Hereditary gastrointestinal cancer syndromes

Hereditary gastrointestinal tumours present along a clinical spectrum ranging from polyposis-associated to non-polyposis phenotypes. Both syndromic and non-syndromic forms occur: syndromic entities are characterised by extraintestinal manifestations (e.g., mucocutaneous pigmentation in ; desmoid tumours and osteomas in ; sebaceous gland tumours and urothelial cancers in ), whereas nonsyndromic presentations may be limited to early-onset or multifocal gastrointestinal cancer without distinctive extraintestinal features. Across this spectrum, malignancies of the colon, rectum, stomach, small intestine, pancreas, and gastrointestinal stromal tumours (GISTs) are observed, often occurring in combination within a single syndrome. The age of onset varies depending on the underlying condition. In familial adenomatous polyposis, adenomatous polyps can appear from the teenage years. In Lynch syndrome, familial adenomatous polyposis, , and polymerase proofreading polyposis, colorectal cancer typically develops between the third and fifth decades of life. In Peutz–Jeghers syndrome and , gastric and pancreatic cancers may arise from the third to fifth decades.

The population prevalence of hereditary gastrointestinal cancer syndromes is largely driven by Lynch syndrome, which affects approximately 1 in 280–350 individuals. Recognised hereditary cancer predisposition syndromes account for 3% of colorectal cancers and a smaller proportion of gastric cancers, although familial clustering may be observed in up to 5–10% of cases.

A large number of genes have been associated with hereditary gastrointestinal tumours. The hereditary forms can broadly be grouped into Lynch syndrome and polyposis syndromes; the most common genetic cause is Lynch syndrome which is characterised by mismatch-repair deficiency in the absence of diffuse polyposis. Examples of polyposis syndromes include familial adenomatouspolyposis (APC; hundreds to thousands of colorectal adenomas) and Peutz-Jeghers syndrome (STK11; hamartomatous polyps with mucocutaneous pigmentation). In addition to classical polyposis and mismatch repair–associated genes, several other genes are also relevant in hereditary gastrointestinal tumour predisposition, including CDH1, CTNNA1, SMAD4, and the SDHx genes.

The genetic conditions associated with hereditary gastrointestinal tumours follow heterogeneous inheritance patterns. Most entities, including Lynch syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer, are inherited in an autosomal dominant manner. Autosomal recessive forms include MUTYH-associated polyposis and NTHL1-associated polyposis.

• Where gastrointestinal tumours are suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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