Abstract IA19: Genetic risk for subsequent breast cancer among female survivors of childhood cancer
Authors: Wang Zhaoming 
Published: December 2020

Abstract
Due to advancement in cancer therapy, greater than 80% of children diagnosed with cancer will survivor five or more years. It is estimated there are half a million childhood cancer survivors currently living in the US. Survivors are at increased risk of subsequent neoplasms, mostly considered therapy related. Breast cancer is one of the most common subsequent neoplasms among female survivors. It is known that radiation dose and volume to the breast is a major risk factor, leading to 20-fold increased risk with rate of cumulative incidence reaching 30% by age of 50 years. For non-irradiated survivors, literature also reported the risk of chemotherapy agents including anthracyclines. However, the genetic contribution was largely unknown before the groundbreaking genomic project was launched for the St. Jude Lifetime Cohort (SJLIFE) a few years ago. We analyzed the whole-genome sequencing data for 4402 survivors (2090 females, median age at follow up = 30 years, and median length of follow up = 22 years) from SJLIFE study. Pathogenic/likely (P/LP) variants were identified for 156 cancer predisposition genes and 127 DNA repair genes, respectively, with a small number of genes overlapped between the two gene sets. We also constructed a polygenic risk score based on 172 SNPs established from de novo breast cancer genetic association studies using the general population. Based on the multivariate piecewise exponential models, rate of subsequent breast cancer was significantly increased for female survivors who carried a P/LP variant in cancer predisposition genes and with or without chest irradiation. In addition, rate of subsequent breast cancer was significantly increased among all female survivors, especially survivors who carried a P/LP variant in homologous recombination DNA repair genes in conjunction with treatment exposures of chest irradiation (≥20Gy) and/or anthracyclines (doses in the second and third tertiles). Finally, we found survivors with high polygenic risk score had increased risk of developing subsequent breast cancer over and beyond the monogenic risk conferred by rare P/LP variants in breast cancer predisposition genes. Interestingly, African Americans seem to have the lowest prevalence of subsequent breast cancer among three different race groups: 1.3% for African Americans, 4.1% for European Americans and 5.9% for Asian/Native-Indian Americans. On the other hand, African Americans seem to have higher risk in developing subsequent breast cancer among carriers of P/LP variants compared to European Americans. We anticipate utilizing common susceptibility loci in combination with rare high-risk P/LP variants and other risk factors may inform a better strategy for breast cancer risk stratification among survivors of childhood cancer.
Citation Format: Zhaoming Wang. Genetic risk for subsequent breast cancer among female survivors of childhood cancer [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA19.