Abstract P5-10-02: Development and validation of a polygenic score to predict breast cancer risk in unaffected Hispanic women negative for mutations on a multi-gene hereditary cancer panel
Authors: Hughes ER , Wagner S , Pruss D , Gallagher SK , Swedlund B , Bulka K , Hoff R , Jammulapati S , Morris B , Perry T , Lanchbury JS , Gutin A 
Published: May 2019

Background: Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer-related death among Hispanic women in the United States. For women of European ancestry, genome-wide association studies (GWAS) have identified common variants, primarily single-nucleotide polymorphisms (SNPs), that individually confer modest risk but together explain a significant proportion of genetic BC predisposition. For Hispanic women, the genetic contribution of SNPs to BC risk is not well understood. In these studies, we aim to develop and validate a polygenic score to improve risk assessment for Hispanic women who test negative for mutations in known BC susceptibility genes.

Methods: Genotypes and clinical histories were collected from consecutive development and validation cohorts of patients referred for hereditary cancer testing. Study subjects include women who report strictly Hispanic or Latin American ancestry, and who test negative for mutations in 11 genes associated with breast cancer (BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1).

Based on a development cohort ascertained through June 2017, we evaluated an 86-SNP Residual Risk Score (RRS) that was previously developed and validated for women of European ancestry. In the same cohort we are developing a Hispanic Residual Risk Score (HRRS) optimized for women of Hispanic ancestry. BC associations of individual SNPs are being established through meta-analysis of the development cohort and published Hispanic studies.

Multivariate logistic regression models were used to evaluate the 86-SNP RRS, and were the primary statistical tool for evaluation of individual SNPs and candidate polygenic scores. All models included personal/family cancer history and age as independent variables. P-values are based on likelihood ratio test statistics, and reported as two-sided. The development and validation studies are being conducted according to a protocol approved by the Quorum Institutional Review Board.

Results: The development cohort included 5,454 Hispanic women, 24% of whom reported a personal history of BC. The 86-SNP RRS was significantly associated with a personal history of BC after accounting for personal and family cancer history (p&lt;10-19) with odds ratio per unit standard deviation 1.39 (95% CI = 1.30-1.50). To date, more than 5,000 Hispanic women have been ascertained for inclusion in the validation cohort. Results comparing discriminatory accuracy of the RRS and the HRRS will be presented.

Conclusions: The implementation of a clinically validated polygenic score may improve risk assessment and medical management of Hispanic women who test negative for monogenic BC mutations. The HRRS will be validated in an independent study population according to a pre-specified statistical analysis plan.

Citation Format: Hughes ER, Wagner S, Pruss D, Gallagher SK, Swedlund B, Bulka K, Hoff R, Jammulapati S, Morris B, Perry T, Lanchbury JS, Gutin A. Development and validation of a polygenic score to predict breast cancer risk in unaffected Hispanic women negative for mutations on a multi-gene hereditary cancer panel [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-10-02.