, Hs.2813, Hs.473894, Hs.502092, Hs.524479, Hs.314261, Hs.382306, Hs.458252, Hs .380222, Hs.379636, Hs.302034, Hs.253495, Hs.345877, Hs.25956 3, Hs.528569, Hs.152337, Hs.436317, Hs.546408, Hs.46700, Hs.l027, Hs. 151219, Hs.279611, Hs.310456, Hs.520319, Hs.406976, Hs.181245, Hs.449621, Hs.5154 65, Hs.310540, Hs.554891, Hs.449601, Hs.355394, Hs.380710 , Hs.171995, Hs.44 9585, Hs.522484, Hs.298023, Hs.52 0339, a gene having Hs.121443, or a variant, homologue or derivative thereof,

 The gene set belonging to the non-TRU type has the following UniGene registration number:

Hs.62661, Hs.200804, Hs.533185, Hs.461329, Hs.479270, Hs.446201, Hs.35086, Hs.500761, Hs.44298, Hs.469030, Hs.309767, Hs.441047, Hs. 98309, Hs.31409, Hs.518299, Hs.532870, Hs.196534, Hs.108106, Hs.289319, Hs.69771, Hs.374378, Hs.369422, Hs.368641, Hs.302963, Hs.530461 , Hs.l955, Hs.513726, Hs.148767, Hs.523220, Hs.525796, Hs.271264, Hs.69321, Hs.231367, Hs.500761, Hs.528304, Hs.148685, Hs.87417, Hs .164060, Hs.514843, Hs.418416, Hs.126521, Hs.51983 9, Hs.103834, Hs.279840, Hs.497741, Hs.531457, Hs.226390, Hs.480143, Hs.473 721, Hs .369762, Hs.514527, Hs.204238, Hs.3104, Hs.519873, Hs.519909, Hs.179 718, Hs.l03183, Hs.520210, Hs.444683, Hs.234545, Hs.80976, Hs. 311187, Hs.89 497, Hs.444118, Hs.541635, Hs.477898, Hs.511776, Hs.434886, Hs.117299, Hs.2 52451, Hs.468058, Hs.21554, Hs.165904, Hs. 445244, Hs.413924, Hs.99120, Hs.5 21171, Hs.462379, Hs.481860, Hs.489207 Hs.414407, Hs.505575, Hs.516826, Hs.62180, Hs.368934, Hs.530509, Hs.278906, Hs.511987, Hs.444082, Hs.471873, Hs.24583, or a gene thereof A variant, homologue or derivative, The gene set belonging to the TRU-a type has the following UniGene registration number:

Hs.220629, Hs.153322, Hs.127821, Hs.218366, Hs.436996, Hs.247824, Hs.55052 6, Hs.62604, Hs.104555, Hs.465720, Hs.480281, Hs.495480, Hs .545862, Hs.1051, Hs.l33062, Hs.115263, Hs.349470, Hs.495774, Hs.155538, Hs.435759, Hs.1280 41, Hs.465643, Hs.169943, Hs.534496, Hs. 379010, Hs.184507, Hs.469359, Hs.20 12, Hs.l09358, Hs.438016, Hs.326561, Hs.367956, Hs.271285, Hs.176626, Hs.13 7556, Hs.437806, Hs. 240457, Hs.533055, Hs.532492, Hs.85962, Hs.268698, Hs.5 20627, Hs.524479, Hs.449585, Hs.158339, Hs.522836, Hs.279580, Hs.444535, Hs .446388 , Hs.149769, Hs.513779, Hs.l03983, Hs.512756, Hs.348012, Hs.467529, Hs.434374, Hs.389311, Hs.49653, Hs.424542, Hs.436667, Hs.516036, Hs .533526, Hs.463079, Hs.310456, Hs.125950, Hs.351571, Hs.478930, Hs.483906, Hs.2595 63, Hs.249196, Hs.412792, Hs.183390, Hs.87191, Hs. 171995, Hs.117545, Hs.554 891, Hs.351544, Hs.368353, Hs.482417 Hs.l26561, Hs.154224, Hs.232696, Hs.5 20319, Hs.l53299, Hs.449621, Hs.502092, Hs.537722, Hs.127189, Hs.525589, Hs.476231, Hs.527095, Hs .511839, Hs.372773, Hs.112087, Hs.458252, Hs.181973, Hs.289319, Hs.25333, Hs.513075, Hs.356820, Hs.549577

 , Hs.380222, Hs.46700, Hs.129227, Hs.l00431, Hs.129493, Hs.173656, Hs.9613, Hs.301478, Hs.553740, Hs.151219, Hs.369385, Hs.525383, Hs .473721, Hs.37562 4, Hs.355236, Hs.116724, Hs.9613, Hs.418055, or a variant, homologue or derivative thereof, and

 The gene set belonging to the TRU-b type has the following UniGene registration number:

Hs.334873, Hs.180878, Hs.126521, Hs.519033, Hs.l87636, Hs.518448, Hs.32276 1, Hs.31409, Hs.524513, Hs.253495, Hs.436437, Hs.148989, Hs .279575, Hs.7566 8, Hs.470791, Hs.104476, Hs.494496, Hs.517549, Hs.278906, Hs.498586, Hs.183 617, Hs.499758, Hs.350065, Hs.511138, Hs l50793, Hs.129174, Hs.212606, Hs.2 75775, Hs.279611, Hs.496414, Hs.436142, Hs.282984, Hs.32417, Hs.69321, Hs.4 14629, Hs.502618, Hs .405755, Hs.480143, Hs.90250, Hs.436317, Hs.60371, Hs.

2 83683, Hs.208093, Hs.336768, Hs.1116459, Hs.l31673, Hs.42091, Hs.32417, Hs.7 5812, a gene having Hs.355394, or a variant, homologue or derivative thereof.

 UniGene registration number:

Hs.512690, Hs.153322, Hs.218366, Hs.220629, Hs.436996, Hs.435759, Hs.10455 5, Hs.247824, Hs.127821, Hs.480281, Hs.529117, Hs.545862, Hs .391561, Hs.479 372, Hs.533055, Hs.550526, Hs.322854, Hs.465720, Hs.356664, Hs.26630, Hs.53 4496, Hs.85962, Hs.211267, Hs.128041, Hs .534458, Hs.495774, Hs.437806, Hs.l 33062, Hs.501758, Hs.444535, Hs.495480, Hs.326561, Hs.483906, Hs.169943, Hs.271285, Hs.158339, Hs. 62604, Hs.469359, Hs.436657, Hs.8417, Hs.155538, Hs. 533526, Hs.512756, Hs.87191, Hs.463079, Hs.513779, Hs.476209, Hs.279580, Hs.351544, Hs.269408, Hs.134807, Hs.482417, Hs.176626, Hs.465643, Hs.183390, Hs.411299, Hs.234027, Hs.109358, Hs.103983, Hs.26216, Hs.534352, Hs. 240457, Hs.516036, Hs.144875, Hs.411312, Hs.l03989, Hs.537722, Hs.333130, Hs.5179 62, Hs.90250, Hs.478930, Hs.121629, Hs.l94061, Hs.520627 , Hs.348012, Hs.522 836, Hs.l376, Hs.520049, Hs.51 2856, Hs.355236, Hs.349470, Hs.476231, Hs.137 556, Hs.390567, Hs.368353, Hs.412792, Hs.449207, Hs.527095, Hs.118722, Hs.3 77090, Hs. 232696, Hs.447544, Hs.372773, Hs.222055, Hs.511839, Hs.153299, Hs .434374, Hs.287729, Hs.553740, Hs.l27189, Hs.497723,

Hs.l81973, Hs.173656, Hs.451956, Hs.184507, Hs.532492, Hs.370904, Hs.46046 8, Hs.520612, Hs.436667, Hs.l25116, Hs.459391, Hs.450320, Hs .149769, Hs.32 5890, Hs.356820, Hs.289319, Hs.73893, Hs.129493, Hs.515069, Hs.34560, Hs.47 7278, Hs.351571, Hs.112087, Hs.154224, Hs l25950, Hs.438016, Hs.367956, Hs. 553778, Hs.329266, Hs.479658, Hs.458713, Hs.249196, Hs.467529, Hs.145061, Hs.49653, Hs.129227, Hs.313343 , Hs.194554, Hs.l23114, Hs.126561, Hs.42091, Hs.369385, Hs.98661, Hs.458306, Hs.148584, Hs.501684, Hs.422466, Hs.523732, Hs.525557, Hs .l372, Hs.379097, Hs.208124, Hs.389311, Hs.2561, Hs.117545, Hs.446388, Hs.2813, Hs.473894, Hs.502092, Hs.524479, Hs.314261, Hs.382306 , Hs.458252, Hs.380222, Hs.379636, Hs.302034, Hs.253495, Hs.345877, Hs.25956 2T8S -sH T ^ S-sH SZ9TST • ^S H, 6S 9II ' ^S H 89Z9SS " ^S H S60802" ^S H S89S82 " ^S H TZS09" ^S HS ^ T08 ^ " ^S H SSZSO' SH 8T920S-sH 629 ^ T ^ " ^S H T2S69" ^S H, I ^S HH ^S H W9S ^S H, 96 'SH SS 2 "SH, 909W ^S H ΐ62Γ ^δ Η 6 OSI'SH, 8SIIIS'SH, S900SS' ^S H, 8SZ 66 ^" ^S H ZT9S8r ^s H 98S86 ^ " ^S H, 9068W ^S H 6½ TS" SH 96 ^ 6 ^ " ^S H 9 ^ 0F ^S H ΐ 6L0LV ^S H 899SZ" SH, SZS6W ^S H, 6868 I ' ^S HL £ 9 £ V ^s H

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.686TC / 900Zdf / X3d 8 o / OOZ OAV The method according to claim 1, wherein each of the genes having the sequence comprises a sequence shown in SEQ ID NOs: 1 to 351 or a complementary sequence thereof.

[3] When the difference in the expression level of the gene belonging to the TRU-type or non-TRU-type adenocarcinoma is relatively larger than the difference in the expression level of the gene belonging to the non-TRU-type or TRU-type adenocarcinoma, respectively, The method according to claim 1 or 2, wherein the adenocarcinoma is determined as TRU-type adenocarcinoma or non-TRU-type adenocarcinoma, respectively.

 [4] Difference in expression level of the gene belonging to the TRU-a type or TRU-b adenocarcinoma relative to the difference in the expression level of the gene belonging to TRU-b type or TRU-a adenocarcinoma, respectively The method according to claim 1 or 2, wherein the adenocarcinoma is determined to be a TRU-a type adenocarcinoma or a non-TRU type-b adenocarcinoma, respectively, when it is particularly large.

 [5] The method according to any one of claims 1 to 4, wherein the expression level of the gene is determined by measuring the presence or amount of a nucleic acid or protein corresponding to the gene.

 [6] The method according to any one of claims 1 to 5, wherein the expression level of the gene is measured by a hybridization method.

[7] The method according to [6], wherein the hybridization method is a microarray method or a plotting method.

 [8] The method according to any one of claims 1 to 5, wherein the expression level of the gene is measured by an immunological method.

[9] The method according to claim 8, wherein the immunological method comprises detecting an immunological complex of a specific antibody against a protein encoded by the gene or a fragment thereof and a target protein.

 [10] In the TRU-type lung adenocarcinoma, when the epidermal growth factor receptor (EGFR) gene contains a mutation, the postoperative prognosis of the patient is poorer than that of the lung adenocarcinoma containing the wild-type EGFR gene. 10. The method of any one of claims 1-9, further comprising predicting that there is.

[11] A method for classifying lung adenocarcinoma into TRU type or non-TRU type subtypes, and then classifying TRU type into TRU-a type or TRU-b type, The method is for TRU adenocarcinoma for one or more genes of the corresponding set of genes below in a patient biological sample: The relative expression level difference between non-TRU type adenocarcinoma or between TRU-a type adenocarcinoma and TRU-b type adenocarcinoma was measured, and the gene showing the difference in the expression level was

 (a) The following UniGene registration numbers:

Hs.512690, Hs.153322, Hs.218366, Hs.220629, Hs.436996, Hs.435759, Hs.10455 5, Hs.247824, Hs.127821, Hs.480281, Hs.529117, Hs.545862, Hs .391561, Hs.479 372, Hs.533055, Hs.550526, Hs.322854, Hs.465720, Hs.356664, Hs.26630, Hs.53 4496, Hs.85962, Hs.211267, Hs.128041, Hs .534458, Hs.495774, Hs.437806, Hs.l 33062, Hs.501758, Hs.444535, Hs.495480, Hs.326561, Hs.483906, Hs.169943, Hs.271285, Hs.158339, Hs. 62604, Hs.469359, Hs.436657, Hs.8417, Hs.155538, Hs. 533526, Hs.512756, Hs.87191, Hs.463079, Hs.513779, Hs.476209, Hs.279580, Hs.351544, Hs.269408, Hs.134807, Hs.482417, Hs.176626, Hs.465643, Hs.183390, Hs.411299, Hs.234027, Hs.109358, Hs.103983, Hs.26216, Hs.534352, Hs. 240457, Hs.516036, Hs.144875, Hs.411312, Hs.l03989, Hs.537722, Hs.333130, Hs.5179 62, Hs.90250, Hs.478930, Hs.121629, Hs.l94061, Hs.520627 , Hs.348012, Hs.522 836, Hs.l376, Hs.520049, Hs.51 2856, Hs.355236, Hs.349470, Hs.476231, Hs.137 556, Hs.390567, Hs.368353, Hs.412792, Hs.449207, Hs.527095, Hs.118722, Hs.3 77090, Hs. 232696, Hs.447544, Hs.372773, Hs.222055, Hs.511839, Hs.153299, Hs .434374, Hs.287729, Hs.553740, Hs.l27189, Hs.497723,

Hs.l81973, Hs.173656, Hs.451956, Hs.184507, Hs.532492, Hs.370904, Hs.46046 8, Hs.520612, Hs.436667, Hs.l25116, Hs.459391, Hs.450320, Hs .149769, Hs.32 5890, Hs.356820, Hs.289319, Hs.73893, Hs.129493, Hs.515069, Hs.34560, Hs.47 7278, Hs.351571, Hs.112087, Hs.154224, Hs l25950, Hs.438016, Hs.367956, Hs. 553778, Hs.329266, Hs.479658, Hs.458713, Hs.249196, Hs.467529, Hs.145061, Hs.49653, Hs.129227, Hs.313343 , Hs.194554, Hs.l23114, Hs.126561, Hs.42091, Hs.369385, Hs.98661, Hs.458306, Hs.148584, Hs.501684, Hs.422466, Hs.523732, Hs.525557, Hs .l372, Hs.379097, Hs.208124, Hs.389311, Hs.2561, Hs.117545, Hs.446388, Hs.2813, Hs.473894, Hs.502092, Hs.524479, Hs.314261, Hs.382306 , Hs.458252, Hs.380222, Hs.379636, Hs.302034, Hs.253495, Hs.345877, Hs.25956 3, Hs.528569, Hs.152337, Hs.436317, Hs.546408, Hs.46700, Hs.l027, Hs.151219, Hs.279611, Hs.310456, Hs.520319, Hs.406976, Hs.181245, Hs.449621, Hs.5154 65, Hs.310540, Hs.554891, Hs.449601, Hs.355394, Hs.380710, Hs.171995, Hs.44 9585, Hs.522484, Hs.298023, Hs.520339, If it is a gene in the gene set comprising Hs.121443, or a variant, homologue or derivative thereof, the lung adenocarcinoma is determined to be TRU type, or

 (b) The following UniGene registration numbers:

 Hs.62661, Hs.200804, Hs.533185, Hs.461329, Hs.479270, Hs.446201, Hs.35086, Hs.500761, Hs.44298, Hs.469030, Hs.309767, Hs.441047, Hs. 98309, Hs.31409, Hs.518299, Hs.532870, Hs.196534, Hs.108106, Hs.289319, Hs.69771, Hs.374378, Hs.369422, Hs.368641, Hs.302963, Hs.530461 , Hs.l955, Hs.513726, Hs.148767, Hs.523220, Hs.525796, Hs.271264, Hs.69321, Hs.231367, Hs.500761, Hs.528304, Hs.148685, Hs.87417, Hs .164060, Hs.514843, Hs.418416, Hs.126521, Hs.51983 9, Hs.103834, Hs.279840, Hs.497741, Hs.531457, Hs.226390, Hs.480143, Hs.473 721, Hs .369762, Hs.514527, Hs.204238, Hs.3104, Hs.519873, Hs.519909, Hs.179 718, Hs.l03183, Hs.520210, Hs.444683, Hs.234545, Hs.80976, Hs. 311187, Hs.89 497, Hs.444118, Hs.541635, Hs.477898, Hs.511776, Hs.434886, Hs.117299, Hs.2 52451, Hs.468058, Hs.21554, Hs.165904, Hs. 445244, Hs.413924, Hs.99120, Hs.5 21171, Hs.462379, Hs.481860, Hs.489207 Hs.414407, Hs.505575, Hs.516826, Hs.62180, Hs.368934, Hs.530509, Hs.278906, Hs.511987, Hs.444082, Hs.471873, Hs.24583, or a gene thereof If the gene is in a gene set consisting of a mutant, homologue or derivative, the lung adenocarcinoma is determined to be non-TRU, or

(c) UniGene registration number:

Hs.220629, Hs.153322, Hs.127821, Hs.218366, Hs.436996, Hs.247824, Hs.55052 6, Hs.62604, Hs.104555, Hs.465720, Hs.480281, Hs.495480, Hs .545862, Hs.1051, Hs.l33062, Hs.115263, Hs.349470, Hs.495774, Hs.155538, Hs.435759, Hs.1280 41, Hs.465643, Hs.169943, Hs.534496, Hs. 379010, Hs.184507, Hs.469359, Hs.20 12, Hs.l09358, Hs.438016, Hs.326561, Hs.367956, Hs.271285, Hs.176626, Hs.13 7556, Hs.437806, Hs.240457, Hs.533055, Hs.532492, Hs.85962, Hs.268698, Hs.5 20627, Hs.524479, Hs.449585, Hs.158339, Hs.522836, Hs.279580 , Hs.444535, Hs .446388, Hs.149769, Hs.513779, Hs.l03983, Hs.512756, Hs.348012, Hs.467529, Hs.434374, Hs.389311, Hs.49653, Hs.424542, Hs .436667, Hs.516036, Hs.533526, Hs.463079, Hs.310456, Hs.125950, Hs.351571, Hs.478930, Hs.483906, Hs.2595 63, Hs.249196, Hs.412792, Hs. 183390, Hs.87191, Hs.171995, Hs.117545, Hs.554 891, Hs.351544, Hs.368353, Hs.482417, Hs.l26561, Hs.154224, Hs.232696, Hs.5 20319, Hs. l53299, Hs.449621, Hs.502092, Hs.537722, Hs.127189, Hs.525589, Hs.476231, Hs.527095, Hs.511839, Hs.372773, Hs.112087, Hs.458252, Hs.181973, Hs.289319, Hs.25333, Hs.513075, Hs.356820, Hs.549577

 , Hs.380222, Hs.46700, Hs.129227, Hs.l00431, Hs.129493, Hs.173656, Hs.9613, Hs.301478, Hs.553740, Hs.151219, Hs.369385, Hs.525383, Hs 473721, Hs.37562 4, Hs.355236, Hs.116724, Hs.9613, Hs.418055, or a gene in a gene set comprising a variant, homologue or derivative thereof, the lung gland Determine that the cancer is TR Ua type, or

 (d) UniGene registration number:

Hs.334873, Hs.180878, Hs.126521, Hs.519033, Hs.l87636, Hs.518448, Hs.32276 1, Hs.31409, Hs.524513, Hs.253495, Hs.436437, Hs.148989, Hs .279575, Hs.7566 8, Hs.470791, Hs.104476, Hs.494496, Hs.517549, Hs.278906, Hs.498586, Hs.183 617, Hs.499758, Hs.350065, Hs.511138, Hs l50793, Hs.129174, Hs.212606, Hs.2 75775, Hs.279611, Hs.496414, Hs.436142, Hs.282984, Hs.32417, Hs.69321, Hs.4 14629, Hs.502618, Hs .405755, Hs.480143, Hs.90250, Hs.436317, Hs.60371, Hs.2 83683, Hs.208093, Hs.336768, Hs.1116459, Hs.l31673, Hs.42091, Hs.32417, Hs. 7 5812, if it is a gene in a gene set consisting of a gene having Hs.355394, or a variant, homologue or derivative thereof, the lung adenocarcinoma is determined to be TRU-b type. .

 UniGene registration number:

Hs.512690, Hs.153322, Hs.218366, Hs.220629, Hs.436996, Hs.435759, Hs.10455

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SS'sH 0S992 " ^S H 999SS ' ^S H 02 S9 ^" ^S H, S8 ^ S' ^S H 92S0eS "SH SS0SSS" SH ^ ZLZ UY T9ST6S " ^S H 298S½" SH n62S "SH T8208 ^" ^S H, 8 ^ ^S H, W8ZW ^S HS

8Z .686TC / 900Zdf / X3d 8 o / OOZ OAV Hs.62661, Hs.200804, Hs.533185, Hs.461329, Hs.479270, Hs.446201, Hs.35086, Hs.500761, Hs.44298, Hs.469030, Hs.309767, Hs.441047, Hs. 98309, Hs.31409, Hs.518299, Hs.532870, Hs.196534, Hs.108106, Hs.289319, Hs.69771, Hs.374378, Hs.369422, Hs.368641, Hs.302963, Hs.530461 , Hs.l955, Hs.513726, Hs.148767, Hs.523220, Hs.525796, Hs.271264, Hs.69321, Hs.231367, Hs.500761, Hs.528304, Hs.148685, Hs.87417, Hs .164060, Hs.514843, Hs.418416, Hs.126521, Hs.51983 9, Hs.103834, Hs.279840, Hs.497741, Hs.531457, Hs.226390, Hs.480143, Hs.473 721, Hs .369762, Hs.514527, Hs.204238, Hs.3104, Hs.519873, Hs.519909, Hs.179 718, Hs.l03183, Hs.520210, Hs.444683, Hs.234545, Hs.80976, Hs. 311187, Hs.89 497, Hs.444118, Hs.541635, Hs.477898, Hs.511776, Hs.434886, Hs.117299, Hs.2 52451, Hs.468058, Hs.21554, Hs.165904, Hs. 445244, Hs.413924, Hs.99120, Hs.5 21171, Hs.462379, Hs.481860, Hs.489207 Hs.414407, Hs.505575, Hs.516826, Hs .62180, Hs.368934, Hs.530509, Hs.278906, Hs.511987, Hs.444082, Hs.471873, H s.24583,

 Hs.l051, Hs.115263, Hs.379010, Hs.2012, Hs.268698, Hs.49653, Hs.424542, Hs.525589, Hs.25333, Hs.513075, Hs.549577, Hs.l00431, Hs. 9613, Hs.301478, Hs.5 53740, Hs.525383, Hs.473721, Hs.375624, Hs.l l6724, Hs.9613, Hs.418055, Hs.334873, Hs.180878, Hs.126521, Hs. 519033, Hs.l87636, Hs.518448, Hs.32276 1, Hs.31409, Hs.524513, Hs.436437, Hs.148989, Hs.279575, Hs.75668, Hs.47079 1, Hs.104476, Hs. 494496, Hs.517549, Hs.278906, Hs.498586, Hs.183617, Hs.499 758, Hs.350065, Hs.511138, Hs.150793, Hs.l29174, Hs.212606, Hs.275775, Hs.4 96414, Hs.436142, Hs.282984, Hs.32417, Hs.69321, Hs.414629, Hs.502618, Hs.4 05755, Hs.480143, Hs.60371, Hs.283683, Hs.208093, Hs.336768 , Hs.1116459, Hs.131673, Hs.32417, Hs.75812

The method according to claim 11, wherein each of the genes having the sequence comprises a sequence shown in SEQ ID NOs: 1 to 351 or a complementary sequence thereof.

The method according to claim 11 or 12, wherein the expression level of the gene is measured by a hybridization method. The method according to claim 13, wherein the hybridization method is a microarray method or a plotting method.

 The following UniGene registration numbers:

Hs.512690, Hs.153322, Hs.218366, Hs.220629, Hs.436996, Hs.435759, Hs.10455 5, Hs.247824, Hs.127821, Hs.480281, Hs.529117, Hs.545862, Hs .391561, Hs.479 372, Hs.533055, Hs.550526, Hs.322854, Hs.465720, Hs.356664, Hs.26630, Hs.53 4496, Hs.85962, Hs.211267, Hs.128041, Hs .534458, Hs.495774, Hs.437806, Hs.l 33062, Hs.501758, Hs.444535, Hs.495480, Hs.326561, Hs.483906, Hs.169943, Hs.271285, Hs.158339, Hs. 62604, Hs.469359, Hs.436657, Hs.8417, Hs.155538, Hs. 533526, Hs.512756, Hs.87191, Hs.463079, Hs.513779, Hs.476209, Hs.279580, Hs.351544, Hs.269408, Hs.134807, Hs.482417, Hs.176626, Hs.465643, Hs.183390, Hs.411299, Hs.234027, Hs.109358, Hs.103983, Hs.26216, Hs.534352, Hs. 240457, Hs.516036, Hs.144875, Hs.411312, Hs.l03989, Hs.537722, Hs.333130, Hs.5179 62, Hs.90250, Hs.478930, Hs.121629, Hs.l94061, Hs.520627 , Hs.348012, Hs.522 836, Hs.l376, Hs.520049, Hs.51 2856, Hs.355236, Hs.349470, Hs.476231, Hs.137 556, Hs.390567, Hs.368353, Hs.412792, Hs.449207, Hs.527095, Hs.118722, Hs.3 77090, Hs. 232696, Hs.447544, Hs.372773, Hs.222055, Hs.511839, Hs.153299, Hs .434374, Hs.287729, Hs.553740, Hs.l27189, Hs.497723,

Hs.l81973, Hs.173656, Hs.451956, Hs.184507, Hs.532492, Hs.370904, Hs.46046 8, Hs.520612, Hs.436667, Hs.l25116, Hs.459391, Hs.450320, Hs .149769, Hs.32 5890, Hs.356820, Hs.289319, Hs.73893, Hs.129493, Hs.515069, Hs.34560, Hs.47 7278, Hs.351571, Hs.112087, Hs.154224, Hs l25950, Hs.438016, Hs.367956, Hs. 553778, Hs.329266, Hs.479658, Hs.458713, Hs.249196, Hs.467529, Hs.145061, Hs.49653, Hs.129227, Hs.313343 , Hs.194554, Hs.l23114, Hs.126561, Hs.42091, Hs.369385, Hs.98661, Hs.458306, Hs.148584, Hs.501684, Hs.422466, Hs.523732, Hs.525557, Hs .l372, Hs.379097, Hs.208124, Hs.389311, Hs.2561, Hs.117545, Hs.446388, Hs.2813, Hs.473894, Hs.502092, Hs.524479, Hs.314261, Hs.382306 , Hs.458252, Hs.380222, Hs.379636, Hs.302034, Hs.253495, Hs.345877, Hs.25956 2T8S -sH T ^ S-sH SZ9TST • ^S H, 6S 9II ' ^S H 89Z9SS " ^S H S60802" ^S H S89S82 " ^S H TZS09" ^S HS ^ T08 ^ " ^S H SSZSO' SH 8T920S-sH 629 ^ T ^ " ^S H T2S69" ^S H, I ^S HH ^S H W9S ^S H, 96 'SH SS 2 "SH, 909W ^S H ΐ62Γ ^δ Η 6 OSI'SH, 8SIIIS'SH, S900SS' ^S H, 8SZ 66 ^" ^S H ZT9S8r ^s H 98S86 ^ " ^S H, 9068W ^S H 6½ TS" SH 96 ^ 6 ^ " ^S H 9 ^ 0F ^S H ΐ 6L0LV ^S H 899SZ" SH, SZS6W ^S H, 6868 I ' ^S HL £ 9 £ V ^s H

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1-8 .686TC / 900Zdf / X3d 8 o / OOZ OAV A nucleic acid capable of detecting the expression of a gene having the above, or a variant, homologue or derivative thereof,

 (1) a nucleotide sequence represented by SEQ ID NOs: 1-351,

 (2) a nucleotide sequence comprising the nucleotide sequence shown in SEQ ID NOs: 1-351,

(3) a nucleotide sequence complementary to the nucleotide sequence of (1) or (2),

 (4) The nucleotide sequence that is hybridized under stringent conditions with any one of the sequences (1), (2), or (3), and

 (5) a partial sequence of less than the total number of bases from 15 bases of the nucleotide sequence of (1), (3) or (4),

An operation for a patient with lung adenocarcinoma comprising a nucleic acid having a sequence selected from the group consisting of: an antibody against a protein or fragment encoded by the gene, or a variant, homologue or derivative thereof, or a fragment thereof. A composition for predicting prognosis in vitro or for classifying lung adenocarcinoma into a subtype of TRU, non-TRU, TRU-a or TRU-b.

 The composition according to claim 15, wherein the composition is in the form of a kit or a DNA chip or a protein array.