Work

Double jeopardy: how BRCA2, TP53, and DNMT3A redefine the link between infertility and cancer risk

Year: 2026

Type: review

Abstract: Background Germline mutations in genes governing DNA repair, cell cycle regulation, and epigenetic modification are now recognized as common etiological factors for both cancer predisposition and reproductive dysfunction. This reveals a profound intersection between reproductive biology and oncogenesis. Method A systematic narrative review was conducted. The literature search spanned PubMed/MEDLINE, Scopus, and Web of Science using keywords and MeSH terms related to infertility phenotypes, cancer predisposition syndromes, and shared molecular mechanisms (e.g., DNA repair, epigenetics). Outcomes The analysis identifies a core set of genes including BRCA1/2, TP53, ATM , and DNMT3A with pleiotropic roles. Mechanistically, defects in pathways like homologous recombination and mismatch repair disrupt meiotic fidelity, causing gametogenesis failure (e.g., BRCA2 -mediated azoospermia), while fostering genomic instability that drives carcinogenesis. Clinically, distinct phenotypes emerge, such as BRCA1 -associated premature ovarian insufficiency and TP53 -related germ cell apoptosis. Mouse models validate these links, showing that homozygous loss often causes complete sterility. Translational strategies, including PGT-M for high-risk variants and microsurgical testicular sperm extraction (micro-TESE) with intracytoplasmic sperm injection (ICSI) for azoospermia, offer concrete methods for risk mitigation within integrated oncofertility programs. Conclusion Infertility and cancer susceptibility are fundamentally linked through shared genetic vulnerabilities and molecular pathways. This necessitates a paradigm shift toward dual-risk management, involving universal genetic screening in idiopathic infertility, the development of polygenic risk models, and close multidisciplinary collaboration. While ethical challenges persist, these advances pave the way for personalized care that simultaneously addresses reproductive and oncologic health.

Source: Frontiers in Cell and Developmental Biology

DOI: 10.3389/fcell.2026.1803566

Authors: Zhengbin Huang, Musavir Abbas, Ansar Hussain, Ming Long, Muhammad Muzammal, Kaiyong Song

Institutions: Chongqing Technology and Business University, University of Science and Technology of China, Gomal University

Language: English

Topic: BRCA gene mutations in cancer

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801