Study Shows Colon and Rectal Tumors Constitute a Single Type of Cancer
The National Cancer Institute (NCI) estimates that in 2012, more than 143,000 people in the US will be diagnosed with colorectal cancer and that 51,500 are likely to die. Colorectal cancer is the fourth most common cancer in men, after non-melanoma skin, prostate and lung cancer. It is also the fourth most common cancer in women, after non-melanoma skin, breast and lung cancer.
According to the Cancer Genome Atlas (TCGA) project’s large-scale study of colon and rectal cancer tissue specimens published online in the journal Nature (19 July 2012), the pattern of genomic alterations in colon and rectal tissues appear the same regardless of anatomic location or origin within the colon or the rectum, thus leading to the conclusion that these two cancer types can be grouped as one. The study also found several of the recurrent genetic errors that contribute to colorectal cancer.
There is a known negative association between aggressiveness of colorectal tumors and the phenomenon of hypermutation, in which the rate of genetic mutation is abnormally high because normal DNA repair mechanisms are disrupted. In this study, 16% of the specimens were found to be hypermutated. Three-fourths of these cases exhibited microsatellite instability (MSI), which often is an indicator for better prognosis. Microsatellites are repetitive sections of DNA in the genome. If mutations occur in the genes responsible for maintaining those regions of the genome, the microsatellites may become longer or shorter; this is called MSI.
The authors observed that in the 224 colorectal cancer specimens examined, 24 genes were mutated in a significant numbers of cases. In addition to genes found through prior research efforts (e.g., APC, ARID1A, FAM123B/WTX, TP53, SMAD4, PIK3CA and KRAS), the authors identified other genes (ARID1A, SOX9 and FAM123B/WTX) as potential drivers of this cancer when mutated. It is only through a study of this scale that these three genes could be implicated in this disease.
The research network also identified the genes ERBB2 and IGF2 as mutated or overexpressed in colorectal cancer and as potential drug targets. These genes are involved in regulating cell proliferation and were observed to be frequently overexpressed in colorectal tumors. This finding points to a potential drug therapy strategy in which inhibition of the products of these genes would slow progression of the cancer.
A key part of this study was the analysis of signaling pathways. Signaling pathways control gene activity during cell development and regulate the interactions between cells as they form organs or tissues. Among other findings, the TCGA Research Network identified new mutations in a particular signaling cascade called the WNT pathway. According to the authors, this finding will improve development of WNT signaling inhibitors, which show initial promise as a class of drugs that could benefit colorectal cancer patients.
In addition to examining the WNT pathway, the authors also identified RTK/RAS and AKT-PI3K as pathways that are altered in a substantial set of colorectal tumors, which may show promise for targeting therapies for colorectal cancer. Because of these findings, drug developers may now be able to narrow their scope of investigation with an expectation of producing more focused therapeutic approaches.