In a groundbreaking study published in Nature Communications, researchers have revealed a crucial genetic link that increases susceptibility to a particularly aggressive form of breast cancer among Hispanic/Latina women. Using whole exome sequencing, a powerful genomic technique that deciphers nearly all protein-coding regions of the genome, the team identified mutations in the FANCM gene as a novel risk factor for estrogen-receptor-negative breast cancer (ER-negative BC). This discovery not only adds a vital piece to the complex breast cancer susceptibility puzzle but also underscores the importance of genetic studies in diverse populations, which historically have been underrepresented in cancer genomics research.
Breast cancer remains the most frequently diagnosed cancer and the leading cause of cancer mortality among women globally. While advances in hormone receptor-targeted therapies have improved outcomes for estrogen-receptor-positive (ER-positive) breast cancer, ER-negative subtypes, including triple-negative breast cancer, continue to show poor prognoses and limited treatment options. These cancers do not respond to hormonal therapies, making early detection and understanding of genetic predispositions critically important for preventive strategies and the development of novel targeted treatments.
The FANCM gene, previously recognized for its role in the Fanconi anemia DNA repair pathway, emerged as a gene of interest through this extensive whole exome sequencing analysis performed on a large cohort of Hispanic/Latina women diagnosed with ER-negative breast cancer. FANCM encodes a protein integral to maintaining genomic stability by orchestrating the repair of DNA interstrand cross-links and managing replication stress, processes that are fundamental to preventing malignant transformation. Mutations that impair FANCM’s function could therefore lead to a failure in DNA repair mechanisms, fostering the accumulation of genomic alterations that drive cancer development.
Importantly, this study leveraged one of the most comprehensive and ethnically diverse cohorts assembled to date for breast cancer genetic research. Hispanic/Latina populations have been notably understudied despite being the second largest ethnic group in the United States and carrying a disproportionate burden of aggressive breast cancer. By focusing on this cohort, the researchers filled a significant gap in understanding the genetic landscape that confers risk in minority populations often overlooked in precision medicine initiatives.
The discovery of FANCM as a susceptibility gene for ER-negative breast cancer in Hispanic/Latina women holds profound implications for the clinical management of breast cancer risk in this demographic. Current genetic screening panels typically emphasize genes like BRCA1 and BRCA2, which, while highly penetrant, are not the sole contributors to hereditary breast cancer. Including FANCM mutations could refine risk prediction models and enable the development of targeted screening programs, facilitating earlier detection and preventative interventions tailored to high-risk women in this population.
Technically, the identification of FANCM mutations was achieved through high-depth sequencing of the exome, allowing for precise detection of rare coding variants that might have otherwise been missed in studies focusing on more limited genomic regions. This approach is particularly advantageous when investigating complex diseases with heterogeneous etiology like breast cancer. By analyzing variants in the coding regions of thousands of genes simultaneously, the researchers pinpointed specific deleterious variants strongly enriched among patients with ER-negative breast cancer.
Moreover, functional assays performed in parallel validated the pathogenicity of these FANCM mutations. Using cellular models, the research team demonstrated how these variants compromised FANCM’s ability to resolve replication fork stalling and DNA damage, processes critical for genomic integrity. Cells harboring mutant FANCM exhibited increased sensitivity to DNA cross-linking agents and accumulated chromosomal abnormalities indicative of genomic instability, mechanistically establishing a causal link between FANCM dysfunction and tumorigenesis.
This study also highlights the evolutionary and population genetics aspects of FANCM variants. Certain mutations appeared at higher frequencies in Hispanic/Latina groups, suggesting a population-specific founder effect or genetic drift. These insights emphasize the necessity of including diverse ethnicities in genomic studies to capture population-specific risk alleles, which could otherwise remain hidden in studies dominated by European ancestry cohorts.
From a translational perspective, the findings open new avenues for personalized medicine. Given FANCM’s role in DNA repair, tumors arising from FANCM deficiency may exhibit unique vulnerabilities to DNA-damaging chemotherapy or agents that target compensatory repair pathways, such as PARP inhibitors. Clinical trials evaluating these therapeutic strategies could be prioritized for ER-negative breast cancer patients harboring FANCM mutations, potentially improving outcomes in an otherwise challenging patient subset.
The research also prompts a reevaluation of genetic counseling practices. Incorporating FANCM testing into multi-gene panels could alter risk assessment and management decisions for families with histories of ER-negative breast cancer, particularly in Hispanic/Latina women. Genetic counselors would need to interpret new variants of uncertain significance and provide guidance tailored to the nuanced risks associated with FANCM alterations.
Beyond breast cancer, FANCM mutations have been implicated in other malignancies and conditions marked by genomic instability. Therefore, this work may have broader implications for cancer biology, emphasizing the interconnectedness of DNA repair pathways across different tumor types and highlighting the potential for cross-cancer preventive strategies targeting these molecular vulnerabilities.
The timing of the study is especially propitious as advances in sequencing technology continue to drive down costs and increase accessibility, enabling more comprehensive genetic screening on a population scale. Incorporating genes like FANCM into next-generation sequencing panels could become standard practice, significantly advancing early detection and personalized prevention methods for high-risk individuals worldwide.
Despite these exciting developments, the authors caution that further research is necessary to fully elucidate the spectrum of FANCM mutations and their penetrance in diverse populations. Longitudinal studies and larger multi-ethnic cohorts will be instrumental in refining risk estimates and confirming the gene’s role across different breast cancer subtypes and ancestries.
Additionally, integrating genomic data with epidemiological and clinical information will enhance understanding of gene-environment interactions that modulate cancer risk. Sociodemographic factors, lifestyle, and reproductive history, when combined with FANCM status, could inform multifactorial models that more accurately predict individual susceptibility, moving closer to the goal of truly personalized cancer prevention.
This landmark study exemplifies how the intersection of advanced genomics, molecular biology, and population genetics can unravel the complexities of cancer susceptibility in historically underserved populations. It challenges the research community to prioritize inclusivity in genomic studies to ensure that precision oncology benefits all, not just a privileged few.
In conclusion, the identification of FANCM as a susceptibility gene for estrogen-receptor-negative breast cancer in Hispanic/Latina women marks a significant leap forward in breast cancer genomics. This discovery not only enriches the catalog of hereditary breast cancer genes but also paves the way for innovative prevention, diagnostic, and therapeutic strategies tailored to an ethnically diverse patient population enduring a disproportionate burden of aggressive cancer forms. As the field progresses, FANCM-focused research will undoubtedly play a pivotal role in shaping the future landscape of breast cancer care.
Subject of Research: The identification of FANCM gene mutations as a susceptibility factor for estrogen-receptor-negative breast cancer in Hispanic/Latina women through whole exome sequencing.
Article Title: Whole exome sequencing identifies FANCM as a susceptibility gene for estrogen-receptor-negative breast cancer in Hispanic/Latina women.
Article References:
Nierenberg, J.L., Adamson, A.W., Hu, D. et al. Whole exome sequencing identifies FANCM as a susceptibility gene for estrogen-receptor-negative breast cancer in Hispanic/Latina women. Nat Commun 16, 7816 (2025). https://doi.org/10.1038/s41467-025-60564-0
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