Somatic mutations in tumor-adjacent normal breast tissue in young women with high risk family history.

576 Background: It’s incompletely understood why some women without germline breast cancer predisposing mutations develop early onset breast cancer. Breast cancer in young women is often more aggressive, with high histologic grade, worse prognosis, and higher risk of recurrence. We hypothesize that these women have somatic mutations in the normal breast tissue that contribute to breast cancer tumorigenesis. Methods: Whole exome sequencing (WES) data was analyzed from normal tissue adjacent to breast tumor and compared to matched peripheral blood (n=28). All patients were <50yo, had high risk family history as per NCCN guidelines, and had negative Ambry Genetics panel testing. FFPE sections were reviewed by two pathologists to identify normal breast tissue furthest away from tumor. WES was performed on Illumina HS4000 using 100-base pair paired-end reads. Samples were mapped to the human reference genome (vGRCh38). PCR duplicates were marked (Picard), and indel regions were adjusted (GATK). High-quality germline variants (HaplotypeCaller), somatic mutations (Mutect), and indels (IndelGenotyper) were called. Low-quality variants were filtered out. The classification and number of mutations per gene per sample were extracted and analyzed. Results: Majority of patients were white (86%), median age 45, with invasive ductal carcinoma (86%), ER+/PR+/HER2- (100%). Median somatic variants per sample were 97 (range: 45-285), all single nucleotide variants, mostly missense mutations, C>T conversions were seen in 45% of mutations. This suggests cytidine deaminase (APOBEC) involvement. All samples had alterations in at least one of the top ten affected genes which include transcription factors in zinc finger family (listed below). Zinc finger proteins play a key role in tumorigenesis, cancer progression and metastasis in a variety of cancers. Upregulation of zinc finger proteins has been associated with worse prognosis in breast cancer. Conclusions: We describe novel somatic mutations in zinc finger proteins in normal breast tissue adjacent to tumor that may contribute to early onset breast cancer in patients with high risk family history. [Table: see text]