Which Family Histories Actually Suggest — a Hereditary Cancer Syndrome?

Pathogenic variants in BRCA1 or BRCA2 substantially raise lifetime risk for breast cancer in women and ovarian cancer, and also elevate risk for pancreatic cancer and, with BRCA2, prostate cancer. Male carriers of BRCA2 face elevated breast cancer risk as well. NCCN and ESMO recommend enhanced breast surveillance beginning in the late twenties or early thirties, and discuss risk-reduction options including risk-reducing surgery and medication. The pattern that typically triggers BRCA testing includes breast cancer before 40, ovarian cancer at any age, male breast cancer in any relative, or multiple relatives on the same side with breast or ovarian cancer.

Lynch syndrome is caused by a pathogenic variant in one of several DNA mismatch repair genes — most often MLH1, MSH2, MSH6 or PMS2. It significantly raises lifetime risk for colorectal cancer and, in women, endometrial cancer, and also elevates risk for cancers of the ovary, stomach, urinary tract and small intestine. NCCN recommends colonoscopy starting much earlier than the general population programme and at shorter intervals. The family patterns that raise suspicion include colorectal cancer before 50, multiple Lynch-associated cancers in the same person, or a tumour that shows microsatellite instability on laboratory testing — a result that should prompt referral for genetic assessment.

FAP is caused by a pathogenic variant in the APC gene and leads to the development of large numbers of polyps in the colon, with a very high likelihood of colorectal cancer developing without intervention. NCCN recommends surveillance colonoscopy beginning in the early teens for people from affected families. MAP is caused by biallelic variants in the MUTYH gene and produces a similar but typically less severe polyposis picture. For both conditions, surgical management is frequently part of long-term care, and surveillance of the upper gastrointestinal tract is recommended because polyps can develop outside the colon as well.

Li-Fraumeni syndrome is caused by a pathogenic variant in the TP53 gene and is associated with a very high lifetime risk of cancer across multiple tumour types, including soft tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumours, adrenocortical carcinoma, and leukaemia. Cancers can occur at any age, including childhood. NCCN recommends comprehensive whole-body surveillance for carriers, often including annual MRI. Radiation-based imaging is avoided where possible because TP53 carriers may have heightened sensitivity to radiation. A new diagnosis of adrenocortical carcinoma in a child is sufficient grounds for TP53 testing without waiting for a family history to confirm the pattern.

A pathogenic variant in the CDH1 gene substantially raises lifetime risk for diffuse-type gastric cancer and, in women, lobular breast cancer. The gastric cancer associated with CDH1 grows beneath the stomach lining rather than forming polyps, making it difficult to detect by endoscopy alone. NCCN and the International Gastric Cancer Linkage Consortium discuss prophylactic total gastrectomy for confirmed carriers alongside enhanced breast surveillance for women. This syndrome should be considered when multiple relatives have diffuse-type gastric cancer, particularly at younger ages, or when a single case occurs before age 50 in a family with other suggestive features.

Cowden syndrome is caused by a pathogenic variant in the PTEN gene and raises risk for breast cancer, thyroid cancer, endometrial cancer, colorectal cancer and kidney cancer. It is often associated with benign overgrowths called hamartomas, which can appear in the skin, gut and other tissues, and these non-cancer features sometimes appear before any cancer diagnosis. NCCN recommends enhanced surveillance across multiple organ systems for confirmed carriers. Cowden syndrome is frequently underrecognised because its features are variable and may be subtle — the diagnosis is sometimes made only after a second cancer or after testing done for another reason.