Abstract 4358: Landscape of allelic imbalance in pan-cancer adjacent normal tissue: Insights into field cancerization and cancer pathogenesis
Authors: Jakubek Yasminka A. , Lucas Francis A. San , Sivakumar Smruthy , Fowler Richard G. , Kadara Humam , Scheet Paul 
Published: August 2018

Abstract
It has been observed that tumors and adjacent normal appearing tissues share molecular signatures. This phenomenon has been observed in tissues of the skin, colon, and lung among others, particularly for patterns of gene expression. A recent pan cancer study of gene expression in normal tissue adjacent to the tumor (NAT) has shown that NATs have unique expression profiles that are distinct from non-tumor-bearing tissues. In this work, we sought to further characterize the molecular profile of NAT samples across cancer types. We have previously applied our haplotype based statistical technique to survey allelic imbalance (AI) in putatively normal lung tissues adjacent to tumor. Using this method, we can detect changes indicative of chromosomal alteration (gain, loss and copy-neutral LOH) even when present at low mutant cell fractions (&lt; 5%). We focused our analysis on a subset of TCGA patients with both a solid tumor and NAT sample (n = 1530). In addition, to serve as a control, we surveyed alterations in normal samples derived from blood (n = 7,796). We detected 218 (megabase scale) chromosomal alterations in 44 of the NAT samples. These somatic alterations were present at a higher rate in NAT (2.9%) compared to the control normal blood set (1.9%). NAT samples with detectable AI had an average of 5 AI events compared to an average of 2 events in blood samples. We did not detect AI in the blood samples from the 44 patients with AI in the NAT. The most common recurrent alterations in NAT were 8p23.1, 17q21.31 and 1q42.12-1q42.13; each found in 14% of NAT AI positive samples. Chromosomal alterations in NAT were present at different rates between cancer types. We detected AI in more than 10% of NATs from breast invasive carcinoma, sarcoma, and bladder urothelial carcinoma. Of the 218 AI events in NAT, 67% were detected in the matching tumor sample. Two cancers, kidney renal papillary cell carcinoma and thyroid carcinoma, had a positive correlation between presence of AI in NAT and AI burden in the matched tumor sample (P = 0.005 and 0.03 respectively). The most common mutations in the tumors of patients with chromosomal aberrations in NAT were TP53 and MUC16 found in 39% and 20%, of tumors respectively. Lung squamous carcinoma and ovarian serous cystadenocarcinoma patients with detectable AI in NAT had a worse survival rate (P = 0.0241 and 0.0439 respectively). Our survey of AI in NAT tissues provides further support for NAT tissues as a model for understanding cancer pathogenesis.
Citation Format: Yasminka A. Jakubek, Francis A. San Lucas, Smruthy Sivakumar, Richard G. Fowler, Humam Kadara, Paul Scheet. Landscape of allelic imbalance in pan-cancer adjacent normal tissue: Insights into field cancerization and cancer pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4358.