Biomarkers and uses thereof in prognosis and treatment strategies for right-side colon cancer disease and left-side colon cancer disease

Inactive Publication Date: 2012-07-05
UNIV OF NOTRE DAME DU LAC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]In a general and overall sense, the present invention provides powerful and highly significant biomarkers for quantifying risk of recurrence of location-specific colon cancer. The present disclosure demonstrates that different processes dominate disease progression in left-side colon cancer (LCC) and right-side colon cancer (RCC), and that genes that are most predictive of relapse in LCC are much less significant in RCC, and vice-versa. Thus

Problems solved by technology

However, Genomic Health's test and others reports of a test for relapse in colon cancer is widely considered a failure.
The Oncotype DX Colon test identifies a small group of poor prognosis patients, but the test does not isolate good prognosis patients who can avoid further therapy, such as chemotherapy.
Unfortunately, there does not exist a prognostic test for colon cancer that provides a consistent and accurate assessment of colon relap

Method used

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  • Biomarkers and uses thereof in prognosis and treatment strategies for right-side colon cancer disease and left-side colon cancer disease
  • Biomarkers and uses thereof in prognosis and treatment strategies for right-side colon cancer disease and left-side colon cancer disease
  • Biomarkers and uses thereof in prognosis and treatment strategies for right-side colon cancer disease and left-side colon cancer disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

Identification of RT-PCR Primer-Probes that Measure in FFPE Tissue the mRNA Species Targeted by the ap-Colon Microarray Probes

[0108]mRNA will be extracted from a number of colon cancer cell lines as well as from paraffin (FFPE) blocks prepared from these cell lines. This will enable direct assessment of the probes in the FFPE material and comparison with the “fresh state”. Initial assessment will be performed using 13 different assay primer-probes pairs (8 from ap-Colon (two per gene) and 5 normalization controls). All assays will be performed in triplicate. The probes will be verified as providing comparable results in fresh tissues (cell lines) and matched FFPE counterparts. Quantitative RT-PCR with ΔΔCT methods for data analysis will be used to assess the utility of the probes. If suitable primer-probes cannot be found for the initial choice of genes, the list will be screened to identify replacement genes found in the development of ap-Colon. The RL-COLON pair of tests will use ...

example 2

Materials and Methods

[0113]The present example is provided to present the various materials, methods and statistical tools employed in the development and practice of the present invention.

[0114]Statistical analysis. The language R http: / / www.r-project.org / was used for all statistical analyses. Survival models were fit with the R package survival. The microarray annotation package hgu133plus2.db in BioConductor http: / / www.bioconductor.org / was also used. The proportional hazard condition was verified with the cox.zph function. All p-values in survival models refer to the p-value of the logrank score of a Cox proportional hazard model (CPH). A CPH is considered statistically significant if the p-value of the logrank score is <0.05.

[0115]Microarray dataset of colon cancer samples. In the present examples, the Gene Expression Omnibus (http: / / www.ncbi.nim.nih.gov / gds) data series GSE14333 was used.13 The characteristics of the data series GSE14333 are provided in Table 323.

[0116]Sample...

example 3

Different Pathways dominate Progression to Relapse in LCC and RCC

[0128]The present example demonstrates the location specificity of the dominant pathway to relapse in colon cancer. Attention is focused on samples in GSE14333 with Dukes stage A, B or C. Table 3 demonstrates the characteristics of patients in GSE14333.

TABLE 3Characteristics of patients in GSE14333relapsechemoin stagein stageDukes stagegenderA, B, CA, B, Cno.(A / B / C / D)(M / F)(no / yes)(no / yes)all tumors29044 / 94 / 91 / 61164 / 126180 / 46 142 / 87 left side12218 / 37 / 40 / 2777 / 4570 / 2355 / 40right side12517 / 44 / 41 / 2359 / 6684 / 1763 / 39rectum398 / 12 / 10 / 926 / 1324 / 6 22 / 8 other41 / 1 / 0 / 22 / 22 / 02 / 0

TABLE 4Genes and associated pathways most significantly implicated in relapse in leftside colon cancer with Dukes stage A, B or C. Left side:CPHdirectionpathwaysmultistateprobegenep-valuein relapseeffected*marker236028_atIBSP2.7 × 10−5UPFANOX4210095_s_atIGFBP31.0 × 10−4UPP53NOX4213425_atWNT5A2.5 × 10−4DOWNWNTMMP3223121_s_atSFRP23.1 × 10−4UPWNTNOX4229271_x_atCOL11...

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Abstract

Genetic biomarkers for left side colon cancer (LCC) (such as expression levels of an RNA transcript or expression product of NOX4, MMP3, or a combination) and right side colon cancer (RCC) (such as expression levels of an RNA transcript or expression product of CDCX2, FAM69A, or a combination), are disclosed. Methods for using the biomarkers in providing a prognosis of relapse-free survival probability in patients having LCC or RCC are also presented. Prognostic panels using gene expression values of the biomarkers are also presented. Computer implemented methods employing the biomarkers, and as well as for determining relapse-free survival probability in a patient having RCC or LCC are provided. A genetic method for classifying a colon cancer tissue as a RCC or as a LCC is also disclosed.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]Priority to claimed to U.S. Provisional Patent Application 61 / 459,864, filed Dec. 20, 2010. Reference is hereby made to U.S. Provisional Patent Application 61 / 462,592, filed Feb. 4, 2011. The entire content of U.S. Ser. No. 61 / 459,865 and U.S. Ser. No. 61 / 462,592, is specifically incorporated herein by reference.BACKGROUND[0002]Thousands of people around the world have been diagnosed with colon cancer, hundreds ultimately dying of the disease. Patients are typically treated with colon resection surgery, followed by radiation therapy or systemic chemotherapy, the therapy being based on macroscopic traits of the tumor and the tumor stage. The 5-year relapse-free survival rate is improved in some patients receiving chemotherapy after colon surgical resection surgery, while this statistic is not improved in others.[0003]Diagnostic tests for predicting relapse in colon cancer include the Oncotype DX test (Genomic Health). However, Genomic Heal...

Claims

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Application Information

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IPC IPC(8): C40B30/04C12N9/50G06F17/18C40B40/06C12N5/09C12N9/02C07H21/02
CPCG01N33/57419G01N2800/54C12Q2600/158C12Q2600/106C12Q2600/118C12Q1/6886C12N5/0693C12Q1/686G01N33/57484
Inventor BUECHLER, STEVENHUMMON, AMANDA
Owner UNIV OF NOTRE DAME DU LAC
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