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Abstract

The etiology of breast cancer (BC) involves both non-genetic and genetic factors. Environmental and lifestyle factors such as age, use of menopausal hormone therapy, smoking, and body mass index have been associated with the risk of developing BC. Genetic susceptibility determined mainly by family history and ethnic background have an important role in the risk of developing this disease (Dossus and Benusiglio, 2015). In recent years, novel variants robustly associated with BC risk have been identified in large-scale genetic association studies in women of European and Asian origin. However, few studies directed towards the identification of BC susceptibility variants have been conducted among Latin American and Hispanic populations.

This thesis examined the contributions of genetic ancestry, established risk factors, and newly identified susceptibility variants to BC risk in Colombia. A total of 2,045 participants from the Colombian Breast Cancer Case-Control study were included in this analysis: 1,022 BC patients, and 1,023 healthy controls. BC patients were unselected for family history and age at BC diagnosis. European, Native American, and African ancestry proportion were quantified in each woman based on 30 ancestry informative markers, aiming to obtain the relationship between ancestry and BC risk. Seventy-eight previously identified common BC susceptibility variants were genotyped and associations of these variants with BC risk in the Colombian population were determined. To assess the interactions between the variants and ancestry proportions logistic regression models were applied. Native American proportions were lower in Colombian BC patients than in unaffected controls (P-value=5.2x10-16). This difference translated into an unadjusted decreased BC risk of 2.6% per each 1% increase in the Native American proportion (95% CI: 2.0-3.2). Associations with BC risk in Colombian women were obtained for thirteen variants, which in comparison with European women have partially different risk effects and allele frequencies. The risk effects of rs941764 (CCDC88C) and rs3803662 (TOX3) was controlled for ancestry proportions. One variant was associated with estrogen receptor negative (ER-), seven with estrogen receptor positive (ER+), and three with ER+ and ER- disease. The variance in BC liability due to susceptibility variants in European and Colombian women was estimated. Out of 13 variants associated with BC risk in Colombia, four explained a larger attributable heritability in Europe than in Colombia and nine revealed larger attributable heritability in Colombia than in Europe.

Area under the Receiver Operating Characteristic curves (AUCs) with their corresponding 95% CIs were estimated for established risk factors, genetic ancestry, and common BC susceptibility variants based on risk estimates from the literature and own Colombian data. The discriminative ability to separate Colombian cases and controls of family history of BC in first-degree female relatives (AUC=0.58) and the combination of all 13 associated risk variants (AUC=0.57) were similar to the discriminative ability of Native American proportions (AUC=0.61).

The findings demonstrate that individual ancestry proportions predict BC risk in Colombia as accurately as established BC risk factors. Combining Native American proportions, established risk factors, and newly identified genetic susceptibility variants could translate in promising clinical strategies on BC prevention in Latin American and Hispanic women.