The rise of precision oncology has underscored the importance of understanding genetic variation in cancer risk and treatment. However, this progress is unevenly distributed. Hispanic/Latina women, despite constituting a significant and growing demographic in the United States, remain underrepresented in genomic studies related to BRCA1 and BRCA2 mutations. These mutations are highly relevant to the development of breast and ovarian cancer and have been strongly associated with triple-negative breast cancer (TNBC)—an aggressive subtype with limited targeted therapies.

BRCA Mutations and the Case for Genomic Inclusion

Germline pathogenic variants in BRCA1 and BRCA2 disrupt homologous recombination repair pathways, predisposing carriers to breast, ovarian, prostate, and pancreatic cancers. TNBC, characterized by a lack of ER, PR, and HER2 expression, is more commonly associated with BRCA1 mutations and has worse clinical outcomes compared to other subtypes [1,2].

Historically, most BRCA research has focused on women of European descent. A large study by Hall et al. demonstrated disparities in mutation detection and testing rates across ethnic groups, revealing that Latinas, African Americans, and Native Americans are not only under-tested but also carry clinically significant mutations at comparable or even elevated frequencies [3]. In response to these disparities, the National Cancer Institute launched a multicenter study (ClinicalTrials.gov ID: NCT01251900) specifically targeting Hispanic/Latina women to investigate the frequency and distribution of BRCA mutations in this population [4].

Founder Mutations and Ancestral Structure

Recent studies have identified several founder mutations in BRCA1/2 among Latina women. One of the most common, BRCA1 c.3331_3334delCAAG, has been detected across multiple Latin American populations, including those from Colombia, Mexico, and Brazil, suggesting a shared ancestral origin [5]. The NCI study genotyped participants for such known founder variants and incorporated ancestry-informative markers to adjust for admixture among European, African, and Native American lineages.

This is essential because Hispanic/Latina populations are genetically heterogeneous. By controlling for this population structure through AIM panels, researchers could accurately associate genetic variants with cancer subtypes and clinical features using logistic regression models [4].

Implications for Targeted Therapy

Identifying BRCA mutations is not just an academic exercise—it directly impacts clinical care. Tumors deficient in BRCA-mediated DNA repair are particularly susceptible to poly(ADP-ribose) polymerase (PARP) inhibitors, such as olaparib and niraparib. These agents exploit synthetic lethality by preventing single-stranded DNA repair, leading to cell death in BRCA-mutant cancers [6,7].

Fong et al. demonstrated the efficacy of PARP inhibitors in BRCA-associated cancers, including TNBC, establishing a foundation for their regulatory approval and use in clinical practice [8]. However, if Hispanic/Latina women are not adequately screened or identified as mutation carriers, they are less likely to benefit from these therapies. Inclusion in genomic research is thus a prerequisite for therapeutic equity.

Methodological Highlights

The NCI study exemplified best practices in population-based cancer genomics. It recruited 2,000 Hispanic/Latina women (1,000 TNBC; 1,000 ER/PR-positive), used validated questionnaires to capture reproductive and lifestyle risk factors, and implemented secure anonymization protocols to protect participant identity. DNA from saliva samples was coded, de-identified, and linked to clinical variables such as tumor grade and pathology only through non-reversible identifiers [4].

In addition, penetrance was estimated using kin-cohort methods to assess cumulative risk in carriers and non-carriers [9]. These methodologies are crucial in building reliable, translatable models in underrepresented populations.

Moving Toward Equity Through Data Representation

Ultimately, it is emphasized that the path to equitable precision medicine lies through data inclusivity. Population-specific mutation panels, stratified risk models, and tailored screening protocols all depend on robust representation in genomic studies.

The Hispanic/Latina population offers a powerful case study: high prevalence of founder mutations, unique admixture backgrounds, and disproportionate risk for aggressive subtypes like TNBC. Without active efforts to include such populations, the promise of personalized oncology will remain unfulfilled for many.

References

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2. Young SR, Pilarski RT, Donenberg T, et al. The prevalence of BRCA1 mutations among young women with triple-negative breast cancer. BMC Cancer. 2009;9:86.
3. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222–33.
4. Dean M, Silverton L, Sawitzke J. Nationwide Study of Breast Cancer Risk Factors in Latinas. Nature Precedings [Preprint]. 2011 Feb 18. doi:10.1038/npre.2011.5691.2
5. Solano AR, Aceto GM, Delettieres D, et al. Founder mutations in BRCA1 and BRCA2 genes in Latin American countries: state of the art and perspectives. Breast Cancer Res. 2020;22(1):20.
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7. Rottenberg S, Jaspers JE, Kersbergen A, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008;105(44):17079–84.
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9. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336(20):1401–8.