Nobody relishes undergoing colonoscopy the undignified screening examination for colorectal cancer (CRC). Interest might therefore run high in a recently reported pilot study suggesting that a simple blood test might identify people at risk of this deadly disease.
Only malignancies of lung and breast exceed CRC as the leading causes of cancer deaths. An estimated 147,500 patients will be diagnosed with colorectal cancer this year in the U.S., and 57,100 will die of the disease.
But if caught in time, CRC is the most curable of major cancers. Colonoscopy reliably catches the tumors of people over the age of 50 when administered every five to 10 years, depending largely on family history. "Well-known figures who died after getting colon cancer," The New York Times recalled on March 18, 2003, "include the actress Audrey Hepburn and the Peanuts cartoonist Charles Schulz. On the other hand, Supreme Court Justice Ruth Bader Ginsburg and President Ronald Reagan both survived it."
Scientists at Johns Hopkins University School of Medicine (Baltimore, Maryland) analyzed blood samples from 172 patients at a colonoscopy clinic. They were looking for a specific DNA mutation that had previously been found in some CRC tumors. Their findings appear in the March 14 issue of Science.
The odds of finding the marker were five times greater in individuals with a family history of CRC than in those without. Remarkably, the article added, the odds were 22 times greater in patients with a personal history.
A commentary accompanying the paper concluded, "Identification of a large subgroup of persons for whom conventional screening is unnecessary would constitute a major advance."
That identification depends heavily on a subtle but potent phenomenon called "Loss of IGF2 Imprinting," LOI for short. "It's an epigenetic alteration affecting the insulin-like growth-factor II gene," Science explained, adding, "Epigenesis does not involve alterations in the DNA sequence, but rather changes in DNA methylation. LOI is found in normal colonic mucosa of about 30 % of colorectal cancer patients, but in only 10 % of healthy individuals."
LOI of the IGF2 gene was discovered in embryonic tumors of childhood, such as Wilms' tumor, but is commonly encountered in many types of adult cancer, including ovarian, lung, liver and colon. In LOI, certain genes are silenced during embryonic development through methylation the addition of methyl groups.
The Science paper shows that LOI of the insulin-like growth-factor gene is associated with a familial risk of developing CRC and with a personal history of polyps colon adenomas and CRC. This association is potentially important because 30% to 50% of sporadic (environmental, non-hereditary) CRC is associated with familial risk.
The 172 participating volunteers provided biopsy samples from peripheral blood lymphocytes (PBLs) for RNA and DNA analysis. The relation between LOI in PBLs and LOI in the colon was determined in 168 patients. Of these, all 25 patients with LOI in the blood also showed LOI in both left and right colon arms. "Thus, LOI in the colon," the Science paper observed, "appeared to be a diffuse abnormality affecting both the distal and proximal colon."
It concluded: "Two of the three criteria for screening the general population have largely been met for CRC, to wit: its impact on public health and the benefit of intervention. The third criterion, as with any genetic test, can be determined only through evaluation of a large prospective cohort of patients, establishing the positive and negative predictive values."
The commentary noted that "Other types of molecular marker research may be aimed not at measuring the lifetime 'tendency' of developing adenoma [polyps] or CRC, but rather at direct detection of the tumor tissue."