Noninherited Genetic Alteration Discovered for Breast and Ovarian Cancers

March 1, 2001

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,

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

Scientists have linked a nonmutation alteration in the BRCA1gene to a biochemical process known as hypermethylation. This unique alteration,initially reported by Hopkins in April 2000, is associated with 10% to 15% ofbreast cancers and 15% to 20% of ovarian cancers. Moreover, this alterationoccurs in the most common, nonhereditary forms of breast and ovarian cancersrather than the more rare familial cancers typically associated withthe BRCA1 gene.

The Hypermethylation Principle

"Mutation, or the loss of viral tumor-suppressing genes, isfrequently the precursor to inherited susceptibility to cancer," explainedHopkins investigator Manel Esteller, MD, PhD. "As mutations are passedalong from generation to generation, so is a familial inherited cancerpredisposition. On the other hand, methylation is a nonhereditary biochemicalprocess that similarly alters the function of cancer-related genes by turningthem off and on. Normal methylation allows the gene to function normally, butwhen the gene is ‘hyper’ methylated, it turns off inhibitingtumor-suppressing activities, leading to the initiation of cancer."

In the course of their studies, NIH and John Hopkinsinvestigators uncovered such an alteration in a nonfamilial breast cancer samplethat exhibited characteristics typical of a tumor associated with a BRCA1 genemutation. Further examination of the tumor sample by Hopkinsexperts revealed that the tumor was highly methylated in a growth-promotingregion of the BRCA1 gene. This, in turn, caused the deactivation of the gene andthe resulting cancer.

Differentiating Test in Early Stages

A test that would allow physicians to differentiate betweenthose tumors resulting from inherited BRCA1 mutations and those caused bynoninherited abnormal methylation of the gene is in development. "Such atest would give patients the ability to determine if their cancer occurred asthe result of an inherited mutation that could affect other family members orrandomly with no familial link," said Stephen Baylin, MD, who is Ludwigprofessor of oncology and the associate director for cancer research at Hopkins.However, he cautions that test developmentis in its very early stages, so it is not known when suchan 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 methylationpatterns on cancer-related genes for more than a decade, linking it to a varietyof cancers including colon, lung, brain, and head and neck tumors. Breast andovarian cancers affect more than 200,000 American women annually and cause anadditional 60,000 deaths. Experts say the majority of these cancers—nearly 80%—arenot the result of an inherited predisposition.