Hereditary Gynaecological Cancer Syndromes
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Hereditary gynaecological cancer syndromes are inherited mutations that raise the lifetime risk of ovarian, fallopian tube, breast, endometrial and colorectal cancers. BRCA1 and BRCA2 mutations mainly raise ovarian and breast cancer risk, while Lynch syndrome, caused by mismatch repair gene defects, mainly raises endometrial and colorectal cancer risk. Risk-reducing salpingo-oophorectomy, hysterectomy and structured surveillance are the key preventive measures.
What you must remember
- BRCA1 and BRCA2: Autosomal dominant tumour suppressor genes responsible for a large share of hereditary ovarian cancer.
- Ovarian risk: Lifetime ovarian cancer risk is roughly 40 per cent with BRCA1 and about 15 per cent with BRCA2, though estimates vary between studies.
- Histology: BRCA-associated ovarian and tubal cancers are usually high-grade serous.
- Lynch syndrome: Germline mutations in MLH1, MSH2, MSH6 or PMS2, or an EPCAM deletion, causing mismatch repair deficiency.
- Endometrial risk in Lynch: Endometrial cancer is often the first cancer diagnosed in affected women.
- Testing triggers: Family history, early onset, high-grade serous histology, and mismatch repair deficiency on immunohistochemistry prompt genetic referral.
- Risk-reducing surgery: Salpingo-oophorectomy in BRCA carriers timed to age, and hysterectomy with salpingo-oophorectomy in Lynch syndrome after childbearing.
Comparing the syndromes before choosing surveillance
A 38-year-old woman whose mother and aunt had ovarian cancer asks whether she should be tested. The table compares the main syndromes, since the gene determines the cancers, the surveillance and the surgery.
| Feature | BRCA1 and BRCA2 | Lynch syndrome |
|---|---|---|
| Gene defect | Homologous recombination repair | Mismatch repair |
| Main cancers | Ovary, fallopian tube, breast | Endometrium, colon, ovary |
| Typical ovarian histology | High-grade serous | Endometrioid or clear cell |
| Ovarian screening | No proven benefit | Not a substitute for surgery |
| Key surgery | Salpingo-oophorectomy by age, roughly 35 to 40 for BRCA1 and 40 to 45 for BRCA2 | Hysterectomy and salpingo-oophorectomy after childbearing |
A family history of early ovarian, breast or endometrial cancer should trigger genetic counselling. The test result then decides the surveillance and surgical plan.
Testing is usually offered first to an affected relative, so that the result can be interpreted correctly. Positive results then lead to testing of other relatives, which is a central part of counselling.
Where the exam tries to catch you
Most errors come from matching the wrong gene to the wrong cancer or from offering screening in place of surgery.
- Trap: Assuming BRCA mutations cause only breast cancer Correct: BRCA1 and BRCA2 also raise the risk of ovarian and fallopian tube cancer, which is why salpingo-oophorectomy is part of prevention.
- Trap: Offering routine CA-125 and ultrasound as an alternative to surgery Correct: Screening has not been shown to reduce ovarian cancer deaths, so risk-reducing salpingo-oophorectomy remains the main option.
- Trap: Recommending hysterectomy alone for Lynch syndrome Correct: Surgery removes the uterus and both tubes and ovaries after childbearing, and colonoscopy surveillance continues.
Frequently asked questions
Which gene mutation carries the highest risk of hereditary ovarian cancer?
BRCA1 mutations carry the highest lifetime ovarian cancer risk among the hereditary syndromes, at roughly 40 per cent. BRCA2 mutations also raise the risk, but to a lower level. Both are inherited in an autosomal dominant pattern.
What does Lynch syndrome mean for endometrial cancer risk?
Lynch syndrome carries a high lifetime risk of endometrial cancer, which is often the first cancer diagnosed in affected women. Mismatch repair gene defects cause this risk. Endometrial surveillance and risk-reducing hysterectomy after childbearing are the usual responses.
When is risk-reducing salpingo-oophorectomy recommended in BRCA carriers?
Risk-reducing salpingo-oophorectomy is recommended in BRCA carriers after childbearing, typically around 35 to 40 years for BRCA1 and 40 to 45 years for BRCA2. It substantially lowers the risk of ovarian and fallopian tube cancer. Timing is individualised after genetic counselling.
Which tumour features prompt testing for Lynch syndrome?
Tumour features that prompt Lynch testing include mismatch repair deficiency on immunohistochemistry, microsatellite instability, and an endometrial or ovarian tumour in a young patient. A family history of colorectal or endometrial cancer also raises suspicion. Genetic counselling is then used to confirm the diagnosis.
Why is ovarian cancer screening not recommended for BRCA carriers?
Routine ovarian screening with CA-125 and ultrasound has not been shown to reduce ovarian cancer deaths in BRCA carriers. Cancers are often detected at an advanced stage despite screening. Risk-reducing salpingo-oophorectomy is therefore the preferred preventive strategy.