Inherited Susceptibility to Cancer: Past, Present and Future

Abstract

Germline pathogenic variants (GPVs, ‘mutations’) causing inherited susceptibility to certain cancers (cancer susceptibility genes, CSGs) broadly belong to one of two main classes—loss of function variants in tumour suppressor genes (TSGs) or gain of function variants in proto‐oncogenes (an over‐simplification). Genomic analyses of tumours identify ‘driver mutations’ promoting tumour growth and somatic variants which contribute to ‘mutation signatures’ which, with histopathology, can be used to subclassify cancers with implications for causality and treatment. The identification of susceptible individuals is important, as they and their relatives may be at elevated risk of tumours, and this can influence optimal cancer treatment. Classically, cancer risk assessment utilises family history, lifestyle/environment factors, and any non‐neoplastic clinical findings, followed by genetic testing of high/moderate penetrance CSGs. In cancer cases not caused by highly penetrant CSGs, multiple variants conferring relatively small risks play a major role. These were discovered by genome‐wide association (GWAS) studies. The utility of polygenic risk scores (PRS) derived from multiple such variants for clinical risk profiling is being assessed. Access to genetic tests is improved by widening eligibility criteria for testing and empowering non‐genetic clinicians to identify CSG GPVs and manage carriers. This will contribute to expanding programmes of screening, prevention and early detection (SPED), with personalised surveillance and prophylactic interventions, and exploit knowledge of the molecular mechanisms of cancer susceptibility to develop novel cancer therapies. In some jurisdictions, population testing is being considered, but GPV penetrance in this setting can be unclear, and the public health implications are complex.

Publication DOI: https://doi.org/10.1111/ahg.70013
Divisions: College of Health & Life Sciences > Aston Medical School
Aston University (General)
Funding Information: This study was supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312) and the Cancer Research UK (C61296/A27223, EDDPGM Nov22/100004).
Additional Information: Copyright © 2025 The Author(s). Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Publication ISSN: 1469-1809
Last Modified: 31 Jul 2025 07:25
Date Deposited: 30 Jul 2025 10:02
Full Text Link:
Related URLs: https://onlinel ... .1111/ahg.70013 (Publisher URL)
PURE Output Type: Article
Published Date: 2025-07-21
Published Online Date: 2025-07-21
Accepted Date: 2025-07-10
Authors: Hodgson, Shirley V.
Foulkes, William D.
Maher, Eamonn R
Turnbull, Clare

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