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

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...

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, using the information of the present disclosure, highly accurate and specific molecular tools are provided that can identify a patient as having LCC disease apart from those with RCC disease, and as a consequence of this, enable methods for highly accurate and effective techniques of prognosis assessment and treatment tailored to the disease type of the patient. In this way, methods for treating LCC and RCC as separate diseases are now possible.

[0009]The specific and different genetic biomarkers of the invention separates each disease group population of colon cancer patients, the LCC disease group and RCC disease group population, into a good prognosis group and a poor prognosis group. Specifically, the LCC disease group population is divided into a poor prognosis LCC population group and a good prognosis LCC population group. The RCC disease group population is divided into a poor prognosis RCC patient population group and a good prognosis RCC patient population group. The biomarkers possess a bimodal distribution among these specific populations of colon cancer patients, and may be used as part of the presently described methods to provide location specific left-side or right-side colon cancer tumor disease assessment. Use of the biomarkers provides an improved and more accurate quantifier of risk of colon cancer relapse and of survival probability compared to tumor stage alone.

[0013]In specific embodiments, in a population of colon cancer patients having left side colon cancer (LCC) disease, a patient whose tumor expresses a high level of a specific gene or set of genes, such as gene NOX4, are at higher risk for colon cancer relapse within a 5 year post-surgical period. Such patients would be identified as in need of chemotherapy or other treatment to improve their chances of survival, whereas those expressing a low level of NOX4 are not at a higher risk for relapse, and therefore would not be in need of treatment such as chemotherapy or the like to improve their chances of a 5-year relapse free survival.

[0029]A higher percentage of LCC patients that experience a colon cancer relapse after surgical intervention have been determined, according to the methods of the present invention, to present left side colon cancer samples with a higher expression levels of NOX4. These patient samples also evidence elevated integrin-binding sialoprotein (IBSP), and lower expression levels of matrix metallopeptidase 3 (stromelysin 1, progelatinase) (MMP3).

[0030]Therefore, a higher NOX4 expression level in a left-side colon cancer tissue would be indicative of a higher risk of colon cancer relapse. Thus, this patient population would more likely benefit in a higher probability of increased survival without relapse and decreased risk of colon cancer metastasis if additional, post-colon surgery, treatments were administered, such as chemotherapy and / or radiation therapy.

[0054]After transformation of colorectal adenoma into colorectal cancer, the pathological condition of the afflicted individual can be further exacerbated by formation of metastasis. The present invention may be used to discriminate and identify early colon cancer, thus permitting the detection of the colon cancer disease at an early and still benign stage, an early stage or benign stage and / or early colon tumor stages. The early detection enables the physician to timely remove the colorectal adenoma and to dramatically increase the chance of the individual to survive.

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 relapse risk in clinical practice.

Painful and expensive therapies, such as chemotherapy, are typically part of a standard and routinely proscribed clinical care management protocol for the post-colon cancer resection patient.

However, there is no reliable method in existence that is capable of accurately predicting which of these patient populations could successfully avoid the painful and toxic process of chemotherapy without risk of relapse.

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