Hereditary cancer syndromes

Major syndromes: hereditary breast-ovarian (BRCA1/2, PALB2), Lynch (MLH1/MSH2/MSH6/PMS2/EPCAM; colorectal, endometrial, urothelial and more), Li-Fraumeni (TP53; sarcoma, breast, brain, adrenocortical, leukaemia; whole-body MRI surveillance halves cancer mortality), familial adenomatous polyposis (APC), von Hippel-Lindau (VHL; RCC, phaeochromocytoma, haemangioblastoma; belzutifan approved 2021), MEN1/MEN2 (RET; medullary thyroid), hereditary retinoblastoma (RB1), Peutz-Jeghers, Cowden (PTEN), hereditary diffuse gastric cancer (CDH1), hereditary paraganglioma (SDHx), DICER1, and moderate-penetrance genes (CHEK2, ATM). Practice: germline multigene panel testing is now recommended for all patients with ovarian, pancreatic, metastatic prostate, male breast, and many breast and colorectal cancers (NCCN), with cascade testing of relatives; risk-reducing surgery (mastectomy, salpingo-oophorectomy, colectomy, thyroidectomy), intensified surveillance (MRI, colonoscopy), chemoprevention (aspirin in Lynch, CAPP2), and therapy selection (PARP inhibitors, immunotherapy for Lynch tumours, belzutifan in VHL). Population-based BRCA/Lynch screening and polygenic risk scores are the frontier.