BETHESDA, MdA study of breast cancer patients with
hereditary BRCA1 and BRCA2 mutations or sporadic cancers has shown a
distinctive gene-expression profile for each type of breast cancer gene
mutation and also revealed an unanticipated findinga patient with a
nonhereditary BRCA1 mutation.
The study, from the National Human Genome Research Institute
(NHGRI), looked at RNA from 22 samples of primary breast cancers from seven
carriers of the BRCA1 mutation, seven carriers of the BRCA2 mutation (eight
samples), and seven sporadic cases. Gene activity in each sample was measured
using a microarray of 6,512 complementary DNA (cDNA) clones of 5,361 genes, to
look for distinctive gene-expression profiles.
The researchers identified 176 genes that were differentially
expressed in tumors with BRCA1 mutations and BRCA2 mutations, 51 of which were
found to best differentiate between the two types of cancer (NEJM 344:539-548,
"This powerful new technology gives us a snapshot of
exactly which genes are active in a tumor cell," said lead author Dr.
Jeffrey Trent, NHGRI’s scientific director. "Over the last few decades,
scientists have made important progress in understanding the molecular origins
of cancer by studying one gene at a time. Now we can look at thousands, and
even tens of thousands, of genes as they interact to produce a tumor. This
capability will have important implications for both diagnosis and
The BRCA2-mutation gene-expression profile proved less accurate
than that for BRCA1 mutations. Using a class-prediction method, the
BRCA1-mutation profile correctly identified all 7 tumors with BRCA1 mutations
and 14 of 15 tumors without BRCA1 mutations. The BRCA2-mutation gene profile
correctly identified 5 of 8 tumors with BRCA2 mutations and 13 of 14 tumors
without BRCA2 mutations.
In the one tumor (from a patient with sporadic breast cancer)
misclassified by the profile as being positive for a BRCA1 mutation, the
researchers noted a markedly reduced level of BRCA1 expression, compared with
the six other sporadic breast cancers in the study. Further testing showed that
the misclassified tumor was the only sporadic tumor with hyper-methylation of
the BRCA1 promoter region, indicative of the inactivation, or
"silencing," of BRCA1.
Scientists at Johns Hopkins Oncology Center had previously
shown that aberrant methylation silences the BRCA1 gene in sporadic breast and
ovarian cancers with no BRCA1 mutation (J Natl Cancer Inst 92:564-569, 2000).
Further, they found that BRCA1 promoter hyperme-thylation is more frequent in
the medullary and mucinous subtypes of breast
carcinoma, similar to the histologic distribution seen in BRCA1 germline
In a media advisory, Manel Esteller, MD, PhD, of the Division
of Tumor Biology at Hopkins and a coauthor of the NHGRI study, explained that
"normal methylation allows the gene to function normally, but when the
gene is hyper-methylated, it turns off, inhibiting tumor-suppressing activities
and leading to the initiation of cancer."
In the Hopkins study, about 15% of sporadic breast cancers and
about 20% of sporadic ovarian cancers had BRCA1 promoter hypermethylation.
"There are going to be far more patients with sporadic breast cancers with
BRCA1 inactivated with promoter hypermethylation than patients who have such
tumors on an inherited basis secondary to germline BRCA1 mutations,"
Stephen Baylin, MD, Ludwig Professor of Oncology at Hopkins, told ONI.
Dr. Baylin said that 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
"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," Dr. Baylin
said. However, he cautioned that the test is in the very early stages of
Dr. Baylin, James Herman, MD, assistant professor of oncology
at Hopkins, and their research team have been studying the effect of abnormal
methylation patterns on cancer-related genes for more than a decade and have
linked it to a variety of cancers, including colon, lung, brain, and head and