Double jeopardy: how <i>BRCA2</i>, <i>TP53</i>, and <i>DNMT3A</i> redefine the link between infertility and cancer risk.

<h4>Background</h4>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.<h4>Method</h4>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).<h4>Outcomes</h4>The analysis identifies a core set of genes including <i>BRCA1/2, TP53, ATM</i>, and <i>DNMT3A</i> with pleiotropic roles. Mechanistically, defects in pathways like homologous recombination and mismatch repair disrupt meiotic fidelity, causing gametogenesis failure (e.g., <i>BRCA2</i>-mediated azoospermia), while fostering genomic instability that drives carcinogenesis. Clinically, distinct phenotypes emerge, such as <i>BRCA1</i>-associated premature ovarian insufficiency and <i>TP53</i>-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.<h4>Conclusion</h4>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.