Genetic Mechanisms in Hereditary Polyposis Syndromes

Hereditary polyposis syndromes encompass a spectrum of inherited disorders characterised by the development of multiple gastrointestinal polyps and an elevated cancer risk. Central to these conditions are germline mutations in tumour suppressor genes or oncogenes, leading to disrupted cellular signalling and unchecked mucosal proliferation. Syndromes such as familial adenomatous polyposis arise from mutations in the APC gene, resulting in aberrant Wnt/β-catenin activation. MUTYH-associated polyposis reflects a defect in base excision repair. Hamartomatous syndromes, including juvenile polyposis and Peutz–Jeghers syndrome, involve mutations in TGFβ-BMP pathway components (SMAD4, BMPR1A) or the serine/threonine kinase STK11, respectively. Loss of heterozygosity and second-hit mechanisms further impair pathway fidelity. The PTEN hamartoma tumour syndrome illustrates the role of PI3K–AKT–mTOR deregulation in polyp formation. Emerging evidence highlights the influence of genetic modifiers, epigenetic alterations and microenvironmental factors on penetrance and phenotypic variation, informing risk stratification and personalised surveillance strategies.

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Genetic Mechanisms in Hereditary Polyposis Syndromes publication trend

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Technical terms

Germline mutation: A hereditary alteration in DNA present in all cells and transmissible to offspring.

Tumour suppressor gene: A gene that protects cells from progressing to cancer; its inactivation promotes neoplasia.

Loss of heterozygosity: The somatic loss of the remaining normal allele in a cell already carrying a mutant allele, leading to full gene inactivation.

Hamartomatous polyp: A benign overgrowth of native tissue elements in disorganised architecture, characteristic of certain syndromes.

Missense variant: A single nucleotide change resulting in a different amino acid residue in the encoded protein, potentially affecting function.

Genotype–phenotype correlation: The association between specific genetic variants and observable clinical features, guiding management strategies.

References

1. Studying the Effect of the Host Genetic Background of Juvenile Polyposis Development Using Collaborative Cross and Smad4 Knock-Out Mouse Models. International Journal of Molecular Sciences (2024).
2. A Novel Missense Variant of BMPR1A in Juvenile Polyposis Syndrome: Assessment of Structural and Functional Alternations. Human Mutation (2025).
3. Genotype–phenotype correlation of BMPR1a disease causing variants in juvenile polyposis syndrome. Hereditary Cancer in Clinical Practice (2023).
4. Hamartomatous polyposis syndromes: A review. Orphanet Journal of Rare Diseases (2014).