Topics:

Noninherited Genetic Alteration Discovered for Breast and Ovarian Cancers

Noninherited Genetic Alteration Discovered for Breast and Ovarian Cancers

A study headed by the National Institutes of Health (NIH) human genome scientists on the genetic patterns of inherited breast cancer has uncovered unexpected findings regarding nonhereditary breast and ovarian cancers. These unanticipated findings, discovered by scientists at the Johns Hopkins Oncology Center, were published in a recent issue of The New England Journal of Medicine (344:539-548, 2001).

Scientists have linked a nonmutation alteration in the BRCA1 gene to a biochemical process known as hypermethylation. This unique alteration, initially reported by Hopkins in April 2000, is associated with 10% to 15% of breast cancers and 15% to 20% of ovarian cancers. Moreover, this alteration occurs in the most common, nonhereditary forms of breast and ovarian cancers rather than the more rare familial cancers typically associated with the BRCA1 gene.

The Hypermethylation Principle

"Mutation, or the loss of viral tumor-suppressing genes, is frequently the precursor to inherited susceptibility to cancer," explained Hopkins investigator Manel Esteller, MD, PhD. "As mutations are passed along from generation to generation, so is a familial inherited cancer predisposition. On the other hand, methylation is a nonhereditary biochemical process that similarly alters the function of cancer-related genes by turning them off and on. Normal methylation allows the gene to function normally, but when the gene is ‘hyper’ methylated, it turns off inhibiting tumor-suppressing activities, leading to the initiation of cancer."

In the course of their studies, NIH and John Hopkins investigators uncovered such an alteration in a nonfamilial breast cancer sample that exhibited characteristics typical of a tumor associated with a BRCA1 gene mutation. Further examination of the tumor sample by Hopkins experts revealed that the tumor was highly methylated in a growth-promoting region of the BRCA1 gene. This, in turn, caused the deactivation of the gene and the resulting cancer.

Differentiating Test in Early Stages

A test that would allow physicians to differentiate between those tumors resulting from inherited BRCA1 mutations and those caused by noninherited abnormal methylation of the gene is in development. "Such a test would give patients the ability to determine if their cancer occurred as the result of an inherited mutation that could affect other family members or randomly with no familial link," said Stephen Baylin, MD, who is Ludwig professor of oncology and the associate director for cancer research at Hopkins. However, he cautions that test development is in its very early stages, so it is not known when such an assessment would be available for clinical trials in patients.

Dr. Baylin, James Herman, MD, assistant professor of oncology, and their research team have been studying the effect of abnormal methylation patterns on cancer-related genes for more than a decade, linking it to a variety of cancers including colon, lung, brain, and head and neck tumors. Breast and ovarian cancers affect more than 200,000 American women annually and cause an additional 60,000 deaths. Experts say the majority of these cancers—nearly 80%—are not the result of an inherited predisposition.

 
Loading comments...
Please Wait 20 seconds or click here to close