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5. Hereditary Cancer Syndromes: Hereditary Breast and Ovarian Cancer Syndrome (BRCA1/2) and Lynch Syndrome

5.1 Hereditary Breast and Ovarian Cancer Syndrome (BRCA1/2 Germline Mutations)

We recommend that all women with non-mucinous EOC have BRCA testing and be referred for genetic counselling due to the risk of hereditary breast and ovarian cancer syndrome (e.g., germline BRCA1/BRCA2 mutations). 

BRCA1 and BRCA2 are tumour suppressor genes important for DNA repair (through the homologous recombination repair pathway). Less commonly, patients with hereditary ovarian carcinoma may carry germline mutations in genes other than BRCA1 or BRCA2 that are also involved in DNA repair. 

Individuals with mutations in these genes are at increased risk for cancers, particularly breast and ovarian cancers. In British Columbia, all women with ovarian cancer (except for mucinous histology) are eligible for BRCA mutation testing, and should be referred to the Hereditary Cancer Program for counseling and genetic testing by their clinical care team. In women with BRCA mutations who do not have cancer, and have finished childbearing, prophylactic BSO (removal of both tubes and ovaries) has been shown to reduce risk of EOC cancer by 80%.

5.1.1 Pathologic assessment of fallopian tubes following prophylactic BSO  

In patients with known BRCA1/BRCA2 mutations (or other rarer germline mutations which can occur in hereditary breast and ovarian cancer syndrome, e.g., BRIP1, PALB2, etc.) who undergo prophylactic BSO, the ovaries and fallopian tubes should be immediately fixed in formalin and submitted in entirety for histologic examination. The fallopian tubes are examined by SEE-FIM (Sectioning and Extensively Examining the Fimbriated End of the Fallopian Tube) protocol (  This protocol increases the detection of early serous carcinoma precursor lesions (serous tubal intraepithelial carcinoma, STIC) by 4-fold.

5.1.2 Recommendations about breast cancer screening following ovarian cancer diagnosis

BRCA1 and 2 carriers have an increased risk of developing breast cancer. For women with stage III or IV ovarian cancer, particularly HGSC, the risk of developing breast cancer in the first 5 years after ovarian cancer diagnosis is low (3-4%), and as such we do not routinely recommend breast surgery or MRI; yearly mammograms are sufficient32, 33. Five years after diagnosis of ovarian cancer, if there has not been an ovarian cancer recurrence, the risk of developing breast cancer increases and intensified screening or prophylaxis may be reconsidered.

5.2 Lynch Syndrome (LS) and DNA Mismatch Repair Proteins

We recommend that all endometrioid and clear cell ovarian ovarian carcinomas undergo immunohistochemical testing for MMR proteins (MSH6 and PMS2, and if abnormal, then MSH6 or MLH1). Immunohistochemistry is the preferred method of screening (over MSI assay) due to its widespread availability. When abnormal MMR immunohistochemical results are found, a reflex statement is issued in the pathology report recommending referral to the Hereditary Cancer Program, and the referral is made by the submitting clinician/surgeon. If a patient then undergoes germline testing after genetic counseling and is confirmed to have LS, she can consider additional risk-reducing interventions against colorectal cancer.

DNA mismatch repair (MMR) genes can be impaired by methylation events (epigenetic mechanisms), acquired (somatic) mutations or inherited (germline) mutations.  Screening for defective/loss of MMR proteins can be done using 1) immunohistochemistry or 2) microsatellite instability (MSI) assays. MLH1 hypermethylation testing, if available, can be done to determine if loss of MLH1 detected by immunohistochemistry is sporadic or not. Confirmation of LS requires direct sequencing of the MMR gene, which requires both tumor tissue and patient blood samples. 

Patients with LS have an inherited mutation in an MMR gene. The major MMR genes in humans are MLH1, PMS2, MSH2 and MSH6. Patients with LS have a 40-60% lifetime risk of colorectal and endometrial carcinoma, 6-12% lifetime risk of ovarian carcinoma and increased lifetime risks of many other cancer types (stomach, hepatobiliary, urinary, etc.)

Lynch Syndrome-associated ovarian cancers present differently than typical ovarian cancer. Generally, women with LS-associated ovarian cancers are younger (median 43 years of age), with early stage endometrioid or clear cell histology. 

5.3 Unaffected Carriers of Hereditary Syndromes

Cascade testing of family members should ensue if a patient is found to carry a hereditary cancer syndrome. There are published guidelines on screening and interventions for carries of hereditary cancer mutations, developed in a syndrome specific fashion. For example, individuals with Lynch syndrome need to have increased screening for colorectal carcinoma.  Women should be counseled about considering risk reducing surgery (hysterectomy and BSO) after childbearing.  Female family members with BRCA1/2 mutations should be counseled about risk-reducing interventions against breast cancer (mammography +/- breast MRI if premenopausal, and bilateral mastectomy), as well as ovarian cancer (BSO). Age of penetrance varies by affected gene and can be part of the discussion regarding timing of procedures. More information is available from the BC Cancer Hereditary Cancer Program.

SOURCE: 5. Hereditary Cancer Syndromes: Hereditary Breast and Ovarian Cancer Syndrome (BRCA1/2) and Lynch Syndrome ( )
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