Double jeopardy: how BRCA2, TP53, and DNMT3A redefine the link between infertility and cancer risk
Zhengbin Huang1, Musavir Abbas2, Ansar Hussain3
1School of Business Administration, Chongqing Technology and Business University, Chongqing, China.
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.
Insights
Germline mutations in DNA repair and epigenetic genes link infertility and cancer risk. Management requires integrated genetic screening and multidisciplinary care for dual-risk mitigation.
Area of Science:
- Reproductive Biology
- Oncogenesis
- Genetics
Background:
- Germline mutations in DNA repair, cell cycle, and epigenetic genes are linked to cancer predisposition and reproductive dysfunction.
- This highlights a significant intersection between reproductive biology and oncogenesis.
- Shared genetic vulnerabilities underpin both conditions.
Purpose of the Study:
- To systematically review the literature on the intersection of infertility phenotypes and cancer predisposition syndromes.
- To identify shared molecular mechanisms and genetic factors.
- To explore clinical implications and translational strategies.
Main Methods:
- A systematic narrative review was conducted.
- Literature search across PubMed/MEDLINE, Scopus, and Web of Science.
- Keywords included infertility, cancer predisposition, and shared molecular pathways (DNA repair, epigenetics).
Main Results:
- Key genes like BRCA1/2, TP53, ATM, and DNMT3A have pleiotropic roles.
- Defects in DNA repair pathways (e.g., homologous recombination) cause gametogenesis failure and genomic instability.
- Distinct clinical phenotypes include premature ovarian insufficiency and germ cell apoptosis, with mouse models confirming sterility upon homozygous loss.
Conclusions:
- Infertility and cancer susceptibility are fundamentally linked by shared genetic vulnerabilities.
- A paradigm shift towards dual-risk management is necessary, including genetic screening and polygenic risk models.
- Multidisciplinary collaboration is crucial for personalized care addressing both reproductive and oncologic health.
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