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About 5-10% of cancers arise from an inherited gene fault. Recognising the syndromes (BRCA, Lynch, Li-Fraumeni, VHL, MEN, FAP, retinoblastoma and dozens more) changes screening, surgery and treatment for the patient and their relatives.
The main 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.
The rulebook behind the CAPS cohorts and the UK EUROPAC programme; it is also the reason surveillance for carriers is not yet a routine NHS service, because the consortium itself asked for it to stay within research until benefit was shown.
Family history misses most carriers, so the NCCN and ASCO guidelines moved to testing every patient; each carrier found is a family that can be offered surveillance and a patient who may be eligible for platinum and PARP inhibition.
Familial risk is mostly unexplained by the panel genes, which is why surveillance programmes enrol on family history as well as on a named variant.
POLE and POLD1 are now on polyposis and colorectal germline panels, and the paper explains why a patient with many adenomas and an entirely normal mismatch repair panel still needs sequencing.
It is the evidence behind universal mismatch repair testing of every colorectal cancer, which is now standard in most guidelines and which, as a by-product, identifies everyone eligible for immunotherapy.
EPCAM deletion testing is now part of Lynch syndrome panels, and it explains the MSH2-deficient tumours in families where sequencing of the four repair genes comes back clean.
Shares Jon M. Huntsman Sr., Gilda Radner, Founder variant, MEN1 and hereditary neuroendocrine syndromes.
Shares Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium, Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer, Germline BRCA mutation (gBRCA), Germline vs somatic mutations.
Shares Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer, CAPS: the Cancer of the Pancreas Screening consortium and its surveillance studies (CAPS1 to CAPS5), Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium, Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.
Shares CAPS: the Cancer of the Pancreas Screening consortium and its surveillance studies (CAPS1 to CAPS5), Lynch syndrome, Germline BRCA mutation (gBRCA), Germline vs somatic mutations.
Shares MLH1 promoter methylation (sporadic versus Lynch mismatch repair loss), Colectomy, Lynch syndrome, Germline vs somatic mutations.
Shares Lynch syndrome, Germline BRCA mutation (gBRCA), Double-strand break repair: HR versus end joining, Germline vs somatic mutations.
Shares Wilms tumour risk markers (anaplasia, 1p/16q loss, 1q gain, SIOP and COG risk groups), Hyperparathyroidism-jaw tumour syndrome (CDC73-related parathyroid carcinoma), Childhood lung and airway tumours (pleuropulmonary blastoma, tracheobronchial tumours), Retinoblastoma.
Shares CAPS: the Cancer of the Pancreas Screening consortium and its surveillance studies (CAPS1 to CAPS5), Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium, Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer, Germline (hereditary) testing.