Whole genome sequencing analysis identifies recurrent structural alterations in esophageal squamous cell carcinoma

Munmee Dutta; Hidewaki Nakagawa; Hiroaki Kato; Kazuhiro Maejima; Shota Sasagawa; Kaoru Nakano; Aya Sasaki-Oku; Akihiro Fujimoto; Raúl Nicolás Mateos; Ashwini Patil; Hiroko Tanaka; Satoru Miyano; Takushi Yasuda; Kenta Nakai; Masashi Fujita

doi:10.7717/peerj.9294

Whole genome sequencing analysis identifies recurrent structural alterations in esophageal squamous cell carcinoma

PeerJ. 2020 Jun 26:8:e9294. doi: 10.7717/peerj.9294. eCollection 2020.

Authors

Munmee Dutta^{1

2}, Hidewaki Nakagawa³, Hiroaki Kato⁴, Kazuhiro Maejima³, Shota Sasagawa³, Kaoru Nakano³, Aya Sasaki-Oku³, Akihiro Fujimoto⁵, Raúl Nicolás Mateos^{1

2}, Ashwini Patil², Hiroko Tanaka², Satoru Miyano^{2

6}, Takushi Yasuda⁴, Kenta Nakai^{1

2}, Masashi Fujita³

Affiliations

¹ Department of Computational Biology and Medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo, Chiba, Japan.
² Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
³ Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁴ Department of Surgery, Faculty of Medicine, Kindai University, Osaka, Japan.
⁵ Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁶ Health Intelligence Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Abstract

Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in the Asian region, including Japan. A previous study reported mutational landscape of Japanese ESCCs by using exome sequencing. However, somatic structural alterations were yet to be explored. To provide a comprehensive mutational landscape, we performed whole genome sequencing (WGS) analysis of biopsy specimens from 20 ESCC patients in a Japanese population. WGS analysis identified non-silent coding mutations of TP53, ZNF750 and FAT1 in ESCC. We detected six mutational signatures in ESCC, one of which showed significant association with smoking status. Recurrent structural variations, many of which were chromosomal deletions, affected genes such as LRP1B, TTC28, CSMD1, PDE4D, SDK1 and WWOX in 25%-30% of tumors. Somatic copy number amplifications at 11q13.3 (CCND1), 3q26.33 (TP63/SOX2), and 8p11.23 (FGFR1) and deletions at 9p21.3 (CDKN2A) were identified. Overall, these multi-dimensional view of genomic alterations improve the understanding of the ESCC development at molecular level and provides future prognosis and therapeutic implications for ESCC in Japan.

Keywords: Coding mutation; Copy number alteration; Druggable gene; Esophageal squamous cell carcinoma; FAT1; FGFR1; LRP1B; Mutational signature; Structural variation; Whole genome sequencing.

Grants and funding

This work was supported by the Japan Agency for Medical Research and Development (AMED) Project for Cancer Research and Therapeutic Evolution (P-CREATE) (to Hidewaki Nakagawa) and JSPS KAKENHI Grant Number 19K09206 (to Masashi Fujita). Munmee Dutta was supported by the Japanese Government Scholarship (Monbukagakusho, MEXT) for graduate studies. There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.