Mutation landscape and intra-tumor heterogeneity of two MANECs of the esophagus revealed by multi-region sequencing

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// Wenqing Yuan 1 , Zhen Liu 1 , Wanjun Lei 2 , Li Sun 3 , Haijun Yang 4 , Yu Wang 5 , Shweta Ramdas 5 , Xiao Dong 2 , Ruiping Xu 4 , Hong Cai 1 , Jun Z. Li 5, * and Yang Ke 1, * 1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital and Institute, Beijing 100142, PR China 2 Novogene Co., LTD, Beijing 100142, PR China 3 Department of Pathology, Beijing Cancer Hospital, Beijing 100142, PR China 4 Anyang Cancer Hospital, Anyang 455000, PR China 5 Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA * These authors have jointly directed this work Correspondence to: Jun Z. Li, email: junzli@med.umich.edu Yang Ke, email: keyang@bjmu.edu.cn Keywords: mixed adenoneuroendocrine carcinoma (MANEC), esophageal cancer, whole-exome sequencing, intra-tumor heterogeneity, subclone evolution Received: September 22, 2016 Accepted: May 24, 2017 Published: June 27, 2017 ABSTRACT Mixed adenoneuroendocrine carcinoma (MANEC) in the esophagus is an infrequent but highly malignant cancer with few known genomic alterations. We conducted whole-exome sequencing and whole-genome SNP genotyping for 4-6 tumor subregions and 5-6 adjacent normal tissue sites and 1-3 lymph node metastases in two esophageal MANECs to detect somatic mutations and copy number alterations, and to explore their spatial heterogeneity and underlying clonal structure. TP53 mutation, RB1 deletion or LOH, and PIK3CA, PTEN, KRAS, SOX2, DVL3, TP63 amplification appeared in all regions in both tumors. Mutations falling in known cancer genes tended to show higher variant allele frequencies than those not falling in these genes in at least one of the cases. Phylogenetic analyses of the samples and underlying subclones suggested extensive migration across different tumor regions and from some regions to the lymph nodes. Lymph node metastases appeared to have been seeded by both early founder cells as well as subsequent, locally emerging daughter clones. A phenotypically normal tissue site carried most of the mutations found in neighboring tumor samples, implying field cancerization. Understanding such complex genetic heterogeneity within each patient will be important for guiding clinical decisions.