WO2006112483A1 - Methode de diagnotic et methode de pronostic d'un type de lymphome diffus a grandes cellules b - Google Patents

Methode de diagnotic et methode de pronostic d'un type de lymphome diffus a grandes cellules b Download PDF

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WO2006112483A1
WO2006112483A1 PCT/JP2006/308235 JP2006308235W WO2006112483A1 WO 2006112483 A1 WO2006112483 A1 WO 2006112483A1 JP 2006308235 W JP2006308235 W JP 2006308235W WO 2006112483 A1 WO2006112483 A1 WO 2006112483A1
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region
type
nucleic acid
human chromosome
human
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PCT/JP2006/308235
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Japanese (ja)
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Masao Seto
Hiroyuki Tagawa
Yasuko Yoshida
Shigeki Kira
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Aichi Prefecture
Ngk Insulators, Ltd.
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Publication of WO2006112483A1 publication Critical patent/WO2006112483A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification

Definitions

  • the present invention relates to diagnosis of a disease type of diffuse large B-cell lymphoma (DLBCL) and prognosis of DLBCL.
  • DLBCL diffuse large B-cell lymphoma
  • Diffuse large B-cell lymphoma is the most common non-Hodgkin's lymphoma and is known to include pathophysiologically distinct groups (Harris NL, Jaffe Eb, btein H, et al. A revised European- American classification of lym phoid neoplasms: a proposal from the International Lymphoma Study Group.Blood. 1994; 84: 1361-1392, Offit K, Le Coco F, Louie DC, et N Engl J Med 1994; 331: 74—80, Kramer MHH, Hermans J, Wijburg E, et al. Clinical relevance of BCL2, B CL6, and MYC al.
  • BCL6 gene Rearrangement of BCL6 gene as a prognostic marker in diffuse large cell lymphoma. rearrangements in diffuse large B— cell lymphoma. Blood. 1998; 92: 3 152—3162, Gatter KC and Warnke RA. Diffuse large B— cell lymphoma, In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World health classification of tumors.Pathol ogy & Genetics of tumors of haematopoietic and lymphoid tissues.Washington: IAR C press, Lyon; 2001. 171 -174).
  • DLBCL is also known to have clinical heterogeneity because patients have significantly different clinical courses (Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with Three intensive chemotherapy regimens for advanced non—Hodgkin s lymphoma. N Engl J Med. 1993; 328: 1002-10 06.). For this reason, there is interest in the importance of subgroup identification in heterogeneous DLBCL.
  • the ABC group expresses genes specific to activated B cells and plasma cells, while the GCB group maintains a normal germinal center B cell gene expression program (Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffiise lar ge B— cell lymphoma identified by gene expression profiling. Nature. 2000; 403: 503— 511, Wright G, Tan B, Rosenwald A, et al. A gene expression-based method to diag nose Clinically distinct subgroups of diffiise large B cell lymphoma.Proc Natl Acad S ci USA. 2003; 100: 9991-9996, Rosenwald A, Wright G, Chan WC, et al.
  • CD5 +, CD5-CD10 +, and CD5-CD10- have been identified (Harada S, Suzuki R, Uehira K, et al. Molecular and immunological dissection of large B cell lymphoma: CD5 + and CD5 with CD10 + groups may constitute clinically relevant subtypes. Leukemi a. 1999; 13: 1441-1447).
  • the CD5 + group has been shown to account for approximately 10% of all DLBCL cases. This has a CD5 + C10—CD19 + CD20—CD21—CD23—cyclin D1—phenotype and a prognosis over CD5 ”DLBCL.
  • CD5—CD10 + gnole has a lower expression frequency of BCL2 protein than other groups, and usually expresses BCL2. A clear association with normal germinal center cells lacking the CD5-CD10-group was observed most frequently, and the expression rate of BCL6 gene rearrangement was higher than the other two groups. Bur, the disclosure of the difference is not significant (Harada S et al) 0 invention
  • an object of the present invention is to provide a technique for easily diagnosing a subgroup of DLBCL, which greatly affects mortality and prognosis.
  • Another object of the present invention is to provide a method for diagnosing prognosis of DLBCL.
  • the present inventors used a comparative genomic hybridization (microarray CGH method) that uses an array to identify genomic imbalance features of different subgroups of DLBCL (Ota A, fagawa H, Karnan S, et ai. Iaentincation and cnaractenzation of a novel gene, shi 13orl25, as a target for 13q31— q32 amplification in malignant lymphoma. Cancer Res. 2004; 64: 3087-3095, Tagawa H, Tsuzuki S, Suzuki R, et al. Genome-wide array-based comparative genomic hybridization of diffuse large B— cell lymphoma: comparis on between CD5— Positive and CD5— negative cases. Cancer Res.
  • a diffuse large cell type comprising a detection step of detecting an amplified region and Z or a defective region of a human chromosome in a test sample containing a chromosome collected from a human.
  • Methods for diagnosing B cell lymphoma pathology are provided.
  • the amplified region force detected in the detection step is selected from 3, 8q21-q26, Ilq21-q25, 16pl22-q24, 18, 19ql3 and X of the human chromosome.
  • Z or the deletion region is in one or more regions selected from 2pl l, 6ql2-27, 8p22-p23, 9p21 and 17p of the human chromosome It is possible to provide a determination step that positively determines that the disease type of the diffuse large B-cell lymphoma is ABC type, using whether or not it is an index. Further, in the determination step, the amplification region is 3p23-q28, 18ql l of human chromosome. .2-q23 and 9ql3.41-ql3.43 force selected if one or more are selected and said defective region is selected from 6q22.31-q24.1 and 9p21.3 of human chromosome 1 It may be a process using as an index whether there are two or more species.
  • the determination step may be a step using as an index whether the amplification region is 3q23-q28 and Z of a human chromosome or the deletion region is 9p21.3 of a human chromosome. Furthermore, the determination step may be a step of positively determining that the disease type is CD5 + type when the disease type is positively determined to be ABC type.
  • the amplified region force detected in the detection step is 1q22-32, 2pl4-p24, 5pl2-p, 5ql5-q31, 6pl2-p25, 7, 8q22 of the human chromosome.
  • a determination step of positively determining that the disease type of diffuse large B-cell lymphoma is GCB type may be provided using whether or not it is an indicator.
  • the amplification region is selected from human chromosomes q2 1.1-q23.3, lq31.1-q42.13, 2pl5-pl6.1, 7q22.1-q36.2 and 12ql3.1-ql4.
  • the determination step which may be performed using one or two or more types as an index, may be a step using whether or not the amplified region is in 7q22-q36 of a human chromosome.
  • the determination step may include a step of positively determining that the disease type is CD5-DC10 + when the disease type is positively determined to be GCB type.
  • the amplified region detected in the detection step is 3, 6p22-p25, 7p22-q31, 8q24, llq22-q25, 12, 16pl3-q21 of the human chromosome, 18, 19 and X force selected from one or more selected and Z or from the lp36, 2pll, 6ql4-q27, 8p23, 9p21, 15ql3-ql4 and 17pll-pl3 of the human chromosome
  • a step of positively determining that the disease type is CD5 + can be provided by using whether the disease type is one or more selected as an index.
  • the determination step includes determining whether the amplification region is a force of 3 of human chromosome and Z or whether the deletion region is 9p2 of human chromosome. As a process that uses this as an index.
  • the amplification region detected in the detection step is human chromosome lq, 2pl3-p25, 6p21-p25, 7, 8q22-q24, 9q33-q34, 12, 13q31-q33, 15q, 16pl3, 19ql3.3-13.4 and whether it is in one or more selected from X and Z or the deleted region is 1 ⁇ 36, 1 ⁇ 22, 2pll, 3pl4, 4p, human chromosome A determination step of positively determining that the disease type is CD5-CD10 + using one or more selected from 6ql3-q27, 9p2 1 and 13ql4-q21 as an index may be provided .
  • the determination step includes determining whether the amplification region is one or more selected from 7q22-q36 and 12ql3-ql4 of human chromosome, and Z or 17 pl3 of the deletion region of human chromosome. It is good also as a process using as an index whether it is.
  • the detection step includes a step of performing any one of a PCR method, an RT-PCR method and a nucleic acid hybridization on the region in the test sample. And a step of hybridizing a probe containing a region on the human chromosome with a nucleic acid in the test sample.
  • the detection step may be a step of performing an array CGH method.
  • nucleic acid probe for diagnosing the disease type of diffuse large B-cell lymphoma, on the human chromosome in ABC-type diffuse large B-cell lymphoma.
  • nucleic acid probes capable of detecting the amplification region and the Z or deletion region.
  • This nucleic acid probe supplies a test sample collected from a human individual suffering from ABC type diffuse large B cell lymphoma to an array in which nucleic acid probes derived from a predetermined range of human chromosomes are immobilized. Based on the log ratio value of the fluorescence intensity obtained at the fixed site of the nucleic acid probe by performing nucleic acid hybridization.
  • Nucleic acid selected based on the magnitude of the log ratio with respect to a predetermined predetermined upper and lower threshold
  • a probe can be included.
  • nucleic acid probe for diagnosing a disease type of diffuse large B-cell lymphoma, on a human chromosome in a GCB-type diffuse large B-cell lymphoma.
  • nucleic acid probes capable of detecting the amplification region and the Z or deletion region.
  • This nucleic acid probe is a nucleic acid probe derived from a predetermined range of human chromosomes.
  • Immobilizing the nucleic acid probe by supplying a test sample collected from a diffuse large B-cell lymphoma affected by GCB to an array with fixed lobes and performing a nucleic acid hybridization Set based on the log ratio value of fluorescence intensity obtained at the site.
  • Nucleic acid selected based on the magnitude of the log ratio with respect to a predetermined predetermined upper and lower threshold
  • a probe can be included.
  • an array for diagnosing a disease type of diffuse large B-cell lymphoma to which the nucleic acid probe described above is immobilized.
  • This array is selected from human chromosomes 3, 8q21-q26, Ilq21-q25, 16pll-pl3, 16q22-q24, 18, 19ql3, X, 2pll, 6ql2-27, 8p22-p23, 9p21, 17p 1
  • a nucleic acid probe capable of detecting at least a part of a species or two or more regions may be immobilized.
  • This array also includes human chromosomes lq22-32, 2pl4-p24, 5pl2-pl5, 5ql5-q31, 6 pl2—p25, 7, 8q22—q26, 9q33—q34, llq, 12, 13q31—q33, 16pll — Pl3, 18q21—from q23, 1 9p, 19ql3, 21q, X, lp36, 2pll, 3pl4, 4pl2—pl3, 4q33—q34, 6ql4—ql6, 8p22—p23, 9p21, 13ql2-q22, 17pl2, and 18q22-q23
  • a nucleic acid probe capable of detecting at least a part of one or two or more selected regions may be immobilized.
  • a prognostic diagnosis method for diffuse large B-cell lymphoma wherein a test sample containing a chromosome collected from a human is subjected to 9p21 of human chromosome.
  • a method comprising a detection step of detecting a defect or mutation.
  • the detecting step may be a step of performing a hybridization on a probe including a region on the human chromosome and the test sample.
  • the detection step can be a step using array CGH.
  • the detection step can be a step of detecting a deletion or mutation of the pl6 INK4a gene.
  • the detection step may be a step of detecting the presence / absence, expression level or mutation of the protein encoded by the pl6 INK4a gene.
  • an array for prognosis of diffuse large B-cell lymphoma wherein an array of nucleic acid probes for detecting 9p21 of human chromosome is immobilized. Is provided.
  • At least a part of human chromosome 9p21 is detected.
  • a prognostic marker for diffuse large B-cell lymphoma is provided.
  • the polynucleotide can be a polynucleotide having a pl6 INK4a gene, a part thereof, or a base sequence complementary thereto.
  • a prognostic marker for diffuse large B-cell lymphoma which is a protein encoded by the pl6 INK4a gene, a part thereof, or an antibody thereto.
  • FIG. 1 Force plan Meyer analysis of different subgroups.
  • A shows force plan Meyer analysis of ABC (26 cases) and G CB (17 cases).
  • B shows force plan Meyer analysis of CD5 + (33 cases), CD5—CD10 + (19 cases) and CD5—CD10— (44 cases).
  • FIG. 2 Hierarchical cluster of DLBCL cases. 46 cases (22 cases of CD5 +, 7 cases of CD5_CD10 +, 17 cases of CD5—CD10—) force Clustered by Treeview software based on the expression of 67 out of 100 genes described by Rosenwald et al. It was done. The relative expression level of each specimen is shown in the lower part. Samples were divided into two subgroups: ABC (left side) and GC B (right side).
  • FIG. 3 Shows typical features of the genomic profile of DLBCL cases.
  • Two CD5-CD10 cases (A) shows ABC signature and (B) shows GCB signature.
  • Gene amplification 3p26.3— ql2.3, 3ql3.33— q29, 4q32.1-q35.1, 9p24.3-q22.33, 17pll.2-q21.1, 17q 21.32, 17q23.2 -q24.2, and 18q; gene deletion: 9p21.3 (arrow), 13ql4.3-q21.2, 15q21. 3, 17pll.2-pl3.3, and 17q21.33-q22 0 Occurs only in BAC RP11-149 12 (see arrow) containing pl6 INK1 ⁇ 2 .
  • FIG. 4 shows the characteristics of genomic imbalance of DLBCL ABC type and GCB type.
  • A shows a summary of chromosomal imbalances in 28 cases in the ABC group and (B) in 18 cases in the GCB group.
  • the left (red) line supports the deficit and the right (green) indicates amplification.
  • It left square red, homo-deficient (Lo g 2 draw - 1.0) indicates, right green squares, shows the high degree of amplification in the right (Log 2 ratio> +1.0).
  • FIG. 5 shows the genome-wide gene imbalance frequency of the distinguished DLBCL subgroups.
  • Horizontal line Clone 2213 BAC / PAC in order from chromosome 1 to chromosome 22 and chromosome X. Based on the information from the Institute Institute of Information (November 2004 version) within each chromosome [Konii ii, Ensembl Genome Data Resources of Sanger], it is shown in order from p telomer to q telomer.
  • Vertical line shows the frequency (%) of amplification and loss.
  • (A) shows ABC group (28 cases), GCB group (18 cases), and the total of ABC group and GCB group (46 cases).
  • FIG. B shows CD5 + group (36 cases), CD5-CD10 + group (19 cases) and CD5-CD10- group (44 cases).
  • the characteristics of genomic disequilibrium in the CD5 + and CD5-CD10 + groups were similar to those in the ABC and GCB groups, respectively.
  • the region of genomic imbalance in the CD5-CD10 group showed a pattern similar to that of the ABC group and GC B group.
  • FIG. 6 shows 9p21.3 gene deletion, overall survival rate, and pl6INK4a gene in ABC and GCB groups.
  • A shows the power plan Meyer survival rate in all cases, ABC cases, CD + cases and CD5-CD10-cases with or without 9p21.3 (pl6INK4a locus) deficiency.
  • B shows a representative individual genomic profile of 9p21 in 3 cases. The dots indicate the BAC / PAC clone log2 ratio for both p and q telomeres, and the bold line in each profile indicates the missing region.
  • MCR shows the smallest common region in the 9p region, the vertical line is log
  • the present invention relates to an amplification region of a human chromosome in a test sample containing a chromosome collected from a human and It is characterized by diagnosing a DLBCL disease type based on a defective region.
  • a DLBCL disease type can be easily diagnosed by examining human chromosome amplification regions and Z or deletion regions in test samples containing chromosomes collected from DLBCL-affected human individuals.
  • DLBCL disease types are already more malignant by expression analysis and have been classified into ABC type and GCB type. According to the present invention, these disease types can be easily diagnosed.
  • the diagnosis or determination of the disease type is to determine whether a DLBCL patient is ABC type or GCB type, or is DLBCL patient a CD5 + type force CD5-CD10 + type? Is to judge. Such a determination has a characteristic amplification region and Z or a defective region in one of the disease types to be determined, and whether or not it has high frequency in one disease type. Can be based on the number of detected regions.
  • the present invention can be implemented in the form of a diagnostic method and array.
  • the present invention is characterized in that the prognosis of DLBCL is diagnosed based on a 9p21 deletion or mutation of a human chromosome in a test sample containing a chromosome collected from a human.
  • DLBCL prognosis can be easily and accurately performed. Prognosis enables more appropriate selection of treatment.
  • the determination of whether or not the prognosis is made is to determine whether “good prognosis” or “poor prognosis”.
  • “Good prognosis” means that when the force-plan Meier curves are compared between DLBCL patients with two types of disease, the p-value of the log rank test is a significant difference of 0.05 or less and the survival rate indicates the patient group. Can be.
  • “poor prognosis” can indicate a patient group in which the p-value of the log-rank test comparing force-plan Meyer curves is a significant difference of 0.05 or less and the survival rate is poor. Since 9p21 of the human chromosome corresponds to the pl6 INK4a gene, the prognosis of DLBCL can also be diagnosed by detecting the presence of the gene, its expression level, and mutation.
  • the present invention can be implemented in the form of a diagnostic method, an array, and a diagnostic marker.
  • Chromosome amplification and deletion regions that serve as indicators for diagnosing DLBCL disease types are determined using chromosome-containing samples collected from human individuals with DLBCL whose disease type has been previously diagnosed by expression analysis, etc. be able to. Determine amplification and deletion regions as indicators To do so, it is preferable to use array CGH.
  • array CGH the words of high frequency amplification and high frequency loss are defined in detail in the examples described later.
  • Amplification regions useful for determining DLBCL ABC type include amplification regions characteristic of ABC type from the frequency graph of genomic imbalance shown in Table 3 and FIG. 5 of Examples described later. It is done. For example, 3, 8q21-q26, llq21-q25, 16pll-pl3, 16q22-q24, 18, 19ql3 of human chromosome and one or more regions selected from X force can be mentioned. These regions are also forces that are high frequency amplification regions in the ABC type. Among them, 3p23_q28, 18 qll.2-q23 and 9ql3.41-ql3.43 force One or more selected regions are more characteristic for the higher frequency or ABC type. Furthermore, 3q23_q28 is an amplification region characteristic of ABC type.
  • a defective region useful for determining that it is the ABC type of DLBCL a defective region characteristic to ABC from the frequency graph of genomic imbalance shown in Table 3 of the Example described later and FIG. Is mentioned. Examples thereof include one or more selected from 2pll, 6ql2-27, 8p22-p23, 9p21 and 17p of human chromosome. This is because these regions are frequently defective regions in the ABC type. Of these, 6q22.31-q24.1 and 9p21.3 are preferred. Furthermore, it is 9p21.3 of the human chromosome.
  • useful amplification regions for determining the DLBCL GCB type include human chromosomes lq22-32, 2pl4-p24, 5pl2-p, 5ql5-q31, 6pl2-p25, 7, 8q22- one or more selected from q26, 9q33-q34, 1 lq, 12, 13q31-q33, 16pll-pl3, 18q21-q23, 19p, 19ql3, 21q and X. This is because these regions are frequently amplified regions in the GCB type.
  • lq21.1-q23.3, lq31.1-q42.13, 2pl5-pl6.1, 7q22.1-q 36.2 and 12ql3.1-ql4 are selected, 7q22-q36.
  • deletion regions useful for determining DLBCL GCB type include human chromosomes lp36, 2pll, 3pl4, 4pl2-pl3, 4q33-q34, 6ql4-ql6, 8p22-p23, 9p21, Examples thereof include one or more selected from 13ql2-q22, 17pl2, and 18q22-q23. This is because these are frequently defective regions in the GCB type.
  • human amplification stains are useful for determining that DLBCL is CD5 + type. Examples thereof include one or more selected from 3, 6p22-p25, 7p22-q31, 8q24, llq22-q25, 12, 16pl3-q21, 18, 19 and X.
  • Human chromosome 3 is preferred.
  • useful deletion regions include lp36, 2pll, 6ql4-q27, 8p23, 9p21, 15q13-ql4 and 17pll-pl3 of the human chromosome. Preferably, it is 9p2 of the human chromosome.
  • useful amplification regions for determining DLBCL CD5 and DC10 + are lq, 2pl3-p25, 6p21-p25, 7, 8q22-q24, 9q33-q34, 12 on the human chromosome. , 13q31-q33, 15q, 16pl3, 19ql3.3-13.4 and X force One or more selected.
  • the human chromosomes 7q22-q36, 12ql3-ql4 and 17pl3 are also preferred.
  • useful deletion regions include 1 ⁇ 36, 1 ⁇ 22, 2pll, 3pl4, 4p, 6ql3-q27, 9p21 and 13ql4-q21 of human chromosomes.
  • the GBB type may be associated with the CD5 ⁇ DC10 + type due to the genomic imbalance in the DLBCL GCB type and the CD5 ⁇ DC10 + type (particularly, Asian, especially Japanese). Therefore, when the type is ABC type, it may be positively determined that the type is CD5-CD10 + type.
  • Various methods can be employed to detect the amplified region and the defective region on these chromosomes. For example, it can be detected by hybridization using a chromosome-containing test sample collected from a human individual suffering from DLBCL and a probe that hybridizes with various regions on these chromosomes. Nucleic acid samples from patients, etc., can also be obtained by standard DNA extraction methods, etc. for patient lymphoma specimens. On the other hand, any probe that can detect such amplification and deletion may be any probe that hybridizes with at least a part of the region on the chromosome.
  • a BAC clone and / or a PAC clone corresponding to a chromosomal region can be used as a probe by amplifying genomic DNA cloned by DOP-PCR or adapter PCR.
  • this is a BACZPAC clone containing the gene or P Genomic DNA cloned using the CR method can also be used.
  • the form of hybridization between the test sample and the probe is not particularly limited. It may be a liquid phase reaction or a method using a solid phase carrier such as a bead or a substrate.
  • a DNA probe immobilized on a solid phase carrier such as a chip or a bead can be used.
  • Amplification of a specific region on a chromosome and detection of a defect can be performed by preparing a DNA array according to the array CGH method in the Examples.
  • such an amplified region and a defective region on a chromosome are detected by performing PCR using a predetermined primer on a predetermined region on the chromosome of a human individual suffering from DLB CL to obtain a PCR product. It is also possible to detect by the presence or absence and its identification.
  • Primers can be designed based on sequences such as the pi 6 gene.
  • the base length of the primer is preferably 15 to 40 bases, desirably 15 to 30 bases. However, when LA (longaccurate) PCR is performed, it is preferable to use at least 30 bases. It is preferable to select a base sequence so that the sense strand and the antisense strand do not anneal with each other and can avoid the formation of a hairpin-like structure.
  • the detection of the amplified region and the defective region on the chromosome can also be based on the expression level of the genes contained in these chromosomal regions. That is, it is also possible to determine the disease type based on whether the expression level of the gene in each chromosome region is significantly higher or lower than that of a healthy subject.
  • the expression level is significantly higher than 10%, preferably 30% or more, more preferably 50% or more, and even more preferably 70% compared to the expression level of the same gene in healthy individuals. Above, more preferably 100% or more.
  • the expression level is significantly less than 60%, preferably 50% or less, more preferably 20% or less, and even more preferably 10% or less compared to the expression level of the same gene in healthy individuals.
  • Each target gene can be easily obtained by a known method.
  • a cDNA library can be formed and each cDNA can be isolated using a DNA probe prepared based on a known nucleotide sequence.
  • a primer based on the cDNA base sequence may be used to obtain the required amount of cDNA by RT-PCR using mRNA as a saddle.
  • the analysis based on the expression level of the gene can be performed by a known method on a sample collected from a human. For example, in situ hybridization, Northern blotting, dot blot, RT-PCR, real-time PCR, DNA array methods, etc. can be used.
  • an antibody specific to such a protein can be used.
  • a polyclonal antibody or a monoclonal antibody can be used. It may be an antibody molecule or a part thereof. In the case of a polyclonal antibody, for example, such an antibody can be obtained with serum after immunizing an animal using a protein or a partial fragment thereof as an immunogen.
  • eukaryotic cell expression vector can be prepared by introducing the above eukaryotic cell expression vector into an animal muscle or skin by injection or gene gun, and then collecting serum.
  • animals include mice, rats, rabbits, goats, and birds.
  • Monoclonal antibodies are known monoclonal antibody production methods ("monoclonal antibodies”, Kamei Nagamune, Hiroaki Terada, Yodogawa Shoten, 1990; "Monoclonal Antibody James W. Coding, third edition, Academic Press, 1996) [This can be made.
  • the antibody may be appropriately labeled with a labeling substance!
  • a labeling substance an enzyme, a radioisotope or a fluorescent dye can be used.
  • the enzyme include, but are not limited to, enzymes used in normal EIA, such as peroxidase, ⁇ -galactosidase, alkaline phosphatase, glucose oxidase, acetylcholinesterase, glucose 6-phosphate dehydrogenase, Malate dehydrogenase or the like can also be used.
  • an enzyme inhibitor, a coenzyme, etc. can also be used. Binding of these enzymes and antibodies can be performed by a known method using a cross-linking agent such as maleimide compound.
  • the substrate a known substance can be used depending on the type of enzyme used.
  • the fluorescent dye those used in the usual fluorescent antibody method such as fluorescens isothiocyanate (FITC) or tetramethylrhodamine isothiocyanate (TRITC) can be used.
  • fluorescent antibody method such as fluorescens isothiocyanate (FITC) or tetramethylrhodamine isothiocyanate (TRITC) can be used.
  • FITC fluorescens isothiocyanate
  • TRITC tetramethylrhodamine isothiocyanate
  • immunostaining such as tissue or cell staining, competitive or non-competitive radioimmunoassay (RIA), fluorescent immunoassay (FIA ), Luminescent immunoassay (LIA), enzyme immunoassay (EIA, ELISA), and other detection methods can be used.
  • the antigen-antibody reaction in such a measurement method may be performed in a liquid
  • the antigen-antibody reaction product is preferably separated.
  • a solid support such as chromatography or beads or plates may be used.
  • Western blotting may be used.
  • ELISA method etc. can be used.
  • an array in which antibodies are immobilized on a solid support such as a substrate can be used.
  • a marker for diagnosis of a DLBCL disease type comprising a protein or a part thereof or an antibody against them.
  • antibodies are preferred as detection reagents for detecting such proteins.
  • a kit for diagnosing a DLBCL disease type containing such an antibody is provided.
  • the diagnostic kit of the present invention may contain an antibody or a labeled antibody in the liquid phase, or may be one in which the antibody or labeled antibody is bound to a solid phase carrier. It may also contain a fixed antigen or a part thereof. When the antibody is labeled with an enzyme, the diagnostic kit may contain the substrate. Furthermore, in the case of a substance containing a solid phase carrier, a washing solution for washing away non-bound molecules from the solid phase may be contained.
  • elements that can generally be included in diagnostic kits containing antibodies can be included.
  • the nucleic acid probe of the present invention includes a nucleic acid probe capable of detecting a chromosomal amplified region and a defective region, which serve as an index for diagnosing DLBCL disease type. According to such a nucleic acid probe, amplification or deletion of these regions can be easily detected using a hybridization. For example, such a nucleic acid probe should be able to detect a region characteristic of a disease type on the genome-wide chromosome imbalance graph shown in Table 3 and FIG. In other words, BAC / PAC clones containing these regions or DNA obtained from these can be used as probes.
  • the amplification region on the human chromosome and the ABC type DLBCL described above and And a defective region force A probe capable of detecting one or more selected regions, more specifically, a BACZPAC clone containing these regions or a genomic DNA obtained from these forces.
  • a probe suitable for determining ABC type is similar to that already described in the diagnosis method. Which region contains DNA to be used as a probe can be determined, for example, by using an ABC type DLBCL-affected human against an array in which nucleic acid probes derived from human chromosomes in a predetermined range (preferably genome-wide range) are immobilized.
  • a predetermined upper and lower threshold value is obtained.
  • a nucleic acid probe selected based on the magnitude of the log ratio value relative to the threshold value
  • the threshold of the log ratio of fluorescence intensity can also be included.
  • the threshold of the log ratio of fluorescence intensity can also be included.
  • level amplification high level amplification, low level defects and high level defects.
  • the amplification region and deletion region force on the human chromosome in the already described GCB type DLBCL are probes capable of detecting one or more selected regions, and more specifically, these probes. BACZPAC clones containing these regions or genomic DNA obtained from these. Suitable probes for determining the GCB type are similar to those already described in the diagnostic method.
  • a test sample collected from a human individual suffering from DLBCL of the above-mentioned GCB type is supplied to an array in which nucleic acid probes derived from human chromosomes in a predetermined range (preferably genome-wide range) are immobilized. Based on the log ratio value of the fluorescence intensity obtained at the fixed site of the nucleic acid probe by carrying out dialysis
  • Selected nucleic acid probes can also be included.
  • the amplification region and the lacking region force useful for determining CD5 + and CD5 + CD10- described above are nucleic acid probes capable of detecting one or more selected regions.
  • the nucleic acid probe of the present invention is preferably a nucleic acid probe set that can determine two types of DLBCL, ABC type and GCB type.
  • ABC type determination for example, One or more selected from 3, 8q21-q26, llq21-q25, 16pll-pl3, 16q22-q24, 18, 19ql3, X, 2pll, 6ql2-27, 8p22-p23, 9p21, 17p
  • a nucleic acid probe capable of detecting at least a part of the region can be used.
  • a nucleic acid probe capable of detecting at least a part of one or two or more regions selected from can be used.
  • the nucleic acid probe of the present invention also includes an expression analysis probe.
  • a probe need not be completely complementary to a gene as long as it is specifically hybridized to a nucleic acid sample derived from a given gene.
  • Such slightly mutated polynucleotides are ⁇
  • the probe hybridizes with the nucleic acid sample derived from the gene under stringent conditions.
  • the stringent condition is a condition that enables selective and detectable specific binding between the probe and the nucleic acid sample.
  • Stringent conditions are defined by salt concentration, organic solvent (eg, formamide), temperature, and other known conditions. That is, stringency is increased by decreasing the salt concentration, increasing the organic solvent concentration, or increasing the hybridization temperature.
  • stringent salt concentrations are typically about 750 mM or less NaCl and about 75 mM or less trisodium citrate, more preferably about 500 mM or less NaCl and about 50 mM or less trisodium citrate, most preferably about 250 mM or less NaCl and citrate. Trisodium is about 25 mM or less.
  • the stringent organic solvent concentration is about 35% or more of formamide, most preferably about 50% or more.
  • Stringent temperature conditions are about 30 ° C or higher, more preferably about 37 ° C or higher, and most preferably about 42 ° C or higher.
  • Other conditions include hybridization time, washing time.
  • Various stringency can be set by combining these conditions, such as the concentration of detergent (eg, SDS) and the presence or absence of carrier DNA.
  • the hybridization conditions described above are merely examples, and those skilled in the art will consider the conditions such as the nucleotide sequence, concentration and length of the probe, reaction time, reaction temperature, reagent concentration, etc. Appropriate hybridization conditions can be set.
  • the probe may be appropriately labeled as necessary.
  • labeling it is preferable to use the force non-RI method which can be performed by radioisotope (RI) method or non-RI method.
  • RI radioisotope
  • non-RI method include a fluorescent labeling method, a piotine labeling method, a chemiluminescence method, and the like.
  • an immobilization medium in which various nucleic acid probes are immobilized on a solid phase carrier is also provided.
  • the solid phase carrier typically includes a flat substrate such as a slide glass and a granular material such as beads.
  • the immobilized form of the probe is not particularly limited, and includes immobilized forms by various bonds of covalent bond and non-covalent bond such as z or electrostatic or hydrophobic interaction.
  • the solid phase carrier on which such a nucleic acid probe is immobilized is typically a DNA array called a CGH array.
  • the nucleic acid probe applied to such a fixed body includes all embodiments of the nucleic acid probe used in the diagnostic method of the present invention.
  • a nucleic acid probe having a complementary base sequence can be preferably used as a marker for diagnosis of disease type.
  • primers (sets) that can amplify the region and the corresponding gene can be used as markers for diagnosis of disease type.
  • an immobilized body (array or the like) in which such a nucleic acid probe is immobilized on a solid phase carrier can be preferably used for the prognosis of DLBCL.
  • a marker for diagnosing a disease type is a protein encoded by a corresponding gene of an amplified region or a defective region on a human chromosome, or a part thereof, or an antibody against them, and a fixed enzyme in which the antibody is immobilized on a solid phase carrier. It may be a body.
  • a disease type diagnosis pro A kit for diagnosing a disease type including at least one of a probe, a primer (set), an antibody, and an array is also provided.
  • the prognosis diagnosis method of the present invention comprises a detection step of detecting a deletion or mutation of human chromosome 9p21 in a test sample collected from a human. This is because if 9p21 is deficient, D LBCL has a high grade of malignancy and a poor prognosis.
  • a probe such as a BACZPAC clone corresponding to this chromosomal region or genomic DNA obtained from this clone can be used.
  • a DNA array such as array CGH can be used. It can also be detected by site-specific amplification by PCR
  • the deletion or mutation of the pi 6 INK4a gene which is the 9p21 gene, can be directly detected by a noble hybridization method, or PCR, RT-PCR, Northern blotting, ReaKTime PCR It can also be detected by expression analysis using a method or the like.
  • expression analysis when the expression level of the gene in the test sample is significantly smaller than the expression level of healthy subjects, it can be diagnosed that the prognosis is poor in DLBCL.
  • the expression level is significantly less than 60% or less, preferably 50% or less, more preferably 20% or less, and even more preferably 10% or less compared to the expression level of the same gene in healthy individuals.
  • the presence / absence, expression level, and mutation of the protein encoded by the pl6 INK4a gene may be detected.
  • an antibody that specifically binds to such a protein can be used.
  • the same mode as described above can be applied.
  • a nucleic acid probe having at least a part of this region or a nucleotide sequence complementary thereto can be detected so that 9p21 of human chromosome or a part thereof can be detected. It can be preferably used as a marker.
  • the probe may have a pl6 INK 4a gene, a part thereof, or a base sequence complementary thereto.
  • primers (sets) that can amplify the region or responsible gene can also be used as prognostic markers.
  • an immobilized carrier in which such a nucleic acid probe is immobilized on a solid phase carrier can be preferably used for the prognosis of DLBCL.
  • the prognostic marker may be a protein encoded by the pl6 INK4a gene, a part thereof, an antibody thereto, or an immobilized antibody in which the antibody is immobilized on a solid phase carrier.
  • a DBCL prognosis kit including at least one of such a DBCL prognosis probe, a primer (set), an antibody, an array and the like is also provided.
  • Lymph node samples and clinical data were obtained from 99 patients (CD5 + 36 cases, CD-CD10 + 19 cases, CD5-CD10-44 cases) according to the protocol approved by the institutional review board. Three CD5 + cases had CD10 +. Notably, a total of 36 cases of CD5 + DLBCL, a higher proportion than in the general population, were collected for assessment of the genetic status of the disease. The 99 cases of DL BCL were analyzed for genomic imbalance using the array CGH method. Of these, 46 cases (CD 5+ 22 cases, CD5—CD10 + 7 cases, CD5—CD10—17 cases) were followed by gene expression profiling. In addition, these patients had no history of malignant lymphoma.
  • All DLBCL patients will receive therapeutic doses such as cyclophosphamide, adriamycin, vintalistin, and predonin (CHOP) after diagnosis, and all force DNA and RNA samples will be administered before treatment at diagnosis. From the tumor. Table 1 shows data on age, stage, performance status, lactate dehydrogenase (LDH), number of extranodal lesions, and International Prognostic Index (IPI) at diagnosis for all patients.
  • therapeutic doses such as cyclophosphamide, adriamycin, vintalistin, and predonin (CHOP) after diagnosis, and all force DNA and RNA samples will be administered before treatment at diagnosis. From the tumor. Table 1 shows data on age, stage, performance status, lactate dehydrogenase (LDH), number of extranodal lesions, and International Prognostic Index (IPI) at diagnosis for all patients.
  • LDH lactate dehydrogenase
  • IPI International Prognostic Index
  • Cy5- or Cy3-labeled complementary RNA was synthesized from total RNA using the Low RNA Input Amplification Kit (Agilent Technologies, Palo Alto, Calif.).
  • the probe was a mix of experimental Cy5-labeled cRNA and control Cy3-labeled cRNA.
  • the latter is a form of lymph node hyperplasia 1
  • the pool power of the total RNA extracted as well as 0 sample power was prepared.
  • the glass slide microarray used was an Agilent oligonucleotide array (Agilent Technologies) spotted with a total of 21619 genes custom-made for the Cancer Research Institute of the Foundation for Cancer Research.
  • the probe was hybridized on a glass slide using the manufacturer's protocol using In Situ Hybridization Kit Plus (Agilent Technologies). Fluorescence images of hybridized microarrays were acquired with an Agilent scanner G2565AA (Agilent Technologies), analyzed using Feature Extraction software (Agilent Technologies), and the fluorescence ratio of experimental Cy5-labeled samples to Cy3-labeled controls. was calculated. All the flags are raised! /,, (Non-flagged) The fluorescence ratio was logarithmically converted (bottom 2), and the center value of each gene calculated by the cluster analysis was subtracted.
  • DLBCL gene expression profile data obtained from Lymp hochip microarrays: http: ⁇ l It was obtained from the supplementary information contained in reference material 8 of the lmpp.nih.gov/DLBCL site. We have confirmed that the 274 DLBCLs in the Lymphochip microarray dataset can be divided into ABC and GCB and type 3. The distribution of the above 67 genes was almost the same as the 100 genes reported by Rosenwald et af.
  • Array CGH analysis was performed on DLBCL cases using a previously reported method using ACC array slide version 4.0 glass slides.
  • This array consists of 2304 BAC (bacterial artificial chromosomes) and PAC (P-1 derived artificial chromosomes) clones (BAC / PAC clones) that cover the entire human genome with a resolution of about 1.3 Mb (megabase). It is. BAC clones were obtained for RP11 and RP13 libraries, and PAC clones were also obtained for RP1, RP3, RP4, and RP5 libraries.
  • PCR oligonucleotide primed
  • 10 ng of BAC / PAC DNA as a template and degenerate oligonucleotides (5,-CCGACTCGAGNNNNNNATGTGG-3, N is one of A, T, C and G) as primers PCR
  • Amplification was obtained from TaKaRa PCR thermal Cycler MP (Takara, Tokyo, Japan) and ExTaq polymerase (TaKaRa).
  • the PCR product is concentrated by ethanol precipitation, dissolved in distilled water, followed by addition of an equal volume of DNA spotting solution DSP0050 (MATSUNAMI, Osaka, Japan) (; ⁇ 1 g / 1), inkjet technology (NGK, (Nagoya, Japan) was spotted in duplicate on a CodeLink TM active slide (Amersham Biosciences, Piscataway, NJ) by a robot.
  • DSP0050 MATSUNAMI, Osaka, Japan
  • NNK inkjet technology
  • DNA preparation, labeling, array generation and hybridization were performed according to previous reports (Ota A, I'agawa H, Karnan 3 ⁇ 4, et al. Identincation and characterization or a nove 1 gene, C13orf25 , as a target for 13q31— q32 amplification in malignant lymphoma, Cancer Res. 2004; 64: 3087-3095, Tagawa H, Tsuzuki S, Suzuki R, et al. Genome— wide array-based comparative genomic hybridization of diffuse large B— cell lymphoma: Comparison between CD5— Positive and CD5— negative cases. Cancer Res.
  • test DNA and control DNA (1 ⁇ g each) were digested with Dpnll, and Bio prime DNA Laoeling system (Invitrogen Life (Technology, Inc, Tokyo, Japan) [From this, Cy3-dUTP and Cy5-dUTP (Amersham Pharmacia Biotech, Piscataway, NJ) were used for labeling.
  • the array was subjected to simultaneous normalization of healthy men 10 times with respect to healthy men and revealed normal fluctuations in the log ratio. Fluorescence intensity is not 10% of the average of all clones
  • the definition of the region of amplification or deletion is: (a) 3 consecutive clones exhibit amplification or deletion, or (b) one clone repeats high copy number amplification (log ratio> + 1.0) or homology Joining
  • Loss of body 11 was to show (log ratio ⁇ 1.0) '12. High level gain Z amplification area, and
  • the genomic change was amplified by copy number amplification with log ratio + 0.2 or more, and log ratio
  • the data set was constructed with 2 2 defined as a copy number loss of -0.2 or less.
  • Amplification log ratio
  • ⁇ +0.2 is ⁇ 1 '' for clones that show no amplification (+0.2 compared to log)
  • the Mann-Whit-1 U test was used to detect significant differences in pl6 INK4a expression levels between the ABC and GCB groups.
  • Statistical analysis is all STATA ver.8 statistical analysis package (StataCorp, College
  • DLBCL types can be characterized and classified by gene expression profiling and cell surface phenotyping.
  • Clinically ABC DLBC L behaves more malignantly than GCB DLBCL.
  • CD5 + DLBCL cases have a short survival time.
  • CD10 + DLBCL is relatively slow ( Figure 1).
  • Figure 2 To determine whether D LBCL with CD5 and / or CD10 markers is associated with ABC and GCB subgroups, a total of 46 DLB CLs (22 CD5 +, 7 CD5—CD10 +, 17 CD5—CD10—17) Gene expression profiling was performed. The results show that these 46 cases are clearly divided into either ABC or GCB groups ( Figure 2), and most importantly, the CD5 + and CD5—CD10 + phenotypes are ABC and GCB, respectively.
  • CD5 CD10 "9 8 0.5335
  • a P value is based on Fisher's exact test.
  • CD5 + DLBCL cases include 3 cases of CD10 +.
  • DLBCL of ABC and GCB are molecularly different because it is subgroup has been demonstrated previously 6 - 8, we first compared the genomic profiles of these subgroups.
  • Figure 3 shows two typical genomic profiles of one CD5—CD10— case with ABC signature and one case with GCB signature.
  • ABC group is more frequently amplified 3p23-q28, 18qll.2-q23, 9ql3.41-ql3.43, and 6q22.
  • the GCB group has the genomic features of higher frequency lq2 1.1-q23.3, lq31.1-q42.13, 2pl5-pl6.1, 7q22.1-q36.2 and 12ql3.1-ql4 (Fischer's exact method, P ⁇ 0.05).
  • the ABC and GCB D LBCL genomic imbalance ideograms are shown in Figure 4A-B and the ABC and GCB DLBCL groups of genomic imbalances are shown in Figure 5A.
  • CD5 expression did not affect the genomic imbalance observed in the ABC and GCB groups.
  • the genomic imbalance detected in the ABC group in this study reflects the prevalence of cases classified by CD5. That is, 67% (19/28) of the ABC group were CD5 + type.
  • the frequency and region of genomic imbalance between CD5 + and CD5 ⁇ in the ABC group was similar. There was no significant difference in the area or frequency of genomic imbalance between CD5 + and CD5- in the ABC group (data not shown).
  • CD5—CD10—DLBCL genomic imbalance was very similar to that of the “ABC plus GCB” group, as shown in FIG. There was no significant difference in the region or frequency of genomic imbalance between the CD5-CD10 + and “ABC plus GCB” groups (data not shown). These findings correlate well with the results of gene expression profiling that showed that CD5-CD10-DLCL was evenly distributed in ABC and GCB groups.
  • the CD5—CD10 + case also showed no signs suggesting a homozygous defect at 9p21.3.
  • Thirteen of the 37 patients with 9p21 deletion showed a defect in the restriction site of the genome surrounding one RP11-14912 containing the BAC, pl6 INK4a tumor suppressor gene.
  • DLBCL and GCB DLBCL transformed from FL can be used to program genomic abnormalities during lymphoma development. There may be a common step.
  • CD5 + and CD10 + DLBCL constitute clinically relevant subtypes.
  • CD5 + DLBCL is characterized by ABC expression and genomic patterns.
  • Katzenberger et al. (2003) conducted a cytogenetic and LOH study on a new CD5 + DLBCL, which showed a high frequency of loss of the D1 3S25 locus and pl6 INK4a tumor suppressor. Therefore, we suppose that CD5 + DLB CL may be derived from the same progenitor cells as B-chronic lymphocytic leukemia (CLL) (7) (Katzenberger er, Lohr A, 3 ⁇ 4cnwarz 3 ⁇ 4, et al.
  • CLL B-chronic lymphocytic leukemia
  • CD5 + DLBCL differs from CLL and mantle cell lymphoma (MC), which also express CD5, in both origin and route. It is thought that. Both CLL and MCL are characterized by loss of 1 ⁇ 22, 6q, 9p21, l lq22- q23, 13ql4-q21 (recognized in 30-50% of cases) (24. Bentz M, Plesch A, Bullinger L, et al.
  • Genomic DNA chip hybridization in t (ll; 14) — positive mantle cell lymphomas sho ws a high frequency of aberrations and allows a refined characterization of consensus regions.
  • Oncogene. 2005; 24: 1348- 1358) less than 10% of CD5 + DLBCL cases we examined showed Ip22, llq22-q23, and 13ql4-q21 deficiencies. Only the lack of pl6 INK4a appears to be a common feature.
  • CD10 + DLBCL is characterized by GCB expression and genomic patterns.
  • Huang et al. (2002) showed that it is characterized by CD10 + DLBCL force S GCB signature using gene expression profiling, as is evident from our results (Huang JZ , Sanger WG, Greiner TC, et al. The t (14; 18) defines a unique subset of diffiise large B- cell lymphoma with a germinal center B-cell gene expression profile.Blood. 2002; 99: 2285-2290, Iqbal
  • CD5—CD10—DLBCL subtypes ie, CD5 + and CD—CD10 + subtypes
  • CD5—CD10—DLBCL is equal to either ABC or GCB group. It is closely related to the results of gene expression profiling that has been observed, suggesting that CD5—CD 10 ”DLBCL is a genetically heterogeneous disease.
  • 9p21 (pl6 INK4a ) deficiency may be the most aggressive disease feature. Of particular interest in our case is that the cases of ABC and CD5 + DLBCL lacking 9p21 had a worse outcome than those not lacking. 9p21 deficiency may therefore be a factor that may represent the most aggressive form of DLBCL. 9p21.3 (pl6 INK4a locus) deficiency is more common in aggressive lymphomas and acute lymphoblastic leukemia (Serrano M, Hannon GJ, B each D. A new regulatory motif in cell-cycle control causing specific inhibition of cy clin D / CDK4. Nature. 1993; 366: 704—707, Nobori T, Miura K, Wu DJ, et al.
  • Pl6 (INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas .Blood. 1998; 91: 2977-2984)
  • 0 CD5 + DLBCL is also much aggressive Pl6 INK4a inactivity and 9p21 deficiency are likely to be characteristic of CD5 + DLB CL, but in fact, are very frequent in CD5 + DLBCL.
  • 9 p21 deficiency has been reported by us and other groups (12. Tagawa H, Tsuzuk l S, buz uki R, et al.
  • the present invention is useful for diagnosis of DLBCL disease type and prognosis.

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Abstract

L'invention concerne un moyen permettant de diagnostiquer facilement un sous-groupe du lymphome diffus à grandes cellules B. L'invention concerne plus précisément une méthode permettant de diagnostiquer un type de lymphome diffus à grandes cellules B, consistant à détecter une région amplifiée et/ou une région délétée d'un chromosome humain dans une éprouvette contenant un chromosome prélevé sur un humain.
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CN101968491A (zh) * 2010-09-29 2011-02-09 上海生物芯片有限公司 弥漫性大b细胞淋巴瘤分子病理分型方法及试剂盒和应用
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CN111655868A (zh) * 2018-03-14 2020-09-11 深圳华大生命科学研究院 恶性淋巴瘤标志物及其应用

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