Genetic Testing For
Breast and Ovarian Cancers not Sufficient Enough for Recommendations of
Invasive Prophylactic Surgeries - Study Shows
There are some genetic tests that can be performed to determine the risk
of breast and ovarian cancer, but not all cancers are associated with
identified gene mutations. According to research by Mary-Claire King,
Ph.D., of the University of Washington, Seattle, lifetime risks of
breast cancer are as high as 80 percent among U.S. women with mutations
in BRCA1 and BRCA2 genes.
Among white women in the US, mutations in the BRCA1 and BRCA2 genes
account of 5 percent to 10 percent of the breast cancer cases. The risk
for young women with these particular inherited gene mutations is
There are other gene mutations to look out for. Inherited mutations in
other genes, including CHEK2, TP53 and PTEN, can also influence risk of
cancer. There are some advantages for getting tested early for these
and other gene mutations.
There are clinical options available for women at high genetic risk of
breast cancer including screening starting at a younger age, the use of
highly sensitive detection methods, and prophylactic surgeries of the
ovaries or breast. The prophylactic surgeries are highly invasive, so
it should be particularly important to distinguish mutation carriers
from non-carriers with similarly severe family histories.
The genetic testing in as-yet-unaffected women with severe family
histories of breast or ovarian cancer has become an integral part of
some clinical practices.
Between 2002 and 2005 the researchers evaluated DNA and RNA samples from
300 breast cancer probands. A proband is an initial member of a family
to come under study. They used multiple different screening approaches
to identify mutations of all genomic classes in BRCA1, BRCA2, CHEK2,
TP53, and PTEN.
The study was conducted to determine the frequency and types of
undetected cancer-predisposing mutations in BRCA1, BRCA2, CHEK2, TP53,
and PTEN among patients with breast cancer from high-risk families.
These families included 4 or more cases of breast or ovarian cancer.
The researchers found “that of the 300 probands, 52 (17 percent) carried
previously undetected mutations, including 35 (12 percent) with genomic
rearrangements of BRCA1 or BRCA2, 14 (5 percent) with CHEK2 mutations,
and 3 (1 percent) with TP53 mutations. No inherited mutations were
detected in PTEN. At BRCA1 and BRCA2, 22 different genomic
rearrangements were found. Of these, 14 were not previously described
and all were individually rare. Inherited rearrangements of BRCA1 were
more frequent among probands diagnosed when younger than 40 years (16
percent) than among probands diagnosed when 40 years or older (6.5
The point to the study was to determine if genetic testing was
sufficient enough to determine if a woman should undergo invasive and
expensive risk management options. The authors wrote, “Our results
suggest that genetic testing, as currently carried out in the United
States, does not provide all available information to women at risk. Our
data indicate that 12 percent of those from high-risk families with
breast cancer and with negative (wild-type) commercial genetic test
results for BRCA1 and BRCA2 nonetheless carry cancer-predisposing
genomic deletions or duplications in one of these genes."
"The clinical dilemma is what to offer to women with a high probability
of carrying a mutation in BRCA1 or BRCA2 but with negative commercial
test results. Technically, the answer is at hand. The mutations
identified in our study that were missed by commercial testing are
detectable using other approaches that are currently available," the
researchers write. They add that for families testing negative (wild
type) for BRCA1 and BRCA2 by conventional sequencing, multiplex ligation-dependent
probe amplification (MLPA - a molecular method to detect genetic
variation) followed by sequence confirmation of breakpoints in patients'
genomic DNA is the current best choice for evaluating the wide range of
genomic rearrangements in BRCA1 and BRCA2. Clinical testing using MLPA
is currently not available in the U.S.
"As more breast cancer susceptibility genes of different penetrances are
identified, clinicians will be increasingly challenged to offer the most
appropriate genetic tests, to assist patients in interpreting the
results, and to optimize risk reduction strategies," the authors
conclude. "Effective methods for identifying these mutations should be
made available to women at high risk."
By Dan Wilson
Books on Cancer
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