Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
Nobody relishes undergoing a 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 for 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.
But if caught in time, CRC is the most curable of major cancers. Colonoscopies reliably catch 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 Audrey Hepburn and 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 in Baltimore 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 Science dated March 14, 2003, under the title: "Loss of IGF2 Imprinting: A potential marker of colorectal cancer risk."
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 on a 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 percent of colorectal cancer patients, but in only 10 percent of healthy individuals."
LOI of the IGF2 gene was discovered in embryonic tumors of childhood, such as Wilms' tumor, but is encountered in adult cancers, including ovarian, lung, liver and colon. In LOI, certain genes are silenced during embryonic development through methylation. 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 percent to 50 percent 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.
"Other types of molecular marker research," the commentary noted, "may be aimed not at measuring the lifetime tendency' of developing adenoma [polyps] or CRC, but rather at direct detection of the tumor tissue."
Mice Infected With Hypergammaglobulinemia Explore Viral Effects, Autoimmune Diseases
Polyclonal hypergammaglobulinemia (HGG) is a characteristic of chronic inflammatory conditions, including persisting viral infections and autoimmune diseases. A paper by the same HGG name, in Nature Immunology, released online March 10, 2003, studied HGG in mice systemically and persistently infected with lymphocytic choriomeningitis virus (LCMV). That infection induces nonspecific immunoglobulins as a result of switching natural IgM specificities to IgG. The process is dependent on help from CD4+ T cells that specifically recognize LCMV peptides presented by B cells on major histocompatibility complex class II molecules. Thus, HGG might arise when specific helper T cells recognize B cells that have processed viral antigens irrespective of the B-cell receptor specificity. This nonspecific B-cell activation might contribute to antibody-mediated autoimmunity.
"These mouse findings," the journal article concluded, "may be generalized to other viral infections associated with HGG, autoantibodies and immune complex-linked disease in humans."
Copaxone, FDA-Approved Multiple Sclerosis Drug, Doubles as Experimental ALS Vaccine
A compound called Cop-1, (Copaxone) FDA-approved for treating multiple sclerosis, might also slow the progression of ALS (amyotrophic lateral sclerosis), better known as Lou Gehrig's disease. ALS, a degenerative and fatal motor neuron affliction, strikes some 5,000 Americans yearly. Although its cause is not yet understood, many of the factors contributing to ALS pathogenesis are common to other chronic nervous system disorders, such as Alzheimer's disease, Huntington's chorea and glaucoma
A paper in the Proceedings of the National Academy of Sciences, dated March 17, 2003, bears the title: "Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis."
Its authors, from the Weizmann Institute, Rehovot, Israel, investigated the effects of Cop-1 on a mouse model of ALS. Treatment with the compound delayed onset of the disease and extended the animals' lifespan by 52 days to 263 days, compared to 211 days in untreated control mice. Advance treatment of healthy mice also prevented neuron degeneration associated with acute nerve damage. That resulted from severed nerves or toxic doses of the neurotransmitter glutamate. The scientists recommend that future research be directed toward developing a formulation and regimen of Cop-1 specifically for treating ALS.