In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2397-2397
Abstract:
Esophageal squamous cell carcinoma (ESCC) is one of the most common and most aggressive cancers. The epidemiological features of ESCC are extremely complex, with strong geographic differentiation among world's populations. Rural Anyang in the Henan Province of China is a well-known high-incidence area, however the causal factors in this population remain elusive. We performed exome sequencing of 81 tumor-normal pairs, identified TP53, ZNF750 and NOTCH1 as significantly mutated genes, and observed highly recurrent aberrations in several other genes previously reported for ESCC (PIK3CA, KMT2D, FAT2 and FAT1). Our catalog of ∼7,000 single-nucleotide mutations revealed two main signatures: C & gt;T transitions at NpCpG due to spontaneous deamination of 5-methyl-cytosine, and C & gt;T and C & gt;G mutations at TpCpW attributed to the APOBEC family of cytidine deaminases. The latter signature points to HPV infection as one of the potential mutagenic sources, consistent with our previous studies that detected HPV DNA in tumor samples and anti-HPV-E7 antibody in patient's blood. To characterize intratumor heterogeneity we applied our newly developed method, CHAT, to estimate the clonal frequencies of copy number alternations and single nucleotide mutations in each tumor. Many tumors show a multi-modal distribution of clonal frequencies, suggesting extensive within-tumor diversity due to coexistence of multiple clones. Known ESCC-related genes tend to show mutations of higher clonality than those in other genes. To better understand the patterns of growth, migration and metastatic potential among different cells within a tumor we performing exome sequencing to compare multiple regions in 10 ESCC as well as 2 esophageal neuroendocrine carcinoma tumors. For each, we analyzed 4-6 sectors of the tumor, 2-4 of adjacent normal tissue samples, and 1-2 nearby lymph nodes. In many ESCC’s, each local region still contains multiple clones, which are often shared with another region, suggesting extensive dispersal of the clonal populations and relatively slow sweep by the most dominant clone. We constructed “clone trees” to depict the most likely lineage relationship of the clones and the likely driver genes or pathways for each branch. Metastatic samples at lymph node often contain multiple clones, including those appearing in the early portions of the evolutionary tree, suggesting polyclonal seeding to the lymph nodes as well as invasion of early-stage tumor cells. The analysis of spatial heterogeneity of molecular lesions thus revealed likely temporal progression of tumorigenic events that may have driven the initiation, outgrowth as well as metastasis of ESCC. (This work is supported by funding from the Joint Institute for Translational and Clinical Research of the University of Michigan Health System and Peking University Health Sciences Center.) Citation Format: Yu Wang, Wenqing Yuan, Mengfei Liu, Jian Bai, Qingxuan Song, Zhen Liu, Jingjing Li, Amir Abliz, Changqing Zeng, Hong Cai, Yang Ke, Jun Li. Mutation signatures and intratumor heterogeneity of esophageal squamous cell carcinoma in a Chinese cohort. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2397.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2016-2397
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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