HEREDITARY BREAST and OVARY CANCER [HBOC] SYNDROME, Dr BUI DAC CHI.
BRCA are genes that everyone has and
naturally suppress tumors. When one
mutates, cancer is more likely to develop.
There are hundreds of different BRCA
mutations. Some raise the risk for breast,
ovarian, pancreatic or stomach cancers.
Unfortunately, traditional Mendelian inheritance terms like
“dominant” and “recessive” do not apply well in the case
of BRCA1. When looking at a family pedigree,
inheritance of BRCA1 alleles appears to be autosomal
dominant: only one parent is affected and inheriting a
single mutated copy of the gene brings with it inheritance
of an increased risk of cancer. However, at the
molecular level, the BRCA1 protein is a tumor
suppressor, requiring both copies of the BRCA1 gene
to be mutated for cancer to develop. An at-risk individual
typically inherits a single mutated copy of the BRCA1
gene, and at some point during that person’s lifetime, the
second copy may become mutated, leading to cancer. If
two mutated copies of BRCA1 are inherited, the embryo
will not develop. BRCA2 is also a tumor suppressor.
• The BRCA genes produce proteins that
help repair DNA damage, specifically the
repair of simultaneous breaks in both
strands of DNA (called double-strand
breaks). Cells with BRCA mutations are
still viable, but, because they have a
reduced ability to repair DNA damage,
they accumulate mutations in additional
genes, which can lead to the development
and progression of cancer
• Genetic Testing for HBOC
Genetic testing of a blood or saliva sample can identify a mutation in
the BRCA1 or BRCA2 gene. If a mutation is found, then the HBOC
diagnosis is confirmed. Next, other family members may have a
genetic test to learn whether or not they carry the same mutation
and have HBOC.
Sometimes, genetic testing will not find a mutation in the BRCA1 or
BRCA2 genes even in persons with a clinical history that suggests
HBOC. This does not necessarily mean that they do not have
HBOC. A negative genetic test may be due to the fact that the
current genetic testing technology is not able to identify all mutations
or other genes that may cause HBOC.
A third, but rare result is a variant. A variant is a gene change that does
not provide clear information regarding cancer risks. In these cases,
further testing may be ordered to help clarify the result
Genomic technologies, including RT-PCR,
microarrays, NGS, and whole-exome
sequencing have created a significant
revolution in cancer diagnostics, enabling,
for example, analysis of gene expression
signatures and mutation status to enable
more accurate classification with respect
to diagnosis and prognosis.
Referral should be considered for any individual with a personal
history of or first-degree relative with (i) breast cancer diagnosed
at or before age 50; (ii) triple-negative breast cancer diagnosed at
or before age 60; (iii) two or more primary breast cancers in the
same person; (iv) ovarian, Fallopian tube, or primary peritoneal
cancer; (v) Ashkenazi Jewish ancestry and breast or pancreatic
cancer at any age; or (vi) male breast cancer. Individuals with a
family history of three or more cases of breast, ovarian,
and/or aggressive prostate cancer (Gleason score ≥7) should
also be referred. Note that this should not include
families in which all three cases are aggressive prostate cancer
• HEREDITARY BREAST–OVARIAN CANCER (HBOC) SYNDROME IS
CAUSED BY MUTATIONS IN THE BRCA1 AND BRCA2 GENES AND IS
CHARACTERIZED BY INCREASED RISKS FOR EARLY-ONSET
BREAST, MULTIPLE BREAST PRIMARIES, MALE BREAST, AND
EPITHELIAL OVARIAN, FALLOPIAN TUBE, OR PRIMARY PERITONEAL
CANCERS. IN ADDITION, CANCERS OF THE PANCREAS, PROSTATE,
AND MELANOMA ARE MORE COMMON IN INDIVIDUALS WITH HBOC
SYNDROME. THE PATHOLOGY OF “TRIPLE-NEGATIVE PHENOTYPE”
BREAST CANCER (ESTROGEN RECEPTOR–NEGATIVE,
PROGESTERONE RECEPTOR–NEGATIVE, AND HER2/NEU–
NEGATIVE) HAS BEEN STRONGLY ASSOCIATED WITH BRCA1
MUTATIONS. THE LIKELIHOOD OF IDENTIFYING A BRCA1/2
MUTATION IN A WOMAN WITH OVARIAN CANCER AT ANY AGE IS
AROUND 13–18%. OF MALES WITH BREAST CANCER, 15–20% HAVE
A BRCA1/2 MUTATION. THE OVERALL PREVALENCE OF BRCA1
MUTATIONS IS ESTIMATED AT 1 IN 300 AND THAT OF BRCA2
MUTATIONS IS ESTIMATED AT 1 IN 800, BUT FOUNDER MUTATIONS
IN MANY POPULATIONS (E.G., ASHKENAZI JEWISH, ICELANDIC, AND
MEXICAN HISPANIC POPULATIONS) LEAD TO INCREASED
MUTATION PREVALENCE IN THESE POPULATIONS.
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