Abstract 4254: Improved understanding of the etiology of breast cancer in young women through evaluation of the genomic landscape

Abstract

Abstract Background Breast cancer is a disease where biological age and age at menopause are established risk factors, thus diagnosis of breast cancer in young women (<40 years, YW) is not common, representing ~6% of breast cancer diagnoses annually. Germline mutations in cancer predisposition genes accounts for ~20% of breast cancer diagnoses in YW, thus the etiology of breast tumors for the majority of YW is unknown. Methods Frozen tumor specimens and matched genomic DNA samples from 31 women diagnosed <40 years were available. Whole genome sequencing (WGS) was performed by generating sequencing libraries from 1 mg input using the TruSeq PCR-free library preparation workflow and sequencing on the HiSeq X Ten at triple lane depth with 150bp paired-end reads. WGS was analyzed using the Hiseq Analysis Software Tumor Normal Workflow, Bioconductor: deconstructSigs and ad hoc integrated analysis and hypothesis testing. Results Luminal A tumors from YW had significantly lower somatic mutational loads, copy number alterations and structural variants than other subtypes and structural variants on chromosome 17 were enriched in patients with the HER2-enriched subtype and HER2 status = 3+. Aging was the most common signature (28/31) followed by APOBEC activation (14/31). Signatures associated with defects in mismatch repair (9/31) and polymerase ϵ (10/31) were also detected in >25% of patient tumors. Of the six patients with BRCA defect signatures, three had germline mutations in BRCA2 and one had a CHEK2 mutation. Mutational signatures could cluster patients into two groups, with the youngest patients (<35 years) less likely to have signatures associated with aging but an enrichment in signatures of APOBEC, BRCA mutations and smoking; tumors within this group were more likely to be non-luminal A. Conclusions Profiling the genome of tumors from YW supports the idea that most tumors are not characterized by profiles associated with genetic predisposition but rather processes such aging, APOBEC activation, mismatch repair, and defects in DNA replication. Of note, breast tumors in the youngest patients (<35) have a different pattern of mutational signatures suggesting that even within YW, etiology differs by age. Citation Format: Matthew D. Wilkerson, Clifton L. Dalgard, Craig D. Shriver, Rachel E. Ellsworth. Improved understanding of the etiology of breast cancer in young women through evaluation of the genomic landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4254. doi:10.1158/1538-7445.AM2017-4254