The Cancer Genome Atlas generates genomic data for colon and rectal cancers that point to potential targets for treatment
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.”
Aim: Life-time risk of a metachronous colorectal cancer (CRC) is 0.6%-3% following sporadic CRC and 15-26% in Lynch syndrome (LS). The life-time incidence of CRC in individuals with moderate familial risk is 8-17%. Risk of metachronous CRC (mCRC) is unknown.
Method: A retrospective longitudinal study of the Regional Familial CRC Registry was performed. Patients who had at least one CRC were categorised as follows: moderate risk (n=383), LS (n=528) and population risk (n=409). Kaplan-Meier estimate (1-KM) and cumulative incidence function (CI) were used to calculate the risk of mCRC. 1-KM gives the risk for individuals remaining at risk (alive) at a given time point thus is useful for counselling. CI gives the risk for the whole population.
Results: 1-KM and CI demonstrated that the risk of mCRC was significantly higher in moderate risk patients compared with population risk (1-KM p= 0.008, CI p= 0.00097). Both were lower than LS. Moderate risk 1-KM was 2.7%, 6.3% and 23.5% at 5,10 and 20 years. Population risk 1-KM was 1.3%, 3.1% and 7.0% at 5, 10 and 20 years and CI was 0.3%, 0.6% and 2.4%.
Conclusion: These data indicate that the risk of mCRC is significantly higher in patients with a moderate family history than in those at population risk. This justifies pro-active life-long surveillance.
A cake sale to raise funds for, and awareness of, Beating Bowel Cancer Awareness Week attracted a special sweet-toothed shopper on Friday, March 2.
Richmond Park MP Zac Goldsmith popped along to the cake stand at West Middlesex Hospital as Cancer services user group Cube sold teatime treats.
Cube was also on hand to make people aware of the fact bowel cancer is the third most common cancer in the UK for men, second for women, and can be treated if detected early. Visitors also got to walk around inside a giant inflatable bowel.
More than £400 was raised for the NHS Campaign Be clear on cancer.
Dr Kevin Monahan, from the hospital, said: “More than 90 per cent of bowel cancer patients diagnosed with the earliest stage of the disease survive five years from diagnosis compared with only 6.6 per cent of those diagnosed with advanced disease.” Mr Goldsmith said: “One person dies every 30 minutes from bowel cancer, and this number could be greatly reduced if the disease is spotted early. It is imperative that people know the signs.”
For more information visit nhs.uk/bowelcancer.
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The world’s original polyposis registry is based at St Mark’s Hospital, Harrow. FAP (Familial Adenomatous Polyposis) is an inherited condition which mainly affects the large intestine (also known as the large bowel or colon and rectum). People with FAP develop many polyps (which are like small cherries on stalks) inside their large bowel. There are many different types of polyps but these particular polyps are called adenomas (the “adenomatous” in FAP). An adenoma can in time turn into a cancer which is why it is so important to make sure anyone at risk of inheriting FAP is examined.
FAP is a serious condition unless detected early when it can be treated.
(Familial Adenomatous Polyposis) FAP is an inherited condition which mainly affects the large intestine (also known as the large bowel or colon and rectum). People with FAP develop many polyps (which are like small cherries on stalks) inside their large bowel. There are many different types of polyps but these particular polyps are called adenomas (the “adenomatous” in FAP). An adenoma can in time turn into a cancer which is why it is so important to make sure anyone at risk of inheriting FAP is examined.
FAP is a serious condition unless detected early when it can be treated.
Core is the only charity in the UK that funds research into the entire range of gut, liver, intestinal and bowel illnesses. We are called Core because the digestive system is at the core of our body and a good digestive system is the core of good health.
The charity was established in 1971 with the help and support of the British Society of Gastroenterologists and today it supports Clinical Research Fellows and Research Scientists at hospitals and universities throughout the UK, investigating conditions such as pancreatitis, hepatitis, ulcerative colitis, irritable bowel syndrome, Crohn’s disease and digestive cancers. All research that we fund is rigorously peer-reviewed. Core is a member of the Association of Medical Research Charities.
We have a major interest in providing patients with good, accurate information about their illness. We publish 25 patient information leaflets and 15 fact-sheets explaining the nature of various gut illnesses and their treatment. Some 200,000 are distributed annually.