CN112029860B - Marker molecule related to colorectal cancer prognosis and detection kit - Google Patents

Abstract

The invention relates to a marker molecule related to colorectal cancer prognosis, which comprises at least one gene sequence shown as SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9 and SEQ ID NO. 10. The marker molecules provided by the invention are a gene set modified by 6-methyladenine, are verified to be highly related to the prognosis of rectal cancer, and can be used as a biomarker for the prognosis evaluation of clinical rectal cancer patients, so that the life quality of the patients is improved.

Description

Marker molecule related to colorectal cancer prognosis and detection kit

Technical Field

The invention relates to the field of cancer treatment and prognosis evaluation, in particular to a marker molecule and a detection kit related to colorectal cancer prognosis.

Background

Rectal cancer is the third most prevalent cancer occurring worldwide, with mortality rates ranked second among cancers. 30% of the sites of rectal cancer development are located between the dentate line to the rectosigmoid junction, one of the most common malignancies of the digestive tract. Rectal cancer is low in location and is easily diagnosed by digital rectal examination and sigmoidoscopy. But the position of the pelvic cavity is deep, so the anatomical relationship is complex, the operation is not easy to be thorough, and the postoperative recurrence rate is high. In addition, the colon cancer is easy to transfer due to the rapid occurrence of the colon cancer, so that the survival prognosis of colon cancer patients is generally poor. With the innovation of bioinformatics technology and medical treatment, in order to more accurately detect individual prognosis and implement appropriate adjuvant therapy, methods such as high-throughput sequencing and bioinformatics analysis can be utilized to search for rectal cancer occurrence, diagnosis and prognosis indexes on a molecular level to improve the quality of life of patients. Genomic epigenetic modifications, such as histone modifications, RNA modifications, and DNA methylation, play a key role in the development of tumors.

6-Methyl adenine (m) ⁶ A) The modification is one of the most common post-transcriptional modifications of eukaryotic mRNA, and is involved in biological processes such as DNA damage repair and RNA metabolism, such as degradation of mRNA, shear processing, transport, translation, lncRNA, and microRNA synthesis. m is ⁶ The A modification is mainly composed of m ⁶ A regulators mediate the addition, elimination and recognition of methylation, including "writers", "readers" and "erasers", respectively. Currently known "writers" include METTL3, METTL14, METTL16, WTAP, RBM15/15B and KIAA1429; "erasers" includes FTO and ALKBH5; "readers" includes YTHDF1-3, HNRNP family, IGF2BP family, etc. The study of 6-methyladenine modification in tumors is receiving increasing attention, but the relation between 6-methyladenine modification and rectal cancer is poorly understood in the art.

Disclosure of Invention

The first object of the present invention is to provide an isolated marker molecule associated with prognosis of rectal cancer, comprising: at least one gene sequence shown in SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9 and SEQ ID NO. 10.

Specifically, the marker molecule related to the colorectal cancer prognosis provided by the invention can be any one sequence of SEQ ID NO. 1-10, and can also comprise any two, three, four, five, six, seven, eight, nine or all ten sequences.

Among them, the gene sequence shown in SEQ ID NO:1 (also known as ADAMTSL 1) is a component of extracellular matrix, and may play a role in cell or cell-matrix interactions, or may modulate other ADAMTS proteases. ADAMTSL1 is highly expressed in skeletal muscle, while it appears hypermethylated in ER-positive breast cancer cells. At present, reports that the gene sequence is related to the prognosis of the rectal cancer are not found.

The gene sequence shown in SEQ ID NO:2 (also known as CSMD 2) may influence the development and differentiation of central nervous system lymphoma (PCNSL). At present, reports that the gene sequence is related to the prognosis of the rectal cancer are not found.

The gene sequence (also known as FAM 13C) shown in SEQ ID NO. 3 is an independent prognostic marker for prostate cancer. High expression of FAM13C was significantly associated with late pT, high Gleason, lymph node positive, early biochemical recurrence. At present, reports that the gene sequence is related to the prognosis of the rectal cancer are not found.

The gene sequence shown in SEQ ID NO. 4 (also known as FAM 184A) may be involved in the development of cancer, particularly in the prognosis of patients with endometrial cancer. At present, reports that the gene sequence is related to the prognosis of the rectal cancer are not found.

The gene sequence (also known as KLHL 4) shown as SEQ ID NO:5 can be used as a target gene of IGFBP5 and jointly participate in the anti-estrogen desensitization treatment process of ER positive breast cancer cells through a PI3K/Akt signal pathway. At present, no report that the gene sequence is related to the prognosis of the rectal cancer is found.

The gene sequence (also named OLFML 2B) shown in SEQ ID NO. 6 may play a carcinogenic role in the occurrence and development of gastric cancer, and the over-expression of OLFML2B in gastric cancer may become a new gastric cancer diagnosis and prognosis target. At present, reports that the gene sequence is related to the prognosis of the rectal cancer are not found.

The gene sequence shown in SEQ ID NO. 7 (also known as PDZD 4) is expressed in fetal and adult brain tissues and may play a role in cell growth. PDZD4 is likely involved in brain function and development and is significantly increased in synovial sarcoma cells and thus associated with tumor cell proliferation. At present, reports that the gene sequence is related to the prognosis of the rectal cancer are not found.

The gene sequence shown in SEQ ID NO. 8 (also known as SEC14L 5) is a gene of the SEC14 protein family. SEC14L5 is significantly associated with the development of post-traumatic stress syndrome, and may also be a risk gene for the development of intracranial aneurysms. At present, reports that the gene sequence is related to the prognosis of the rectal cancer are not found.

The gene sequence (also named SETBP 1) shown as SEQ ID NO. 9 can be used as a target gene of miR-211-5p in triple negative breast cancer, and can interact with miR-211-5p to inhibit proliferation, invasion, migration and transfer capacity of breast cancer cells. At present, no report that the gene sequence is related to the prognosis of the rectal cancer is found.

The gene sequence shown in SEQ ID NO:10 (also known as TMEM 132B) may be involved in the development of intracranial aneurysms. At present, no report that the gene sequence is related to the prognosis of the rectal cancer is found.

The marker molecules provided by the invention are a gene set modified by 6-methyladenine, are verified to be highly related to the prognosis of rectal cancer, and can be used as a biomarker for the prognosis evaluation of clinical rectal cancer patients, so that the life quality of the patients is improved.

The second object of the present invention is to provide a test kit for evaluating the prognostic effect of rectal cancer, which comprises: reagents for detecting marker molecules associated with the prognosis of rectal cancer; the marker molecule comprises: at least one gene sequence shown in SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9 and SEQ ID NO. 10.

Specifically, the marker molecule can be any one of SEQ ID NO. 1-10, and can also comprise any two, three, four, five, six, seven, eight, nine or all ten of the sequences.

As a preferred embodiment of the present invention, the reagent for detecting a marker molecule comprises a primer pair for the marker molecule for detecting the expression level of the marker molecule in a patient sample.

As a preferable scheme of the invention, the reagent for detecting the marker molecules comprises specific fluorescent probes aiming at the marker molecules, and the marker molecules in the sample of the patient are quantitatively detected by monitoring fluorescent signals in a PCR system in real time.

It is a third object of the present invention to provide an evaluation system for the prognostic effect of rectal cancer, comprising: (1) The data input module is used for inputting the content detection result of the marker molecules related to the prognosis of the rectal cancer into the model calculation module; (2) The model calculation module is used for calculating and processing the input content detection result to obtain the prognosis effect data of the detected patient; (3) And the result output module is used for evaluating the prognosis effect data of the detected patient according to the evaluation standard of the prognosis effect of the rectal cancer and outputting an evaluation result.

The marker molecules relevant to the prognosis of the rectal cancer comprise: at least one gene sequence shown in SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9 and SEQ ID NO. 10.

Specifically, the marker molecule can be any one of SEQ ID NO. 1-10, and can also comprise any two, three, four, five, six, seven, eight, nine or all ten of the sequences.

It is a fourth object of the invention to provide the use of said marker molecule, said kit or said evaluation system in the diagnosis of rectal cancer.

The fifth purpose of the invention is to provide the application of the marker molecule, the kit or the evaluation system in the prognosis evaluation of a patient with rectal cancer.

The method is based on the aspect of 6-methyladenine modification for the first time, a characteristic gene set which is modified by 6-methyladenine and is related to the prognosis of the rectal cancer is screened out from differential genes of a rectal cancer tissue and a normal tissue, and then 10 genes which are remarkably related to the prognosis of the rectal cancer are found through methods such as k-means cluster analysis, PCA analysis, COX regression analysis, ROC curve analysis, risk assessment and the like. When the risk score calculated by the characteristics is used for predicting the prognosis and clinical pathological characteristics of a tumor patient, the area value under the ROC curve is higher, which indicates that the 10 genes can well reflect the prognosis of a rectal cancer patient, and a new thought is provided for improving the diagnosis and survival prognosis of clinical rectal cancer patients.

Drawings

FIG. 1 shows rectal cancer m ⁶ Heat map of expression of a candidate gene over 4 min;

FIG. 2 is a k-means cluster plot of rectal cancer samples;

FIG. 3 shows rectal cancer m ⁶ Heat map of expression of a candidate gene among 2 subgroups;

FIG. 4 is a box plot of age between two subgroups of rectal cancer;

FIG. 5 is a WHO grading pie chart between two subgroups of rectal cancer;

FIG. 6 is a graph of survival between two sub-groups of rectal cancer;

FIG. 7 shows m ⁶ A protein interaction network map of candidate genes;

FIG. 8 shows m ⁶ A candidate gene coexpression network diagram;

FIG. 9 is a graph of principal component analysis of two subgroups (group 1, group 2);

FIG. 10 is a graph of differential gene enrichment for two subgroups (group 1, group 2);

FIG. 11 is a graph of sample survival for high and low risk groups;

FIG. 12 is a predicted effect of risk scoring for combined features on three-year survival outcomes; wherein the left graph is trailing, and the right graph is nesting;

FIG. 13 is a graph of risk score for a combination of features versus the predicted effect on subgroups; wherein the left graph is trailing, and the right graph is nesting;

FIG. 14 is a graph of the predictive effect of risk scoring for combined features on prognostic outcome; wherein the left graph is trailing, and the right graph is nesting;

FIG. 15 is a predicted effect of risk scoring on staging for a combined signature; wherein the left graph is trailing and the right graph is nesting.

Detailed Description

The following examples are intended to illustrate the invention, but are not intended to limit the scope of the invention.

Examples

1. Acquisition of data

Rectal cancer (READ) RNA-seq transcriptome data (rpkm data), rectal cancer clinical survival data (including pathology characteristics and survival time, etc.) were downloaded from TCGA, gene annotation files were downloaded from Genecode. Samples with pathological characteristics (stages of StageI, stageII, stageIII and StageIV) and RNA-seq expression data are selected to obtain 88 samples of rectal cancer.

13 widely reported m were obtained from the literature ⁶ A RNA methylation regulator (for m involved in different roles during methylation) ⁶ A RNA methylation modulators: writers (methyltransferase) -METTL3, METTL14, WTAP, KIAA1429, RBM15, ZC3H13; readers (binding proteins) -YTHDC1, YTHDC2, YTHDF1, YTHDF2, HNRNPC; erasers (demethylases) -FTO, ALKBH 5). Downloading READ m from m6 avatar database ⁶ A related genes to obtain 1047 rectal cancers m ⁶ A related gene.

2. Data preprocessing and differential gene screening

1047 rectal cancers m were constructed using gene annotation files using 88 rectal cancer samples containing both pathological feature (staging StageI, stageII, stageIII, stageIV) data and RNA-seq expression data ⁶ Expression profiles of A-related genes (rpkm data), and rectal cancer samples were classified into four categories (StageI, stageII, stageIII, stageIV) according to their stage.

Differential expression genes were screened among four classes of samples (StageI, stagiii, stageIV) using analysis of variance. Selecting a P value adj. Pvalue corrected by Benjamini-Hochberg (FDR)<0.05 and | log2Foldchange non-woven cells>1 is used as the threshold. Among them, log2Foldchange>1, the differential gene is considered to be up-regulated, whereas log2Foldchange<-1, the differential gene is considered to be down-regulated. The larger the | log2Foldchange | is, the larger the fold difference is, and the smaller adj. 974 differentially expressed genes were selected as m ⁶ A candidate Gene set and use of m ⁶ The A candidate gene set was used to construct an expression heatmap, and the results are shown in FIG. 1.

3. Sample consistency clustering

Differential expression m in selected READ intervals ⁶ A related gene (i.e. 974 rectal cancers m) ⁶ A candidate gene) as a feature vector, and k-means clustering (k = 2) was performed on 88 samples, and the results are shown in fig. 2. Two subgroups group1 and group2 are obtained, wherein the subgroups group1 and group2 contain 47 and 41 samples, respectively. Cancer of rectum m ⁶ The heatmap of the expression of the A candidate gene across the 2 subgroups is shown in FIG. 3.

4. Comparative analysis of pathological features and survival time between two subgroups

Samples containing age data from both subgroups were extracted and analyzed for age differences between group1 and group2 using a T-test comparison, the results of which are shown in fig. 4. The results indicated that the difference between the ages of the two groups was not significant.

Samples containing staging data from both subgroups were extracted and analyzed for differences between the two subgroups of WHO using the chi-square test, the results are shown in figure 5. The results indicated a significant difference in WHO ranking for the two subgroups (p = 0.00337).

Samples containing survival data from both subgroups were extracted and survival analysis was performed on both subgroups using COX regression, the results are shown in fig. 6. The results show that the survival rate of the group2 subgroup is obviously improved.

5、m ⁶ Analysis of interaction relationships between candidate gene sets

Analysis of m Using STRING database ⁶ The interaction between the A candidate genes is shown in FIG. 7. The interactive network is constructed by using the Cytoscape software, and the network with more than 10 nodes is reserved, and the result is shown in figure 8. The size of the node is related to the size of the node degree, the thickness of the edge is related to the comprehensive fraction of the interaction degree between the nodes, and the color of the node is related to the differential expression multiple.

6. Screening and function analysis of differential expression genes between group1 and group2 subgroups

Constructing m of two subgroups of group1 and group2 ⁶ The A candidate gene expression profiles were analyzed for differences in gene expression between the two subgroups using Principal Component Analysis (PCA), the results of which are shown in FIG. 9. The results show that there is a clear difference between the expression profiles of group1 and group 2.

Two subgroups of differentially expressed genes were annotated and analyzed for enrichment using an R-package clusterifier, the enrichment content including GO Biological Processes (BP), KEGG Pathways. The differential gene enrichment map is shown in FIG. 10. The results show that the differential genes mainly participate in the pathways such as Notch signaling pathway, MAPK6/MAPK4 signaling pathway, wnt signaling pathway and the like, and the research shows that the differential genes are related to the rectal cancer.

7. COX regression analysis and prediction of prognosis and pathological features using risk scoring

Study m ⁶ A prognostic role of RNA methylation candidate genes in rectal cancer, univariate analysis of data setAnd (4) Cox regression analysis, namely screening the gene with the obvious p value in the single-factor COX regression analysis as a colorectal cancer prognosis gene, and carrying out the next analysis.

And (3) carrying out risk scoring on each rectal cancer sample, wherein the formula is as follows:

where Coefi is the regression coefficient of COX regression (coefficient) and xi is the expression value of each rectal cancer prognostic gene, this formula is used to calculate the risk score for each rectal cancer sample. Samples were classified into high risk groups and low risk groups according to this risk score. Looking for the difference between the Overall Survivals (OS) between the two classes, the survival graph of the high and low risk group samples is shown in fig. 11. The results showed that 112 of 118 candidate genes were significantly associated with colorectal cancer OS.

Because too many candidate genes which are obtained by screening and are obviously related to the rectal cancer OS are difficult to be used for clinical diagnosis, a rebuilt likelihood-based survival model is constructed to screen characteristic genes, and 10 characteristic genes related to the rectal cancer prognosis are found by using R-enveloped rbsurf and the rebuilt likelihood-based survival model.

The 10 genes and their Cox-p-value results are shown in Table 1.

Table 1: 10 selected survival related characteristic genes

Gene ID	Cox-p-value
		ADAMTSL1	0.001766
CSMD2	3.32E-05
		FAM13C	0.000341
FAM184A	8.66E-06
		KLHL4	0.000204
OLFML2B	8.93E-08
		PDZD4	0.000875
SEC14L5	0.025102
		SETBP1	0.000401
TMEM132B	0.002578

8. ROC curve analysis

A Receiver Operating Characteristic (ROC) curve is adopted to estimate the classification performance, and the higher the value of area under the curve (AUC), the higher the classification performance is. The 10 prognostic genes are found to have better area under the ROC curve, and the 10 genes are shown to well reflect the prognosis of the rectal cancer patient.

9. Predicting prognosis and clinicopathologic characteristics of tumor patients using feature-calculated risk scores

From m ⁶ Obtaining factors which are obviously related to the survival period in the candidate gene A set and constructingThe risk characteristics are that 10 prognostic genes are taken as combined characteristics, are mapped to TCGA-READ, and the risk scores of the combined characteristics are respectively evaluated by using a Support Vector Machine (SVM), so that the prediction effects of the risk scores on the three-year survival rate of tumor patients, the prediction outcome of RM1/2 subgroups, the prognosis results, the stages and the like are evaluated. Wherein TCGA rectal cancer samples were divided into 5 sections, 5-fold cross-validation was applied, the model was trained with four-fifths of the samples and tested on the test set (one-fifth of the samples remaining).

The predicted effect of the risk score for the combined signature on the three-year survival outcome is shown in fig. 12, the risk score for the combined signature on the subgroup is shown in fig. 13, the risk score for the combined signature on the prognostic outcome is shown in fig. 14, and the risk score for the combined signature on the stage is shown in fig. 15. The results show that the marker molecule provided by the invention has good prediction effect on colorectal cancer prognosis.

Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

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tccagcagtc tgtggcttga tttcatcact gatgctgaaa acaccagcaa gggctttgaa 3720

ctgcactttt ccagctttga actcatcaaa tgtgaggacc caggaacccc caagtttggc 3780

tacaaggttc atgatgaagg tcattttgca gggagctccg tgtccttcag ctgtgaccct 3840

ggatacagcc tgcggggtag tgaggagctg ctgtgtctga gtggagagcg ccggacctgg 3900

gaccggcctc tgcccacctg tgtcgccgag tgtggaggga cagtgagagg agaggtgtcg 3960

gggcaggtgc tgtcacccgg gtatccagct ccctatgaac acaatctcaa ctgcatctgg 4020

accatcgaag cagaggccgg ctgcaccatt gggctacact tcctggtgtt tgacacagag 4080

gaggttcacg acgtgctgcg catctgggat gggcctgtgg agagcggggt tctgctgaag 4140

gagctgagtg gcccggccct gcccaaggac ctgcatagca ccttcaactc ggtcgtcctg 4200

cagttcagca ctgacttctt caccagcaag cagggctttg ccattcaatt ttcagtgtcc 4260

acagcaacgt cctgcaatga ccctgggatc ccgcagaatg ggagtcggag tggtgacagt 4320

tgggaagccg gcgactccac agtgttccag tgtgaccctg gctacgcgct gcagggaagt 4380

gcagagatca gctgtgtgaa gatcgagaac aggttcttct ggcagcccag cccgccaaca 4440

tgcatcgctc cctgcggggg agacctgaca ggaccatctg gagtcatcct ctcaccaaat 4500

tacccagaac cctacccgcc aggcaaggag tgtgactgga aagtgaccgt ctcaccagac 4560

tacgtcatcg ccctggtatt taacatcttt aacctggagc ctggctatga cttcctccat 4620

atctacgacg gacgggactc tctcagccct ctcataggaa gcttctatgg ctcccagctc 4680

ccaggccgca ttgaaagcag cagcaacagc ctcttcctcg ccttccgcag cgatgcatct 4740

gtgagcaatg ctggcttcgt cattgactat acagaaaacc cgcgggagtc atgttttgat 4800

cctggttcca tcaagaacgg cacacgggtg gggtccgacc tgaagctggg ctcctccgtc 4860

acctactact gccacggggg ctacgaagtt gagggcacct cgaccctgag ctgcatcctg 4920

gggcctgatg ggaagcccgt gtggaacaat ccccggccag tctgcacagc cccctgtggg 4980

ggacagtatg tgggttcgga cggagtggtc ttgtccccca actaccccca gaactacacc 5040

agtggacaga tctgcttgta ttttgttact gtgcccaagg actatgtggt gtttggccag 5100

ttcgccttct ttcacacggc cctcaacgac gtggtggagg ttcacgacgg ccacagccag 5160

cactcgcggc tcctcagctc cctctcgggc tcccatacag gagaatcact gcccttggcc 5220

acctccaatc aagttctcat taagttcagc gccaaaggcc tcgcaccagc cagaggcttc 5280

cactttgtct accaagcggt tcctcgaacc agcgccacgc agtgcagctc tgtgccggaa 5340

ccccgctatg gcaagaggct gggcagtgac ttctcggtgg gggccatcgt ccgcttcgaa 5400

tgcaactccg gctatgccct gcaggggtcg ccagagatcg agtgcctccc tgtgcctggg 5460

gccttggccc aatggaatgt ctcagcgccc acgtgtgtgg tgccgtgtgg aggcaacctc 5520

acagagcgca ggggcaccat cctgtcccct ggcttcccag agccgtacct caacagcctc 5580

aactgtgtgt ggaagatcgt ggtccccgaa ggcgctggca tccagatcca agttgtcagt 5640

tttgtgacag agcagaactg ggactcgctg gaagtatttg atggtgcaga taacactgta 5700

accatgctgg ggagtttctc aggaacaacc gtgcctgccc ttctgaacag cacctccaac 5760

cagctctacc ttcatttcta ctcagatatc agcgtatctg cagctggctt ccacttggag 5820

tacaaaacgg tgggcctgag cagttgtccg gaacctgctg tgcccagtaa cggggtgaag 5880

actggcgagc gctacttggt gaatgatgtg gtgtctttcc agtgtgagcc gggatatgcc 5940

ctccagggcc acgcccacat ctcctgcatg cccggaacag tgcggcgatg gaactaccct 6000

cctccactct gtattgcaca gtgtggggga acagtggagg agatggaggg ggtgatcctg 6060

agccccggct tcccaggcaa ctaccccagt aacatggact gctcctggaa aatagcactg 6120

cccgtgggct ttggagctca catccagttc ctgaacttct ccaccgagcc caaccacgac 6180

tacatagaaa tccggaatgg cccctatgag accagccgca tgatgggaag attcagtgga 6240

agcgagcttc caagctccct cctctccacg tcccacgaga ccaccgtgta tttccacagc 6300

gaccactccc agaatcggcc aggattcaag ctggagtatc aggcctatga acttcaagag 6360

tgcccagacc cagagccctt tgccaatggc attgtgaggg gagctggcta caacgtggga 6420

caatcagtga ccttcgagtg cctcccgggg tatcaattga ctggccaccc tgtcctcacg 6480

tgtcaacatg gcaccaaccg gaactgggac caccccctgc ccaagtgtga agtcccttgt 6540

ggcgggaaca tcacttcttc caacggcact gtgtactccc cggggttccc tagcccgtac 6600

tccagctccc aggactgtgt ctggctgatc accgtgccca ttggccatgg cgtccgcctc 6660

aacctcagcc tgctgcagac agagccctct ggagatttca tcaccatctg ggatgggcca 6720

cagcaaacag caccacggct cggcgtcttc acccggagca tggccaagaa aacagtgcag 6780

agttcatcca accaggtcct gctcaagttc caccgtgatg cagccacagg ggggatcttc 6840

gccatagctt tctccgctta tccactcacc aaatgccctc ctcccaccat cctccccaac 6900

gccgaagtcg tcacagagaa tgaagaattc aatataggtg acatcgtacg ctacagatgc 6960

ctccctggct ttaccttagt ggggaatgaa attctgacct gcaaacttgg aacctacctg 7020

cagtttgaag gaccaccccc gatatgtgaa gtgcactgtc caacaaatga gcttctgaca 7080

gactccacag gcgtgatcct gagccagagc taccctggaa gctatcccca gttccagacc 7140

tgctcttggc tggtgagagt ggagcccgac tataacatct ccctcacagt ggagtacttc 7200

ctcagcgaga agcaatatga tgagtttgag atttttgatg gtccatcagg acagagtcct 7260

ctgctgaaag ccctcagtgg gaattactca gctcccctga ttgtcaccag ctcaagcaac 7320

tctgtgtacc tgcgttggtc atctgatcac gcctacaatc ggaagggctt caagatccgc 7380

tattcagccc cttactgcag cctgcccagg gctccactcc atggcttcat cctaggccag 7440

accagcaccc agcccggggg ctccatccac tttggctgca acgccggcta ccgcctggtg 7500

ggacacagca tggccatctg tacccggcac ccccagggct accacctgtg gagcgaagcc 7560

atccctctct gtcaagctct ttcctgtggg cttcctgagg cccccaagaa tggaatggtg 7620

tttggcaagg agtacacagt gggaaccaag gccatgtaca gctgcagtga aggctaccac 7680

ctccaggcag gcgctgaggc cactgcagag tgtctggaca caggcctatg gagcaaccgc 7740

aatgtcccac cacagtgtgt ccctgtgact tgtcctgatg tcagtagcat cagcgtggag 7800

catggccgat ggaggcttat ctttgagaca cagtatcagt tccaggccca gctgatgctc 7860

atctgtgacc ctggctacta ctatactggc caaagggtca tccgctgtca ggccaatggc 7920

aaatggagcc tcggggactc tacgcccacc tgccgaatca tctcctgtgg agagctcccg 7980

attcccccca atggccaccg catcggaaca ctgtctgtct acggggcaac agccatcttc 8040

tcctgcaatt ccggatacac actggtgggc tccagggtgc gtgagtgcat ggccaatggg 8100

ctctggagtg gctctgaagt ccgctgcctt gccactcaga ccaagctcca ctccattttc 8160

tataagctcc tcttcgatgt actctcttcc ccatccctca ccaaagctgg acactgtggg 8220

actcctgagc ccattgtcaa cggacacatc aatggggaga actacagcta ccggggcagt 8280

gtggtgtacc aatgcaatgc tggcttccgc ctgatcggca tgtctgtgcg catctgccag 8340

caggatcatc actggtcggg caagacccct ttctgtgtgc caattacctg tggacaccca 8400

ggcaaccctg tcaacggcct cactcagggt aaccagttta acctcaacga tgtggtcaag 8460

tttgtttgca accctgggta tatggctgag ggggctgcta ggtcccaatg cctggccagc 8520

gggcaatgga gtgacatgct gcccacctgc agaatcatca actgtacaga tcctggacac 8580

caagaaaata gtgttcgtca ggtccacgcc agcggcccgc acaggttcag cttcggcacc 8640

actgtgtctt accggtgcaa ccacggcttc tacctcctgg gcaccccagt gctcagctgc 8700

cagggagatg gcacatggga ccgtccccgc ccccagtgtc tcttggtgtc ctgtggccat 8760

ccgggctccc cgcctcactc ccagatgtct ggagacagtt atactgtggg agcagtggtg 8820

cggtacagct gcatcggcaa gcgtactctg gtgggaaaca gcacccgcat gtgtgggctg 8880

gatggacact ggactggctc cctccctcac tgctcaggaa ccagcgtggg agtttgcggt 8940

gaccctggga tcccggctca tggcatccgt ttgggggaca gctttgatcc aggcactgtg 9000

atgcgcttca gctgtgaagc tggccacgtg ctccggggat cgtcagagcg cacctgtcaa 9060

gccaatggct cgtggagcgg ctcgcagcct gagtgtggag tgatctcttg tgggaaccct 9120

gggactccaa gtaatgcccg agttgtgttc agtgatggcc tggttttctc cagctctatc 9180

gtctatgagt gccgggaagg atactacgcc acaggcctgc tcagccgtca ctgctcggtc 9240

aatggtacct ggacaggcag tgaccctgag tgcctcgtca taaactgtgg tgaccctggg 9300

attccagcca atggccttcg gctgggcaat gacttcaggt acaacaaaac tgtgacatat 9360

cagtgtgtcc ctggctatat gatggagtca catagagtat ctgtgctgag ctgcaccaag 9420

gaccggacat ggaatggaac caagcccgtc tgcaaagctc tcatgtgcaa gccacctccg 9480

ctcatcccca atgggaaggt ggtggggtct gacttcatgt ggggctcaag tgtgacttat 9540

gcctgcctgg aggggtacca gctctccctg cccgcggtgt tcacctgtga gggaaatggg 9600

tcctggaccg gagagctgcc tcagtgtttc cctgtgttct gcggggatcc tggtgtcccg 9660

tcccgtggga ggagagagga ccgaggcttc tcctacaggt catctgtctc cttctcctgc 9720

catccccctc tggtgctggt gggctctcca cgcaggtttt gccagtcaga tgggacatgg 9780

agtggcaccc agcccagctg catagatccg accctgacca cgtgtgcgga ccctggtgtg 9840

ccacagtttg ggatacagaa caattctcag ggctaccagg ttggaagcac agtcctcttc 9900

cgttgtcaaa aaggctacct gcttcagggc tccaccacca ggacctgcct cccaaacctg 9960

acctggagtg gaaccccacc tgactgtgtc ccccaccact gcaggcagcc agagacgcca 10020

acgcatgcca acgtcggggc cctggatttg ccctccatgg gctacacgct catctactcc 10080

tgccaggagg gcttctccct caagggtggc tccgagcacc gcacctgcaa ggcggatggc 10140

agctggacag gcaagccgcc catctgcctg gaggtccggc ccagtgggag acccatcaac 10200

actgcccggg agccaccgct cacccaagcc ttgattcctg gggatgtttt tgccaagaat 10260

tccctgtgga aaggggccta tgaataccag gggaagaagc agccagccat gctcagagtg 10320

actggcttcc aagttgccaa cagcaaggtc aatgccacca tgatcgacca cagtggcgtg 10380

gagctgcact tggctggaac ttacaagaaa gaagattttc atctcctact ccaggtgtac 10440

cagattacag ggcctgtgga gatctttatg aataagttca aagatgatca ctgggcttta 10500

gatggccatg tctcgtcaga gtcctccgga gccaccttca tctaccaagg ctctgtcaag 10560

ggccaaggct ttgggcagtt cggctttcaa agactggacc tcaggctgct ggagtcagac 10620

cccgagtcca ttggccgcca ctttgcttcc aacagcagct cagtggcagc cgcgatcctg 10680

gtgcctttca tcgccctcat tattgcgggc ttcgtgctct atctctacaa gcacaggaga 10740

agacccaaag ttcctttcaa tggctatgct ggccacgaga acaccaatgt tcgggccaca 10800

tttgagaacc caatgtacga ccgcaacatc cagcccacag acatcatggc cagcgaggcg 10860

gagttcacag tcagcacagt gtgcacagca gtatag 10896

<210> 3

<211> 1464

<212> DNA

<213> Homo sapiens

<400> 3

atgttttctt gtttctgttt cagccttcag gataattcct tcagcagcac cactgtaaca 60

gagtgtgacg aagatccagt ctctctacat gaagaccaga ctgattgctc cagtctcaga 120

gatgaaaaca ataaagagaa ctaccccgac gcaggggctc tggtagaaga gcacgcgccg 180

ccctcttggg agccgcagca gcagaatgta gaggcgaccg tgctggtgga cagcgtattg 240

cgacccagca tgggcaactt caagtccagg aagcccaagt ccatcttcaa agcggagagc 300

gggaggagcc acggagaaag tcaggagaca gagcatgtgg tatccagcca gtcagagtgt 360

caggtgagag caggaacacc agctcatgag agtccacaaa acaatgcctt caagtgccaa 420

gaaacagtgc gacttcaacc aagaatagac cagaggactg ccatttcgcc aaaggatgct 480

tttgaaactc ggcaggactt aaatgaggaa gaagctgctc aggtgcatgg agtcaaggac 540

ccggcgccag catcaaccca gagcgtgctt gccgatggga cagattctgc agacccctca 600

ccagtccaca aagatgggca gaatgaggcc gacagtgcac cagaagacct ccactctgtg 660

gggaccagca ggctgctcta tcacatcact gatggtgata acccactgct gtcgccacga 720

tgctccatct tcagccaaag ccagagattc aacttagacc ccgagtcagc cccatctcca 780

cccagcactc agcagtttat gatgccgcgg agttcttcac gctgcagctg tggagatggc 840

aaggagccac agaccatcac ccagctcacc aagcacatcc agagcctcaa gcggaaaatt 900

cggaaatttg aagaaaaatt tgaacaagaa aagaaatacc gggtaactaa gcaagacaag 960

aacctcataa agccgcttta tgaccgatac agaattatca agcaaatctt gtcaacacct 1020

tcccttattc caacaattca ggaggaagag gactctgatg aagaccgtcc acagggaagc 1080

caacaacctt ctttggcaga tccagcatct caccttcctg ttggtgacca cctcacctac 1140

tctaatgaga ctgagcctgt tagggccctt ttaccagatg aaaagaaaga agtaaaacca 1200

ccagctctct ccatgtctaa tttacatgag gctaccatgc ctgtacttct tgaccatctc 1260

cgagaaacta gggctgacaa gaagagactg cggaaagcct taagagaatt tgaagaacag 1320

ttttttaaac aaacaggaag aagtccacaa aaggaagata ggataccaat ggcagatgag 1380

tattatgaat ataagcacat aaaagccaaa ctgagactat tagaggtcct catcagcaag 1440

caagatgtgg ccaaaactat ttga 1464

<210> 4

<211> 2811

<212> DNA

<213> Homo sapiens

<400> 4

atgaagcagc aggctttgac agaatttgaa gcttataagc acagagttga ggacatgcaa 60

ctttgtgcag aagcccagca tgtccaacgc atagtgacca tgtctagaga agtcgaagag 120

attagaagga aatttgaaga aaaattacgg agctttggac aacttcaagt acagtttgaa 180

aaagacaaac gattggcatt ggaagacttg caagctgctc acagacggga gatacaagag 240

ctattgaagt cacagcagga tcacagtgcc tcagtaaata aaggccagga aaaggcagag 300

gaactacaca gaatggaggt ggagtcccta aacaaaatgc ttgaggagct aagacttgaa 360

cggaagaaac taattgagga ttatgaaggc aagttgaata aagctcagtc cttttatgaa 420

cgtgagcttg atactttgaa aaggtcacag ctttttacag cagaaagcct acaggccagc 480

aaagaaaagg aagctgatct tagaaaagaa tttcagggac aagaagcaat tttacgaaaa 540

actataggaa aattaaagac agagttacag atggtacagg atgaagctgg aagtcttctt 600

gacaaatgcc aaaagcttca gacggcactt gccatagcag agaacaatgt tcaggttctt 660

caaaaacagc ttgatgatgc caaggaggga gaaatggccc tattaagcaa gcacaaagaa 720

gtggaaagtg agctagcagc tgccagagaa cgtttacaac agcaagcttc agatcttgtc 780

ctcaaagcta gtcatattgg aatgcttcaa gcaactcaaa tgacccagga agttacaatt 840

aaagatttag aatcagaaaa atcgagagtc aatgagagat tatctcaact tgaagaggaa 900

agagcttttt tgcgaagcaa aacccaaagt ctggatgaag agcagaagca acagattcta 960

gaactggaga agaaagtaaa tgaagcaaag agaactcagc aagaatatta tgaaagggaa 1020

cttaaaaacc tgcaaagtag attggaagag gaggtgactc aattaaacga ggcccattct 1080

aagactttgg aagaattagc ttggaagcac catatggcaa ttgaagctgt ccacagtaat 1140

gcaattaggg ataagaaaaa actgcaaatg gatttggaag aacaacataa caaagataaa 1200

ctaaacctgg aagaggataa aaatcagctt caacaagagc tagaaaacct aaaggaagta 1260

ctggaagaca agttgaatac agccaatcaa gagattggcc acctccaaga tatggtaagg 1320

aaaagtgaac aaggtcttgg ctctgcagaa ggacttattg ctagtcttca ggactcccag 1380

gaaaggcttc agaatgagct tgacttgact aaagacagcc taaaggagac caaggatgct 1440

ctattaaatg tggagggtga gctagaacaa gaaaggcaac agcatgaaga aacaattgct 1500

gccatgaaag aagaagagaa gctcaaagtg gacaaaatgg cccatgactt agaaattaag 1560

tggactgaaa atcttagaca agagtgttct aaacttcgtg aagagttaag gcttcaacat 1620

gaagaggata agaagtcagc aatgtctcaa cttttgcagt tgaaagatcg agagaaaaat 1680

gcagcaagag attcatggca gaagaaagta gaagatctct taaaccagat ttccttgctg 1740

aaacagaatc tggagataca gctttcccag tctcagactt ctttgcaaca actgcaagcc 1800

cagtttacgc aagaacgaca gcggcttacg caagagcttg aagaattaga ggagcaacat 1860

cagcaaagac acaaatcatt aaaagaagca catgtccttg catttcaaac tatggaagag 1920

gaaaaggaaa aggagcaaag agctcttgaa aatcatttac aacagaagca ttctgcagag 1980

cttcaatcac taaaagatgc acacagagag tcaatggagg gcttccggat agaaatggaa 2040

caggaacttc agactcttcg gtttgaatta gaagatgaag gaaaggctat gcttgcttcc 2100

ttgcgctcag aactcaacca tcaacatgca gctgcaattg atttgttacg gcataatcat 2160

catcaagaat tggcagctgc taaaatggaa ttagagagaa gcatagacat cagcagaaga 2220

cagagtaagg agcacatatg tagaattaca gatctacaag aggaattaag acacagagag 2280

catcacatct ctgaattgga taaggaggtt cagcaccttc atgagaatat aagtgcccta 2340

accaaagaac tggaatttaa ggggaaagaa attctcagaa tacgaagtga atctaaccaa 2400

cagataagat tagaagaaat ggaagaaaaa tatctaatga gagaatcaaa accagaagat 2460

atacagatga ttacagaatt aaaagccatg cttacagaaa gagaccagat cataaagaaa 2520

ctaattcaaa agaagaagaa tgataaatca ccaacaaaca ggtttgtgag tgttcccaat 2580

ctaagtgctc tggaatctgg tggagtgggc aatggacatc ctaaccgcct ggatcccatt 2640

cctaattctc cagtccacga tattgagttc aacagcagca aaccacttcc acagccagtg 2700

ccacctaaag ggcccaagac atttttgagt cctgctcaga gtgaagcttc tccagtggct 2760

tctccagatc cccagcgcca ggagtggttt gcccggtact tcacattctg a 2811

<210> 5

<211> 2163

<212> DNA

<213> Homo sapiens

<400> 5

atgtcagtgt ctggcaagaa agagtttgat gtgaaacaga tcctaaggct acgctggagg 60

tggtttagtc atccttttca aggttccacc aacactggaa gctgtcttca gcaggaagga 120

tatgagcata gagggacccc ggttcagggc aggttgaaga gccactctcg ggacagaaac 180

ggactgaaga aaagcaacag tcctgtccac cacaatatac tggcaccagt gccaggaccg 240

gcccctgccc atcagagagc cgttcagaat ttgcagcaac ataatctgat agtacatttt 300

caagcaaatg aagatactcc taaatcagtt ccagagaaga atttattcaa agaagcttgt 360

gagaaacgcg cacaagattt ggagatgatg gctgatgaca atatagaaga ttctacagca 420

agattagata cacaacactc tgaagacatg aatgccacca gatctgaaga gcagttccat 480

gttataaacc acgcagagca aactcttcgt aaaatggaga actacttgaa agagaaacaa 540

ctatgtgatg tgctactgat tgcaggacac ctccgcatcc cagcccatag gttggttctc 600

agcgcagtgt ctgattattt tgctgcaatg tttactaatg atgtgcttga agccaaacaa 660

gaagaggtca ggatggaagg agtagatcca aatgcactaa attccttggt gcagtatgct 720

tacacaggag tcctgcaatt gaaagaagat accattgaaa gtttgctggc tgcagcttgt 780

cttctgcagc tgactcaggt cattgatgtt tgctccaatt ttctcataaa gcagctccat 840

ccttcaaact gcttagggat tcgatcattt ggagatgccc aaggctgtac agaacttctg 900

aacgtggcac acaaatacac tatggaacac ttcattgagg taataaaaaa ccaagaattc 960

ctcctgcttc cagctaatga aatttcaaaa cttctgtgca gtgatgacat taatgtgcct 1020

gatgaagaga ccatttttca tgctctaatg cagtgggtgg ggcatgatgt gcagaatagg 1080

caaggagaac tggggatgct gctttcttac atcagactgc cattactccc accacagtta 1140

ctggcagatc ttgaaaccag ttccatgttt actggtgatc ttgagtgtca gaagctcctg 1200

atggaagcta tgaagtatca tcttttgcct gagagaagat ccatgatgca aagccctcgg 1260

acaaagccta gaaaatcaac tgtgggggca ctttatgctg taggaggcat ggatgctatg 1320

aaaggtacta ctactattga aaaatatgac ctcaggacca acagttggct acatattggc 1380

accatgaatg gccgtaggct tcaatttgga gtcgcagtta ttgataataa gctctatgtc 1440

gtgggaggaa gagacggttt aaaaactttg aatacagtgg aatgttttaa tccagttggc 1500

aaaatctgga ctgtgatgcc tcccatgtca acacatcggc acggcttagg tgtagccact 1560

cttgaaggac caatgtatgc tgtaggtggt catgatggat ggagctatct aaatactgta 1620

gaaagatggg accctgaggg acgacagtgg aattacgtag ccagtatgtc aactcctaga 1680

agcacagttg gtgttgttgc attaaacaac aaattatatg ctattggtgg acgtgatgga 1740

agttcctgcc tcaaatcaat ggaatacttt gacccacaca ctaacaagtg gagtttgtgt 1800

gctccaatgt ccaaaagacg tggaggtgtg ggagttgcca catacaatgg attcttatat 1860

gttgtagggg ggcatgatgc ccctgcttcc aaccattgct ccaggctttc tgactgtgtg 1920

gaacggtatg atccaaaagg tgattcatgg tcaactgtgg cacctctgag tgttcctcga 1980

gatgctgttg ctgtgtgccc tcttggagac aaactctacg tggttggagg atatgacgga 2040

catacttatt tgaacacagt tgagtcatat gatgcacaga gaaatgaatg gaaagagagc 2100

atgcaagaac ttctacaaaa cttctatacc acacagaagc tgaaagagac tctggggcac 2160

taa 2163

<210> 6

<211> 2253

<212> DNA

<213> Homo sapiens

<400> 6

atggccaagc ctcggctgct agttctctac ttcgctctga ttgtggttcc ggcctgggtg 60

tccagcattg tcctcacagg gacaagcgag cccccagatg cgcagacagt ggcgcctgcg 120

gaggacgaga ctctgcaaaa cgaggcggac aaccaggaga acgttttatc tcagttgctg 180

ggggactatg acaaggtcaa ggctatgtct gagggctcgg actgtcagtg caagtgtgtg 240

gtgagacccc tgggccggga tgcctgccag aggatcaatg cgggggcctc caggaaggaa 300

gacttctata ccgtggaaac catcacctca ggctcgtcgt gcaagtgtgc ctgtgtagca 360

cccccatcgg ccctcaatcc ctgcgaggga gacttcaggc tccagaagct gcgggaggca 420

gacagccagg acttgaagct ctccacaatc atagacatgt tggaaggagc gttctatggc 480

ctggatctcc tgaagctaca ttcagtcacc accaaactgg tggggcgagt ggataaactg 540

gaggaggaag tgtctaaaaa cctcaccaag gaaaatgaac aaatcaaaga ggacatggaa 600

gaaattcgaa ccgagatgaa taagcgaggc aaagaaaatt gctctgaaaa catcctagat 660

agcatgccag acatccgctc agccctgcag agggatgcag cagcagccta cgcccaccca 720

gagtatgaag agcggtttct gcaggaagaa accgtgtccc agcagatcaa ctccatcgaa 780

cttctgcaga cgcgacccct ggctctgcct gaggtggtga agtcacagcg gcccctgcag 840

aggcaggtcc acctgagagg ccggccggcc tcccagccca ctgtcatccg gggcatcacc 900

tactataaag ccaaggtctc tgaagaagag aatgacattg aagagcagca agatgagttt 960

ttcagcggtg acaatggagt ggatttgctg attgaagatc agctcctgag acacaacggc 1020

ctgatgacca gtgtcacccg gaggcctgca gccacccgtc agggacacag cactgctgtg 1080

acaagcgacc tgaacgctcg gaccgcaccc tggtcctcag cactgccaca gccctcgacc 1140

tcagatccca gcatcgccaa ccatgcctca gtgggaccaa cactccaaac aacctcggtg 1200

tctccagatc ccacaaggga gtcagtcctg cagccttctc ctcaggtacc agccaccact 1260

gtggcccaca cagccaccca gcaaccagca gccccagctc ctccggcagt gtctcccagg 1320

gaggcattga tggaagctat gcacacagtc ccagtgcctc ccaccacagt cagaacagac 1380

tcgctgggga aagatgctcc tgctgggtgg ggaacaaccc ctgccagccc cacgctgagc 1440

cccgaagaag aagatgacat ccggaatgtc ataggaaggt gcaaggacac tctctccaca 1500

atcacggggc cgaccaccca gaacacatat gggcggaatg aaggggcctg gatgaaggac 1560

cccctggcca aggatgagcg gatttacgta accaactatt actacggcaa caccctggta 1620

gagttccgga acctggagaa cttcaaacaa ggtcgctgga gcaattccta caagctcccg 1680

tacagctgga tcggcacagg ccacgtggta tacaatggcg ccttctacta caatcgcgcc 1740

ttcacccgca acatcatcaa gtacgacctg aagcagcgct acgtggctgc ctgggccatg 1800

ctgcatgacg tggcctacga ggaggccacc ccctggcgat ggcagggcca ctcagacgtg 1860

gactttgctg tggacgagaa tggcctatgg ctcatctacc cggccctgga cgatgagggc 1920

ttcagccagg aggtcattgt cctgagcaag ctcaatgccg cggacctgag cacacagaag 1980

gagaccacat ggcgcacggg gctccggagg aatttctacg gcaactgctt cgtcatctgt 2040

ggggtgctgt atgccgtgga tagctacaac cagcggaatg ccaacatctc ctacgctttc 2100

gacacccaca ccaacacaca gatcgtcccc aggctgctgt tcgagaatga gtattcctat 2160

acgacccaga tagactacaa ccccaaggac cgcctgctct atgcctggga caatggccac 2220

caggtcactt accatgtcat ctttgcctac tga 2253

<210> 7

<211> 1983

<212> DNA

<213> Homo sapiens

<400> 7

atgggatgta atatgtgcgt ggtccagaaa ccggaggagc agtacaaagt gatgctgcag 60

gaggtggagc tgtataaaag cagccaccgg gacaagctgg gcctgatggt ttgctaccgc 120

acggacgacg aggaggacct gggcatttat gtcggagagg taaatcccaa cagcattgca 180

gccaaagacg gccggatccg tgagggagac cgcatcatcc agattaacgg tgtagacgtc 240

cagaaccggg aagaggcggt ggccatcctg agccaggaag agaacaccaa catctccctg 300

ctggtggccc gacctgagag tcagctggcg aaaaggtgga aggacagcga ccgggatgac 360

ttcctggatg actttggctc tgagaatgag ggggagctgc gtgctcgtaa actgaaatca 420

ccccctgccc agcagcccgg aaacgaagag gagaaggggg ctcccgatgc cggcccaggc 480

ctgagcaaca gccaggagct ggacagcggg gtgggccgga ctgacgagag cacccggaac 540

gaagagagct ctgagcacga cctgctgggg gacgaacccc cgagctccac caacaccccg 600

ggaagcctgc gcaagtttgg cctgcaaggg gacgccctgc agagccggga cttccatttc 660

agcatggact ctctgctggc cgagggggcg gggctgggag ggggcgacgt cccgggcctc 720

acggatgagg agtatgagcg ctaccgtgag ctcctggaga tcaagtgcca cctggagaac 780

ggcaaccagc tgggcctcct ctttccccgg gcctccggag gcaacagcgc cctggacgtc 840

aaccgcaacg agagcctggg ccacgagatg gccatgctgg aggaggagct aaggcacctg 900

gaattcaagt gccgcaacat actgcgggcg cagaagatgc agcagctgcg tgagcgctgc 960

atgaaggcct ggctgctgga ggaggagagc ctctacgacc tggcggccag cgagcccaag 1020

aagcacgagc tgtccgacat ctccgagctg cccgagaagt cggacaagga cagcaccagc 1080

gcctacaaca ctggggagag ctgccgcagc accccgctgc ttgtggagcc cctgcccgag 1140

agccccctgc ggcgggccat ggccggcaac tccaacttga accggacccc tcccggcccc 1200

gctgttgcca cccccgccaa ggcagctcct ccaccgggga gccccgccaa gttccggtcc 1260

ctctcccggg atcctgaggc cggccggagg cagcacgcgg aggagcgcgg ccgccgcaac 1320

cccaagacgg ggttgaccct ggagcgtgtg ggccctgaaa gcagccctta cctctcgcgg 1380

cgccaccgcg gccagggcca ggagggcgag cactaccaca gctgcgtgca gctggccccg 1440

acgcgaggcc tggaggagct gggccacggc cccctgagct tggccggtgg ccctcgggtg 1500

ggcggggtgg cggccgcggc cactgaagca ccgcgcatgg agtggaaagt gaaggtgcgc 1560

agcgacggaa cccgctacgt ggccaagcgg cccgtgcgag atcggctgct gaaagcccgt 1620

gccctgaaga tccgggagga gcgcagcggt atgacgaccg acgacgacgc ggtgagcgag 1680

atgaagatgg gccgctactg gagcaaggag gagcggaagc agcacctgat ccgggcccgt 1740

gagcagcgga agcggcgcga gttcatgatg cagagccggc tggagtgcct gcgggagcag 1800

cagaatggcg acagcaagcc cgagctcaac atcattgccc tgagccaccg caaaaccatg 1860

aagaagcgga acaagaagat cctggacaac tggatcacca tccaggagat gctggcccac 1920

ggcgcgcgct ccgccgatgg caagcgggtc tacaaccctc ttctctcagt caccaccgtg 1980

tga 1983

<210> 8

<211> 2091

<212> DNA

<213> Homo sapiens

<400> 8

atggtgcaaa gataccagtc tcctgtccga gtctacaagt acccgtttga gctggtcatg 60

gcggcctacg agaagcgttt ccccacgtgc ccacagatcc cagtcttcct gggcagcgag 120

gtcttgcgcg agtcccgcag cccggacggg gctgtgcacg tggtggagcg gagctgccgg 180

ctgcgcgtgg acgccccgcg gctgctgcgg aagatcgcag gtgttgagca cgtggtcttc 240

gtgcagacaa acatcttgaa ctggaaggag aggacgctcc tcatcgaagc gcacaatgag 300

accttcgcca accgcgtggt ggtgaacgag cactgcagct acacggtcca ccctgagaat 360

gaagactgga cttgcttcga gcagtctgcc tcactggaca ttcggtcttt ctttggcttt 420

gaaaatgcct tggagaagat cgccatgaag cagtacaccg ccaacgtcaa gagggggaag 480

gaggtgattg agcattacct gaatgagctc atctcccagg gtacctcgca cattccgcgc 540

tggacgcctg ccccagtccg tgaggaggat gcccgcaacc aggctggacc gagggacccc 600

agctccctgg aggcccacgg gccccgtagc accctggggc ccgctctgga ggcggtcagt 660

atggacgggg acaagctgga tgcggactac attgagaggt gcctgggcca cctcacgccc 720

atgcaggaga gctgcctgat ccagcttcgg cactggttac aggagaccca caaaggcaag 780

attcccaaag atgagcacat ccttcggttc ctgcgggctc atgacttcca cctggacaag 840

gcccgggaaa tgctgcgcca gtccttgagc tggcgcaagc agcaccaggt ggatctcctc 900

cttcagacct ggcaaccccc tgccctgctg gaggagttct atgcaggggg ctggcattac 960

caggacatag atggccgccc cctctacatc ctccgcctgg gccagatgga caccaaaggc 1020

ttgatgaagg ccgtggggga ggaggcgctg ctgcggcatg ttctctccgt caacgaggaa 1080

ggacagaagc ggtgtgaggg gagcacaagg cagctgggcc gtcccatcag ctcctggacc 1140

tgcctgctag acctggaggg actcaacatg cggcacctgt ggcggccggg ggtgaaggcc 1200

ctgctgcgga tgattgaggt ggttgaggac aattacccag agaccctggg tcggctgctc 1260

atcgtgcgag ccccccgagt cttccccgtg ctctggacac tgatcagccc cttcatcaat 1320

gagaacacca ggcggaagtt cctcatctac agtggcagca actaccaggg acccggaggc 1380

cttgtggact atctggatag agaagtgatc cctgacttcc ttgggggaga gagtgtgtgt 1440

aatgtccccg aaggagggct ggtccccaag tccctctaca tgacagaaga ggagcaggag 1500

cacacggacc agctgtggca gtggagtgag acctaccatt cagccagcgt gctccgcgga 1560

gccccccacg aggtggccgt ggagatcctg gaaggagagt cggtcatcac ctgggacttt 1620

gacatcctgc gaggggacgt ggtgttcagc ctgtaccaca ccaagcaggc gcccaggctg 1680

ggcgcccggg aaccggggac cagggccagc gggcagctga tcgacaaagg ctgggtcctg 1740

ggcagggatt acagccgtgt ggaggctccc cttgtctgcc gggaggggga gagcatccag 1800

ggctcccatg tgacccggtg gcccggcgtc tacctgctcc agtggcaaat gcacagcccc 1860

cccagcagcg tggcctgcag cctcccgggt gtggacgatg tcctgacggc tctgcacagc 1920

cccgggccca agtgcaaact tctctactac tgtgaggtgc tcgcctctga ggacttcagg 1980

ggctccatgt ccagcctgga atcctgcacc agcggcttct cccagctcag cgccgccacc 2040

tcgtcctcct cctccggcca gtctcatagc agctccctgg tctccagata g 2091

<210> 9

<211> 4791

<212> DNA

<213> Homo sapiens

<400> 9

atggagtcca gggaaacctt aagcagctcc cggcaaagag ggggcgagtc agacttcctg 60

ccggtctcct cagccaagcc cccagctgct cctggctgtg caggagaacc tttgctctcc 120

actccaggac ctgggaaggg gatcccggtg ggcggagagc gcatggagcc agaggaggag 180

gatgaactag gctcagggcg ggatgtggat tccaactcca acgcggacag tgagaaatgg 240

gtggcaggag atggtttgga agagcaggaa ttttctatca aggaggcaaa cttcacagag 300

ggaagtctga agctaaagat tcagaccaca aagcgggcta agaaaccccc aaagaatttg 360

gagaactata tatgtccacc tgagatcaag atcaccatca agcagtctgg ggaccagaag 420

gtgtcccgtg ctggaaaaaa tagcaaagcc acgaaggagg aagaaagaag ccactccaaa 480

aagaagctcc tcacagccag tgaccttgca gccagtgacc tcaaaggatt tcagccacag 540

gcttacgaga ggccccagaa acattcaact ctccattatg acacgggcct cccacaggac 600

ttcaccggtg acaccttaaa accaaagcac cagcaaaaaa gcagcagcca gaaccacatg 660

gactggtcca ccaactctga cagcggaccc gtcactcaga attgcttcat cagtccagag 720

tctggcagag aaactgcaag caccagcaag atccccgctc ttgagcccgt ggcttccttt 780

gcaaaggccc agggtaagaa aggcagtgca gggaacacgt ggagtcagtt gtctaacaat 840

aacaaagatc tgctcttggg aggtgtggct ccatccccaa gcagccacag ctcaccagcc 900

ccacccagca gctctgctga gtgcaacggg cttcagccct tggtggatca agatggagga 960

ggtacaaagg agcccccaga accacctacg gtgggcagca agaaaaagtc cagtaaaaaa 1020

gatgtgataa gtcagaccat accaaaccca gacctggatt gggtcaagaa tgcccagaaa 1080

gcatttgaca atacagaagg gaaaagggaa ggttattccg cagatagtgc ccaagaggca 1140

tcaccagcca ggcagaacgt gagttctgcc agtaatcctg aaaatgactc aagtcatgtc 1200

cggattacta tccccatcaa ggcaccctct ctggatccaa ccaaccataa gaggaaaaaa 1260

agacagtcca ttaaagcggt ggtggaaaag atcatgccag agaaagcctt ggcttctgga 1320

atcaccatga gcagtgaagt agttaacagg atactttcca actctgaggg gaataagaag 1380

gatccccgtg tccctaagtt gagtaaaatg atagagaatg agtccccctc agttggcctt 1440

gaaactggtg gaaatgctga gaaagttatc ccaggaggtg tgtctaagcc gcggaagcca 1500

cccatggtca tgacacctcc aacgtgcaca gatcactctc catccagaaa gctgccagaa 1560

atccagcatc caaaatttgc tgcaaaacga aggtggactt gcagcaaacc aaaacctagc 1620

accatgcttc gagaggcagt tatggccacc tctgataaac tgatgctgga gcccccgtct 1680

gcatatccca tcaccccatc cagccctctc tacaccaaca cagacagtct tactgtgatc 1740

actccagtca aaaagaagcg gggacgacca aagaagcagc ctttgctcac agtcgagacg 1800

attcatgagg gaacttccac cagccccgtc agtcccatca gccgagagtt tcctggcact 1860

aagaaaagaa agcgacgacg caatttagcg aagttggccc agctagtgcc gggagaggac 1920

aaacccatga gcgagatgaa atttcacaag aaagttggaa agctcggcgt gttggataag 1980

aagaccatca aaactatcaa taagatgaag acactcaaga ggaaaaacat cttgaatcag 2040

atcttgtcct gttccagcag cgttgctctg aaggcaaaag ctcccccaga gaccagccct 2100

ggggcagcag ccattgaaag caaactgggc aagcagatta atgtcagcaa gaggggaacc 2160

atctacattg gcaagaagcg gggcaggaag ccaagagcag agctgccacc cccatccgaa 2220

gaacccaaaa cagccatcaa gcaccccagg cctgtttcta gccagccgga tgttccagcc 2280

gtgccttcca actttcagtc acttgtggcg tcttcaccag cagctatgca cccactttca 2340

acacagttag gtgggtccaa tggcaacctg agccctgcca gcactgaaac caatttttca 2400

gagttgaaaa ctatgccaaa tctccagccc atcagtgctc ttccaaccaa aacccaaaag 2460

ggaatacaca gtggaacctg gaagctgtct ccacccagac tgatggccaa ctccccttca 2520

cacctgtgcg agattggctc cctaaaggaa atcacgctgt cccctgtgag cgagtcccac 2580

agtgaggaga cgatccccag cgacagcggc attgggacag acaacaacag cacttctgac 2640

caagcggaga agagctcaga atcccgaagg aggtactctt ttgatttctg ctccctggac 2700

aacccggagg ccattccgtc cgacaccagc acaaagaacc ggcatggcca ccggcaaaag 2760

catctcattg tggacaactt tctggcccac gaaagcctca agaagccaaa gcacaagagg 2820

aaacggaaaa gcctgcaaaa ccgcgatgac ctccagtttc tggcagacct ggaggagcta 2880

atcaccaagt tccaagtgtt cagaatctcc caccggagtt acaccttcta ccacgagaat 2940

ccatatccca gcatttttcg gattaatttt gatcactatt acccggtgcc atatatccag 3000

tatgacccgt tgctctatct tcgtaggact tcagacttga agtcaaagaa gaagcgtggt 3060

aggcctgcaa aaaccaatga caccatgaca aaggtgcctt ttttacaagg gttcagctac 3120

cctattccca gtggaagtta ctatgcaccc tatggaatgc cttacacatc aatgcctatg 3180

atgaaccttg gttattacgg tcagtaccca gctcctttgt acctatcgca cacgcttgga 3240

gcagcttccc cattcatgag gccaacagtg ccaccacctc agttccacac aaactcccac 3300

gtaaagatgt ccggtgcagc taagcataaa gccaagcatg gagtacacct gcagggacct 3360

gttagcatgg gccttggtga catgcagcct tctctgaacc ctcccaaggt aggcagtgcc 3420

agtctgtcca gtggtcggct ccataagagg aaacacaaac acaagcataa gcacaaggaa 3480

gaccggatcc tagggaccca tgacaacctg agtggtcttt ttgcaggcaa agccacaggc 3540

ttctccagcc acatcctgag cgagcggctg agtagcgcag acaaagagct cccgctggtg 3600

agtgagaaga acaagcataa ggagaaacag aagcaccagc acagcgaagc cggccacaaa 3660

gcttctaaga acaactttga ggtggacacc ctgtctacac tgtcactttc cgacgcccag 3720

cattggacac aggccaagga aaaaggagac ttgagcagtg agcctgtgga ctcatgcacg 3780

aaaagatact ctggcagtgg cggggatggt ggcagcacga gatcagagaa cctggacgtg 3840

ttcagtgaaa tgaacccttc gaatgacaag tgggacagtg acgtgagtgg gagtaaaagg 3900

aggagctatg aaggctttgg aacgtacagg gaaaaggaca tccaagcctt caagatgaac 3960

cgcaaggaga gaagttctta tgactcctcc atgtctccag ggatgccaag tccccactta 4020

aaagtggacc agacagcagt gcatagtaag aacgaaggct cagtgcccac catgatgacc 4080

aggaagaagc cagccgcagt tgacagtgtt acaattccac cagccccagt gttatctctc 4140

cttgctgcat ctgcagcaac gtcggatgca gtcggctcct ccctgaagaa gaggttcaag 4200

cggcgggaga tcgaagccat ccagtgcgaa gtgcggaaga tgtgcaacta caccaagatc 4260

ctgtccacca agaagaacct ggaccacgtg aacaagatcc tgaaggccaa gcggctgcag 4320

agacaatcaa aaacaggcaa caacttcgtg aagaagaggc gcgggcgtcc caggaagcag 4380

cccacccagt tcgatgagga ctccagagac caaatgccgg tgctggaaaa atgcatcgac 4440

ctgcccagca aaagaggcca gaagcccagc ctgagcccgc tggtgctgga gcccgccgcc 4500

agccaagaca ccatcatggc caccatcgag gcggtcatcc acatggcccg ggaggcgccg 4560

cccctgcccc cgccaccgcc gccgcccctg ccgccaccgc cgccaccacc cctgcccccg 4620

ccaccccctc tacccaagac cccccgaggc ggaaagagga aacacaaacc gcaggccccc 4680

gctcagcccc cacagcagtc gcccccgcag cagccccttc cccaggaaga ggaggtgaaa 4740

gccaaaaggc agaggaagtc ccgagggagt gagagcgagg tccttcccta g 4791

<210> 10

<211> 1773

<212> DNA

<213> Homo sapiens

<400> 10

atgaagagca aagtggacac gattgtgaac ttcacccacc agcacttcac ctcccagttc 60

gaggtcactg tctgggcacc caggctcccc ctgcagattg agatctcaga caccgagctg 120

agccagatca agggctggag gatcccggtt gctgccaaca gaaggcctac ccgggaaagc 180

gatgacgagg acgatgagga gaagaaggga cgaggctgct ccctgcagta ccagcacgcc 240

acagtgcgtg tcctcaccca gtttgtggcc gagtcacctg acttagggca gctgacctac 300

atgctgggcc ccgactggca gtttgacatc actgaccttg tgaccgagtt catgaaggtg 360

gaggagccga aaatcgctca gttacaggac ggcaggaccc tggctggtcg ggagccggga 420

ataaccacgg tgcaggtcct ctcgccgttg tctgactcca tcctggctga gaagacggtg 480

attgtcctgg atgaccgagt caccatcgcg gagctgggag tgcagctcgt agctggcatg 540

tctctctccc tgcagccaca ccgagcagac aaaagggcca tcgtctccac agctgctgcc 600

ctggatgttc ttcagtcccc acagcaggaa gcaatagtaa gttcttggat tttgttcagt 660

gatggttcgg tgacaccttt agacatttac gatcctaagg attattctgt tactgtctca 720

tcattggatg aaatggtggt gtctgtccag gcaaaccttg agtccaaatg gccaattgtg 780

gttgcagagg gtgaaggaca agggcctttg attaagttag aaatgatgat aagtgaacct 840

tgtcagaaga ccaagaggaa gagtgttctt gccgtgggta aaggaaatgt caaggtcaaa 900

ttcgaaccaa gtagtgatga gcaccaagga ggcagcaatg atattgaggg cataaatcgg 960

gaatataaag accacctcag taattccata gagcgcgaag gaaaccagga gagagcagtc 1020

caggaatggt tccaccgtgg cacacctgtt ggccaagagg aaagtaccaa caaaagcaca 1080

accccccagt ctcccatgga agggaagaat aagttactca aaagtggtgg tccagatgcc 1140

tttacaagct tccccactca agggaagtca ccggacccca ataatcctag tgacctcaca 1200

gtgacctcaa gggggctaac ggacttggag attggcatgt atgccttgct ctgcgtcttc 1260

tgtctggcca ttctggtctt cttgatcaac tgcgtggcgt ttgcctggaa atacagacac 1320

aaaaggtttg ctgtgagtga gcagggcaac atcccccatt cccacgactg ggtctggctt 1380

gggaatgaag tggaactttt ggagaaccct gttgacatta cactcccatc agaggagtgc 1440

acaaccatga tagacagggg cctgcagttc gaggagagga acttccttct gaatggcagt 1500

tcccagaaga cttttcatag tcaactactc agaccctctg actatgtcta tgagaaagaa 1560

attaaaaatg aacctatgaa ttcttcgggc ccaaagagga agagagtcaa gttcacttcc 1620

tacaccacca tcctcccaga ggacggcggc ccatacacca actccatcct gtttgacagc 1680

gatgataaca tcaagtgggt ctgccaagat atggggctgg gggattcaca ggactttaga 1740

gactatatgg aaagtctgca agaccagatg taa 1773

Claims (7)

1. The marker molecule related to the colorectal cancer prognosis is characterized by comprising gene sequences shown as SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9 and SEQ ID NO. 10.

2. A test kit for assessing the prognostic effect of rectal cancer, comprising: reagents for detecting marker molecules associated with the prognosis of rectal cancer; the marker molecule comprises gene sequences shown as SEQ ID NO 1, SEQ ID NO 2, SEQ ID NO 3, SEQ ID NO 4, SEQ ID NO 5, SEQ ID NO 6, SEQ ID NO 7, SEQ ID NO 8, SEQ ID NO 9 and SEQ ID NO 10.

3. The kit of claim 2, wherein the reagents for detecting the marker molecule comprise a primer pair for the marker molecule.

4. The kit of claim 3, wherein the reagents for detecting the marker molecule comprise a fluorescent probe specific for the marker molecule.

5. A system for assessing the prognostic effect of rectal cancer, the system comprising:

(1) The data input module is used for inputting the content detection result of the marker molecules related to the prognosis of the rectal cancer into the model calculation module;

the marker molecule comprises gene sequences shown as SEQ ID NO 1, SEQ ID NO 2, SEQ ID NO 3, SEQ ID NO 4, SEQ ID NO 5, SEQ ID NO 6, SEQ ID NO 7, SEQ ID NO 8, SEQ ID NO 9 and SEQ ID NO 10;

(2) The model calculation module is used for calculating and processing the input content detection result to obtain the prognosis effect data of the detected patient;

(3) And the result output module is used for evaluating the prognosis effect data of the detected patient according to the evaluation standard of the prognosis effect of the rectal cancer and outputting an evaluation result.

6. Use of the marker molecule of claim 1 for the preparation of a diagnostic agent for rectal cancer.

7. Use of the marker molecule of claim 1 for the preparation of a reagent for the prognostic evaluation of a patient having rectal cancer.

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