Key points
- About 5–10% of cancers are due to an inherited gene.
- Red flags: young age, bilateral or multiple cancers, several relatives, rare cancers such as male breast cancer.
- Most are autosomal dominant: each child has a 50% chance.
- Some are prevented by surgery: colectomy (FAP), thyroidectomy (RET), gastrectomy (CDH1), mastectomy and salpingo-oophorectomy (BRCA).
Red flags for an inherited cancer
- Cancer at a young age (for example, colorectal or breast cancer under 50)
- Two or more primary cancers in one person, or bilateral cancer
- Several relatives on the same side with related cancers
- Rare cancers: male breast cancer, medullary thyroid cancer, adrenocortical cancer
- A known mutation in the family
The syndromes
| Syndrome | Gene | Main cancers | Surgical point |
|---|---|---|---|
| Hereditary breast and ovarian cancer | BRCA1, BRCA2 | Breast, ovary; BRCA2 also prostate, pancreas, male breast | Risk-reducing mastectomy; salpingo-oophorectomy once the family is complete |
| Lynch syndrome | MLH1, MSH2, MSH6, PMS2 | Colorectal (often right-sided), endometrial, ovarian, stomach, urinary tract | Regular colonoscopy from early adulthood; test every colorectal cancer for mismatch repair |
| Familial adenomatous polyposis | APC | Hundreds to thousands of colorectal polyps: cancer is almost certain by 40 without surgery; duodenal cancer; desmoid tumours | Prophylactic colectomy, usually in the late teens or twenties |
| MUTYH-associated polyposis | MUTYH (recessive) | Colorectal polyps and cancer | Like an attenuated FAP; siblings at risk |
| MEN 1 | MEN1 | Parathyroid hyperplasia, pancreatic neuroendocrine tumours, pituitary | Parathyroid surgery is subtotal or total with autotransplant |
| MEN 2A / 2B | RET | Medullary thyroid cancer, phaeochromocytoma; parathyroid (2A); mucosal neuromas (2B) | Prophylactic thyroidectomy timed by the mutation; exclude phaeochromocytoma first |
| Li-Fraumeni | TP53 | Sarcoma, early breast cancer, brain, adrenocortical, leukaemia | Avoid radiotherapy where possible |
| Hereditary diffuse gastric cancer | CDH1 | Diffuse (signet-ring) gastric cancer, lobular breast cancer | Prophylactic total gastrectomy |
| Peutz-Jeghers | STK11 | Hamartomatous polyps (intussusception), lip pigmentation; many cancers | Polyp surveillance and removal |
| Von Hippel-Lindau | VHL | Clear-cell kidney cancer, phaeochromocytoma, haemangioblastoma, pancreatic NETs | Nephron-sparing surgery |
The Amsterdam “3-2-1” rule (Lynch)
At least 3 relatives with a Lynch cancer, across 2 generations, with 1 diagnosed under 50 (and FAP excluded). Many families do not meet it, which is why every new colorectal cancer is now tested for mismatch repair.
Inheritance
Almost all are autosomal dominant: each child of a carrier has a 1 in 2 chance of inheriting the gene. MUTYH is autosomal recessive. Refer to clinical genetics for counselling before testing relatives.
Frequently asked questions
What are the most common hereditary cancer syndromes?
Hereditary breast and ovarian cancer (BRCA1 and BRCA2) and Lynch syndrome are the most common. Others include FAP, MEN 1 and 2, Li-Fraumeni and hereditary diffuse gastric cancer.
What are the Amsterdam criteria for Lynch syndrome?
The 3-2-1 rule: at least three relatives with a Lynch-associated cancer, across two generations, with one diagnosed before 50, and FAP excluded.
Which hereditary syndromes are treated with preventive surgery?
FAP (colectomy), MEN 2 with a RET mutation (thyroidectomy), CDH1 (total gastrectomy) and BRCA (risk-reducing mastectomy and salpingo-oophorectomy).
Further reading
- Monahan KJ, et al. Guidelines for the management of hereditary colorectal cancer (BSG/ACPGBI/UKCGG). Gut 2020;69:411–44.
- Wells SA Jr, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015;25:567–610.
- Blair VR, et al. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol 2020;21:e386–97.