Hereditary colorectal cancer

Hereditary colorectal cancer encompasses a clinically and genetically heterogeneous group of germline-defined predisposition syndromes in which colorectal tumours represent a principal manifestation within a broader multiorgan tumour predisposition phenotype. Affected individuals typically present at younger ages than those with sporadic disease, although age at onset varies by underlying syndrome and gene defect. Onset spans approximately the third to sixth decade: -associated colorectal cancer occurs at mean ages of 44 to 66 years depending on the affected mismatch repair gene; classic presents with adenomas from adolescence (mean age ~16 years) and colorectal cancer at a mean age of ~39 years; at a mean age of ~48 years; at 42 to 46 years; and juvenile polyposis syndrome at approximately 42 years. The associated tumour spectrum is broad and extends beyond the colorectum to include endometrial, ovarian, gastric, small-bowel, urinary tract, biliary tract, central nervous system, pancreatic, and, in certain subtypes, cutaneous tumours.

The estimated global incidence of colorectal cancer was approximately 1.9 million new cases in 2020, based on GLOBOCAN data with around one quarter occurring in Europe. Hereditary syndromes account for about 5–10% of cases, with Lynch syndrome alone affecting approximately 1 in 280-350 individuals.

The genetic conditions associated with hereditary colorectal cancer follow heterogeneous inheritance patterns. The majority of well-characterized syndromes, including Lynch syndrome and familial adenomatous polyposis, are inherited in an autosomal dominant manner, whereas MUTYH-associated polyposis and constitutional mismatch repair deficiency exhibit autosomal recessive inheritance. De novo pathogenic variants account for a minority of cases, most notably in familial adenomatous polyposis while being extremely low in Lynch syndrome.

Multiple genes have been associated with hereditary colorectal cancer, encompassing both non-polyposis and polyposis syndromes. Lynch syndrome (germline variants in MLH1, MSH2, MSH6, PMS2, or EPCAM), characterised by mismatch repair deficiency and microsatellite instability, represents the most common cause. Other examples include familial adenomatous polyposis (APC; characterised by hundreds of colorectal adenomas), MUTYH-associated polyposis (biallelic MUTYH variants causing base-excision-repair deficiency), and (STK11; characterised by gastrointestinal hamartomas).

• Where hereditary colon cancer is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity determines condition-specific surveillance and follow-up. A confirmed molecular diagnosis enables targeted clinical pathways established for that entity.
• A confirmed molecular diagnosis 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.

• Idos G, Valle L. Lynch Syndrome. 2004 Feb 5 [Updated 2021 Feb 4]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301390. Available from:
• Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, Vignat J, Ferlay J, Murphy N, Bray F. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut. 2023 Feb;72(2):338-344. doi: 10.1136/gutjnl-2022-327736. Epub 2022 Sep 8. PMID: .
• Park J, Karnati H, Rustgi SD, Hur C, Kong XF, Kastrinos F. Impact of population screening for Lynch syndrome: insights from the All of Us data. Nature Communications 2025;16(1):523. doi: 10.1038/s41467-024-52562-5. PMID: ; PMCID: PMC11718231.
• Yen T, Stanich PP, Axell L, et al. APC-Associated Polyposis Conditions. 1998 Dec 18 [Updated 2022 May 12]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from:
• Yildiz S, Musarurwa TN, Algar U, Chambuso R, Rebello G, Goldberg PA, et al. Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer. Frontiers in oncology. 2023;13:1253867. doi: 10.3389/fonc.2023.1253867. PMID: . PMCID: PMC10642181.