The National Institute of Health says that the pattern of genomic alterations in colon and rectal tissues is the
same regardless of anatomic location or origin within the colon or the
rectum, leading researchers to conclude that these two cancer types can
be grouped as one, according to The Cancer Genome Atlas (TCGA) project's
large-scale study of colon and rectal cancer tissue specimens.
In multiple types of genomic analyses, colon and rectal cancer
results were nearly indistinguishable. Initially, the TCGA Research
Network studied colon tumors as distinct from rectal tumors.
"This finding of the true genetic nature of colon and rectal cancers
is an important achievement in our quest to understand the foundations
of this disease," said NIH Director Francis S. Collins, M.D., Ph.D. "The
data and knowledge gained here have the potential to change the way we
diagnose and treat certain cancers."
The study also found several of the recurrent genetic errors that
contribute to colorectal cancer. The study, funded by the National
Cancer Institute (NCI) and the National Human Genome Research Institute
(NHGRI), both parts of the National Institutes of Health, was published
online in the July 19, 2012, issue of the journal Nature.
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 percent 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.
NCI estimates that more than 143,000 people in the United States will
be diagnosed with colorectal cancer and that 51,500 are likely to die
from the disease in 2012. 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.
The researchers 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 scientists
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.
"While it may take years to translate this foundational genetic data
on colorectal cancers into new therapeutic strategies and surveillance
methods, this genetic information unquestionably will be the springboard
for determining what will be useful clinically against colorectal
cancers," said Harold E. Varmus, M.D., NCI director.
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 researchers, 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 investigators 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,
noted the researchers.
"It takes a critical group of researchers to conduct research at this
scale and of this quality," said Eric. D. Green, M.D., Ph.D., NHGRI
director. "This study is among the most comprehensive of its kind to
date and vividly illustrates how TCGA data sets can shed new light on
fundamental properties of human cancers."
Source: NIH
Source: NIH
