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 cancersnearly 80%are
not the result of an inherited predisposition.