Abstract 4797: Mutation signature and intratumor heterogeneity of esophageal squamous cell carcinoma in a Chinese cohort

Esophageal squamous cell carcinoma (ESCC) is one of the most common and most aggressive cancers. The epidemiological features of ESCC are extremely complex, with remarkable geographic differentiation among world9s populations. While rural Anyang in the Henan Province of China is a well-known high-incidence area, the causal factors in this population remain elusive. We performed exome sequencing of 81 tumor-normal pairs, identified TP53, PIK3CA and NOTCH1 as significantly mutated genes, and observed highly recurrent aberrations in several other genes previously reported for ESCC (ZNF750, MLL2, FAT1, FAT2, and FAT3). Our catalog of ∼7,000 single-nucleotide mutations revealed two main signatures: C>T transitions due to spontaneous deamination of 5-methyl-cytosine, and C>T and C>G mutations at TpCpN attributed to the APOBEC family of cytidine deaminases. Per-sample loadings of these two signatures are uncorrelated with the patient9s smoking and drinking status. Since APOBEC activities are associated with exogenous viruses, the prominence of this signature suggests a role of HPV in ESCC etiology, consistent with our previous studies that detected HPV DNA in tumor samples and anti-HPV-E7 antibody in patient9s blood. To characterize intratumoral heterogeneity we applied our newly developed method, CHAT, to summarize the clonal frequencies of copy number alternations and single nucleotide mutations in each tumor. Many tumors show a multi-modal distribution of the clonal frequencies, suggesting extensive within-tumor diversity. To better understand the patterns of growth, migration and metastatic potential among different cells within a tumor we performing exome sequencing to compare multiple samples in 10 ESCC patients. For each, we analyzed 4-6 sectors of the tumor, 2-4 samples of adjacent normal tissue, and 1-2 nearby lymph nodes. The spatial heterogeneity of molecular lesions within each tumor is expected to uncover major genes and pathways affected in each patient, as well as the temporal progression of tumorigenic events that may have driven the initiation and outgrowth of ESCC. By integrating the mutation signatures, introtumoral clonal heterogeneity, and clinical outcomes, we aim to gain a better understanding of the molecular bases and evolutionary path of this lethal disease. Citation Format: Qingxuan Song, Mengfei Liu, Jian Bai, Amir Abliz, Wenqing Yuan, Zhen Liu, Jingjing Liu, Changhong Zeng, Hong Cai, Yang Ke, Jun Li. Mutation signature and intratumor heterogeneity of esophageal squamous cell carcinoma in a Chinese cohort. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4797. doi:10.1158/1538-7445.AM2015-4797