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.

1 . A genetic biomarker for left side colon cancer (LCC) in a patient, said biomarker comprising an expression level of an RNA transcript or expression product of NOX4, MMP3, or a combination of NOX4 and MMP3. 
     
     
         2 . The genetic biomarker of  claim 1  wherein a relatively high expression level of an RNA transcript or expression product of NOX4 from a tissue harvested from a left colon tumor tissue sample is predictive of a decreased 5-year relapse-free survival probability for colon cancer. 
     
     
         3 . The genetic biomarker of  claim 1  wherein a relatively low expression level of an RNA transcript or expression product of NOX4 from a tissue harvested from a left colon tumor tissue sample is predictive of an increased 5-year relapse-free survival probability for colon cancer. 
     
     
         4 . The genetic biomarker of  claim 1 , wherein said biomarker is NOX4. 
     
     
         5 . A panel of genetic probes for assessing 5-year survival probability without relapse in a patient population having a cancerous left-side colon tumor, said panel consisting essentially of the genetic probes of Table 2, Table 4, or a combination thereof. 
     
     
         6 . A genetic biomarker for assessing 5-year survival probability without relapse in a patient having a cancerous right-side colon tumor (RCC) comprising an expression level of an RNA transcript or expression product of CDX2, FAM69A, or a combination of CDX2 and FAM69A. 
     
     
         7 . The genetic biomarker of  claim 6  wherein a relatively low expression level of an RNA transcript or expression product of CDX2 from a tissue harvested from a right colon tumor tissue is predictive of a decreased 5-year relapse-free survival probability for colon cancer. 
     
     
         8 . The genetic biomarker of  claim 6  wherein a relatively high expression level of an RNA transcript or expression product of CDX2 from a tissue harvested from a right colon tumor tissue is predictive of an increased 5-year relapse-free survival probability for colon cancer. 
     
     
         9 . A panel of genetic probes for assessing 5 year survival probability without relapse in a patient population having a cancerous right-side colon tumor, said panel consisting essentially of the genetic probes of Table 1, Table 5, or a combination thereof. 
     
     
         10 . A method for assessing a 5-year relapse free survival probability of a patient diagnosed with right side colon cancer (RCC) disease, comprising:
 a) measuring an expression level of a set of RCC-related genes comprising CDX2, FAM69A, or both CDX2 and FAM69A, or an expression product thereof, from a right side colon tissue sample obtained from the patient having RCC disease to provide a test RCC test level;   b) comparing said RCC test level to a threshold expression level of like RCC-related genes from an RCC colon cancer population, said RCC colon cancer population comprising relapse and relapse-free RCC colon cancer patients, and determining if said test expression level is higher or lower than said threshold expression level; and   c) identifying a decreased probability without relapse for the RCC patient having a lower RCC test expression level, and identifying an increased probability of survival without relapse in a RCC patient having a higher RCC test level.   
     
     
         11 . The method of  claim 10  wherein the right side colon tissue sample is embedded in paraffin. 
     
     
         12 . The method of  claim 10  wherein a patient sample having a higher test level of the RCC-related gene CDX2 identifies a patient who can avoid chemotherapy without increased risk of colon cancer relapse or metastasis. 
     
     
         13 . The method of  claim 8  wherein the set of RCC related genes consists essentially of a CDX2 expression level. 
     
     
         14 . A method for assessing a 5-year relapse free survival probability of a patient diagnosed with left side colon cancer (LCC) disease, comprising:
 a) measuring NOX4, MMP3, or a combination of NOX4 and MMP3, or an expression product thereof from a left side colon tumor tissue sample obtained from the patient to provide a test LCC level;   b) determining if said LCC test level(s) is high or low,   wherein an expression level is considered low or high as compared to a threshold value, wherein said threshold value is calculated from a reference set of like-gene expression levels from a like-classified colon cancer patient population, said like-classified patient population comprising relapse and relapse-free colon cancer patients; and   c) identifying an improved survival probability without relapse for the patient having a low expression level of NOX4, high expression level of MMP3, or both according to the selection of genes in a), and identifying a poor/lower survival probability of survival without relapse in a patient having a high expression level of NOX4 or low expression level of MMP3.   
     
     
         15 . The method of  claim 14  wherein the left side colon tumor tissue is embedded in paraffin. 
     
     
         16 . The method of  claim 14  wherein the set of LCC related genes consists essentially of a NOX4 expression level, and a patient sample having a lower NOX4 expression level identifies a patient who can avoid adjuvant chemotherapy without increased risk of metastasis or relapse. 
     
     
         17 . A computer implemented method of determining relapse free survival probability for a patient having undergone colon cancer surgery, said method comprising:
 a) classifying the colon cancer patient as a right side colon cancer (RCC) or as a left side colon cancer (LCC) disease patient by identifying the side of the colon on which the colon cancer was localized and providing said identifying classification to a receiver module;   b) where the identifying classification of the patient is LCC disease, measuring an expression level of an RNA transcript or expression product of NOX4 in a colon cancer tissue obtained from the LCC patient, to provide a test NOX4 test level, and where the identifying classification of the patient is RCC disease, measuring an expression level of an RNA transcript or expression product of CDX2 in a colon cancer tissue obtained from the RCC patient, to provide a test CDX2 level, and providing said expression level data to a receiver module; and   c) determining the relapse free survival probability of the LCC patient as good in a LCC patient tissue with a low NOX4 expression level, and a relapse-free survival probability to a LCC patient as poor with a high NOX4 expression level; and determining the relapse-free survival probability of an RCC patient as poor in a RCC patient tissue with a low CDX2 expression level, and a relapse-free survival probability as good with a high CDX2 expression level,   wherein an expression level is considered low or high as compared to a threshold value, wherein said threshold value is calculated from a reference set of like-gene expression levels from a like-classified colon cancer patient population, said like-classified patient population comprising relapse and relapse-free colon cancer patients.   
     
     
         18 . The computer implemented method of  claim 17  further including generating a prognosis report of said LCC patient or RCC patient. 
     
     
         19 . A method for reducing reactive oxidative species (ROS) production in colon cancer tissues comprising inhibiting expression of a NOX4 gene in colon cancer cells. 
     
     
         20 . A genetic method of classifying a colon cancer tissue sample as a right side colon cancer or as a left side colon cancer comprising:
 a) measuring a level of PRAC gene expression in the colon cancer tissue sample; and   b) determining that a colon cancer tissue sample is a right side colon cancer where the PRAC gene expression negligible, and determining that a colon cancer tissue sample is a left side colon cancer sample where the PRAC gene expression is positive.   
     
     
         21 . A computer implemented method of determining a probability of a lack of responsiveness to chemotherapy treatment in a patient having had surgical intervention for right side colon cancer (RCC) or left side colon cancer (LCC), comprising:
 a) classifying the colon cancer patient as a right side colon cancer (RCC) or as a left side colon cancer (LCC) disease patient by identifying the side of the colon on which the colon cancer was localized and providing said identifying classification to a receiver module;   b) where the classification of the patient is LCC disease, measuring an expression level of an RNA transcript or expression product of NOX4 in a colon cancer tissue obtained from the LCC patient, to provide a test NOX4 test level, and where the identifying classification of the patient is RCC disease, measuring an expression level of an RNA transcript or expression product of CDX2 in a colon cancer tissue obtained from the RCC patient, to provide a test CDX2 level, and providing said expression level data to a receiver module; and   c) determining the likelihood of response to chemotherapy of the LCC patient as low in a patient with a low NOX4 expression level; and determining the likelihood of response to chemotherapy of the RCC patient as low in a patient with a high CDX2 expression level,   wherein an expression level is considered low or high as compared to a threshold value, wherein said threshold value is calculated from a reference set of like-gene expression levels from a like-classified colon cancer patient population, said like-classified patient population comprising relapse and relapse-free colon cancer patients not having received chemotherapy.