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 persons 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 personalhistory of or first-degree relative with (i) breast cancer diagnosedat or before age 50; (ii) triple-negative breast cancer diagnosed ator before age 60; (iii) two or more primary breast cancers in thesame person; (iv) ovarian, Fallopian tube, or primary peritonealcancer; (v) Ashkenazi Jewish ancestry and breast or pancreaticcancer at any age; or (vi) male breast cancer. Individuals with afamily history of three or more cases of breast, ovarian, pancreatic,and/or aggressive prostate cancer (Gleason score 7) should also be referred. Note that this should not includefamilies in which all three cases are aggressive prostate cancer
HEREDITARY BREASTOVARIAN 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 RECEPTORNEGATIVE, PROGESTERONE RECEPTORNEGATIVE, AND HER2/NEUNEGATIVE) 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 1318%. OF MALES WITH BREAST CANCER, 1520% 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.