Interaction between genetic ancestry and common breast cancer susceptibility variants in Colombian women

Abstract

Latino women show lower incidences of breast cancer (BC) than non-Hispanic whites. Large-scale genetic association studies have identified variants robustly associated with BC risk in European women. We examine here the relevance of these variants to Colombian BC and possible interactions with genetic ancestry. Native American, European and African proportions were estimated for 1022 Colombian BC cases and 1023 controls. Logistic regression was applied to assess the association between 78 variants and BC risk and interactions between the variants and ancestry proportions. We constructed a multifactorial risk score combining established BC risk factors, associated risk variants and individual ancestry proportions. Each 1% increase in the Native American proportion translated into a 2.2% lower BC risk (95% CI: 1.4-2.9). Thirteen variants were associated with BC in Colombian women, with allele frequencies and risk effects partially different from European women. Ancestry proportions moderated the risk effects of two variants. The ability of Native American proportions to separate Colombian cases and controls (area-under-the-curve (AUC) = 0.61) was similar to the discriminative ability of family history of BC in first-degree female relatives (AUC = 0.58) or the combined effect of all 13 associated risk variants (AUC = 0.57). Our findings demonstrate ample potential for individualized BC prevention in Hispanic women taking advantage of individual Native American proportions, information on established susceptibility factors and recently identified common risk variants.

Genetic Epidemiology of Breast Cancer in Latin America

“…Women with higher European ancestry had an increased risk of breast cancer compared to women with higher Indigenous American ancestry. Subsequent studies in Latin American populations (two in Mexicans and one in Colombians) replicated this finding [189,190,191]. A study from Uruguay did not find a statistically significant difference in genetic ancestry between breast cancer cases and controls, possibly due to the lack of statistical power given the size of the sample and the relatively small proportion of Indigenous American ancestry in this population [192].…”

<p>Genetic Variability in the microRNA Binding Sites of <em>BMPR1B</em>, <em>TGFBR1</em>, <em>IQGAP1</em>, <em>KRAS</em>, <em>SETD8</em> and <em>RYR3</em> and Risk of Breast Cancer in Colombian Women</p>

“…Cases and controls were only eligible if they were of Colombian origin and resided in the study region. 23,24 Data on established and potential BC risk factors were collected from all study participants including age at diagnosis (cases)/age at interview (controls), proportion of European, Native American and African genetic ancestry, family history of BC in first-degree female relatives (yes, no), oral contraceptive (OC) use (yes, no), menopausal status and postmenopausal hormone therapy (HT) use (premenopausal and postmenopausal women who never used HT, postmenopausal women who ever used HT), body mass index (BMI) (<25, 25-29.9, ≥30 kg/m 2 ), smoking status (never, former, current), parity (0, 1-2, ≥3), age at first full-term pregnancy (<20, 20-29, ≥30 years), age at menarche (≥14, 12-13, <12 years), and breastfeeding (never, ≤12, >12 months). Clinical and histopathological parameters were also collected from all cases ( Table 1).…”

“…OncoTargets and Therapy 2020:13 (MALDI-TOF MS) (Sequenom, San Diego, CA, USA) as previously described by us. 24 All primers were synthesized by Sigma-Aldrich Chemie GmbH, Steinheim, Germany. Primer sequences are shown in Supplementary Table 1.…”

“…26 Genotyping of 1757 native DNA samples and 288 Whole Genome Amplified (WGA) DNA samples was performed using the KASP allelic discrimination method (LGC Genomics, Teddington TW11 0LY, UK) as previously described. 24 Cluster plots and genotypes were inspected with the SNPviewer2 software version 4.0.0 (http://www. lgcgroup.com/products/genotyping-software/snpviewer/ #.-V1aqCEYppXg, LGC Genomics, Teddington TW11 0LY, UK).…”

“…The individual proportions of European, Native American, and African ancestry were estimated based on the 30 genotyped AIMs using the ADMIXTURE software as described previously. 24 The association between the investigated genetic variants and BC risk was tested using logistic regression. An additive model was assumed for individual genotypes and the regression analyses were adjusted for the individual proportions of genetic ancestry, family history of BC in first-degree female relatives, OC use, menopausal status and postmenopausal use of HT, BMI, smoking status, parity, age at first full-term pregnancy, age at menarche, and breastfeeding (Table 1).…”