Association Between Ancestry-Specific 6q25 Variants and Breast Cancer Subtypes in Peruvian Women

Background: Breast cancer incidence in the United States is lower in Hispanic/Latina (H/L) compared with African American/Black or Non-Hispanic White women. An Indigenous American breast cancer-protective germline variant (rs140068132) has been reported near the estrogen receptor 1 gene. This study tests the association of rs140068132 and other polymorphisms in the 6q25 region with subtype-specific breast cancer risk in H/Ls of high Indigenous American ancestry.

Methods: Genotypes were obtained for 5,094 Peruvian women with (1,755) and without (3,337) breast cancer. Associations between genotype and overall and subtype-specific risk for the protective variant were tested using logistic regression models and conditional analyses, including other risk-associated polymorphisms in the region.

Results: We replicated the reported association between rs140068132 and breast cancer risk overall [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.47-0.59], as well as the lower odds of developing hormone receptor negative (HR-) versus HR+ disease (OR, 0.77; 95% CI, 0.61-0.97). Models, including HER2, showed further heterogeneity with reduced odds for HR+HER2+ (OR, 0.68; 95% CI, 0.51-0.92), HR-HER2+ (OR, 0.63; 95% CI, 0.44-0.90) and HR-HER2- (OR, 0.77; 95% CI, 0.56-1.05) compared with HR+HER2-. Inclusion of other risk-associated variants did not change these observations.

Conclusions: The rs140068132 polymorphism is associated with decreased risk of breast cancer in Peruvians and is more protective against HR- and HER2+ diseases independently of other breast cancer-associated variants in the 6q25 region.

Impact: These results could inform functional analyses to understand the mechanism by which rs140068132-G reduces risk of breast cancer development in a subtype-specific manner. They also illustrate the importance of including diverse individuals in genetic studies.

Citing Articles

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PMID: 39625644 PMC: 11799839. DOI: 10.1158/1055-9965.EPI-24-1247.

Breast cancer subtype and clinical characteristics in women from Peru.

Zavala V, Casavilca-Zambrano S, Navarro-Vasquez J, Tamayo L, Castaneda C, Valencia G Front Oncol. 2023; 13:938042.

PMID: 36925912 PMC: 10013058. DOI: 10.3389/fonc.2023.938042.

References

Wang Y, He Y, Qin Z, Jiang Y, Jin G, Ma H . Evaluation of functional genetic variants at 6q25.1 and risk of breast cancer in a Chinese population. Breast Cancer Res. 2014; 16(4):422. PMC: 4303231. DOI: 10.1186/s13058-014-0422-x. View

Acheampong T, Kehm R, Terry M, Argov E, Tehranifar P . Incidence Trends of Breast Cancer Molecular Subtypes by Age and Race/Ethnicity in the US From 2010 to 2016. JAMA Netw Open. 2020; 3(8):e2013226. PMC: 7431997. DOI: 10.1001/jamanetworkopen.2020.13226. View

Dunning A, Michailidou K, Kuchenbaecker K, Thompson D, French J, Beesley J . Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nat Genet. 2016; 48(4):374-86. PMC: 4938803. DOI: 10.1038/ng.3521. View

Chacon-Duque J, Adhikari K, Fuentes-Guajardo M, Mendoza-Revilla J, Acuna-Alonzo V, Barquera R . Latin Americans show wide-spread Converso ancestry and imprint of local Native ancestry on physical appearance. Nat Commun. 2018; 9(1):5388. PMC: 6300600. DOI: 10.1038/s41467-018-07748-z. View

Cai Q, Wen W, Qu S, Li G, Egan K, Chen K . Replication and functional genomic analyses of the breast cancer susceptibility locus at 6q25.1 generalize its importance in women of chinese, Japanese, and European ancestry. Cancer Res. 2011; 71(4):1344-55. PMC: 3083305. DOI: 10.1158/0008-5472.CAN-10-2733. View

Gelaye B, Zhong Q, Basu A, Levey E, Rondon M, Sanchez S . Trauma and traumatic stress in a sample of pregnant women. Psychiatry Res. 2017; 257:506-513. PMC: 5626654. DOI: 10.1016/j.psychres.2017.08.016. View

Hoffman J, Fejerman L, Hu D, Huntsman S, Li M, John E . Identification of novel common breast cancer risk variants at the 6q25 locus among Latinas. Breast Cancer Res. 2019; 21(1):3. PMC: 6332913. DOI: 10.1186/s13058-018-1085-9. View

Auton A, Brooks L, Durbin R, Garrison E, Kang H, Korbel J . A global reference for human genetic variation. Nature. 2015; 526(7571):68-74. PMC: 4750478. DOI: 10.1038/nature15393. View

Heinz T, Alvarez-Iglesias V, Pardo-Seco J, Taboada-Echalar P, Gomez-Carballa A, Torres-Balanza A . Ancestry analysis reveals a predominant Native American component with moderate European admixture in Bolivians. Forensic Sci Int Genet. 2013; 7(5):537-42. DOI: 10.1016/j.fsigen.2013.05.012. View

10.

Manichaikul A, Mychaleckyj J, Rich S, Daly K, Sale M, Chen W . Robust relationship inference in genome-wide association studies. Bioinformatics. 2010; 26(22):2867-73. PMC: 3025716. DOI: 10.1093/bioinformatics/btq559. View

11.

Jin T, Zhang W, Zhou Z . The 6q25.1 rs2046210 polymorphism is associated with an elevated susceptibility to breast cancer: A meta-analysis of 261,703 subjects. Mol Genet Genomic Med. 2019; 7(3):e553. PMC: 6418377. DOI: 10.1002/mgg3.553. View

12.

Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M . Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet. 2010; 42(6):504-7. PMC: 3632836. DOI: 10.1038/ng.586. View

13.

Fejerman L, Chen G, Eng C, Huntsman S, Hu D, Williams A . Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas. Hum Mol Genet. 2012; 21(8):1907-17. PMC: 3313799. DOI: 10.1093/hmg/ddr617. View

14.

Hein R, Maranian M, Hopper J, Kapuscinski M, Southey M, Park D . Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC). PLoS One. 2012; 7(8):e42380. PMC: 3413660. DOI: 10.1371/journal.pone.0042380. View

15.

Fejerman L, Ahmadiyeh N, Hu D, Huntsman S, Beckman K, Caswell J . Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25. Nat Commun. 2014; 5:5260. PMC: 4204111. DOI: 10.1038/ncomms6260. View

16.

Arpino G, Wiechmann L, Osborne C, Schiff R . Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008; 29(2):217-33. PMC: 2528847. DOI: 10.1210/er.2006-0045. View

17.

Wang S, Zhang K, Tang L, Yang Y, Wang H, Zhou Z . Association Between Single-Nucleotide Polymorphisms in Breast Cancer Susceptibility Genes and Clinicopathological Characteristics. Clin Epidemiol. 2021; 13:103-112. PMC: 7896729. DOI: 10.2147/CLEP.S292429. View

18.

Das S, Forer L, Schonherr S, Sidore C, Locke A, Kwong A . Next-generation genotype imputation service and methods. Nat Genet. 2016; 48(10):1284-1287. PMC: 5157836. DOI: 10.1038/ng.3656. View

19.

Lilyquist J, Ruddy K, Vachon C, Couch F . Common Genetic Variation and Breast Cancer Risk-Past, Present, and Future. Cancer Epidemiol Biomarkers Prev. 2018; 27(4):380-394. PMC: 5884707. DOI: 10.1158/1055-9965.EPI-17-1144. View

20.

Stacey S, Sulem P, Zanon C, Gudjonsson S, Thorleifsson G, Helgason A . Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus. PLoS Genet. 2010; 6(7):e1001029. PMC: 2908678. DOI: 10.1371/journal.pgen.1001029. View