Oncotarget

Research Papers:

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

Wenqing Yuan, Zhen Liu, Wanjun Lei, Li Sun, Haijun Yang, Yu Wang, Shweta Ramdas, Xiao Dong, Ruiping Xu, Hong Cai, Jun Z. Li _ and Yang Ke

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Oncotarget. 2017; 8:69610-69621. https://doi.org/10.18632/oncotarget.18678

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Abstract

Wenqing Yuan1, Zhen Liu1, Wanjun Lei2, Li Sun3, Haijun Yang4, Yu Wang5, Shweta Ramdas5, Xiao Dong2, Ruiping Xu4, Hong Cai1, Jun Z. Li5,* and Yang Ke1,*

1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital and Institute, Beijing 100142, PR China

2Novogene Co., LTD, Beijing 100142, PR China

3Department of Pathology, Beijing Cancer Hospital, Beijing 100142, PR China

4Anyang Cancer Hospital, Anyang 455000, PR China

5Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA

*These authors have jointly directed this work

Correspondence to:

Jun Z. Li, email: [email protected]

Yang Ke, email: [email protected]

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.


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