Whole-exome and RNA sequencing of pulmonary carcinoid reveals chromosomal rearrangements associated with recurrence

Akihiko Miyanaga; Mari Masuda; Noriko Motoi; Koji Tsuta; Yuka Nakamura; Nobuhiko Nishijima; Shun-Ichi Watanabe; Hisao Asamura; Akihiko Tsuchida; Masahiro Seike; Akihiko Gemma; Tesshi Yamada

doi:10.1016/j.lungcan.2020.03.027

Whole-exome and RNA sequencing of pulmonary carcinoid reveals chromosomal rearrangements associated with recurrence

Lung Cancer. 2020 Jul:145:85-94. doi: 10.1016/j.lungcan.2020.03.027. Epub 2020 May 5.

Authors

Affiliations

¹ Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan; Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. Electronic address: a-miyanaga@nms.ac.jp.
² Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.
³ Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
⁴ Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan; Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
⁵ Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.
⁶ Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan.
⁷ Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
⁸ Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan; Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan.

PMID: 32417679
DOI: 10.1016/j.lungcan.2020.03.027

Abstract

Introduction: The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrence. As PC is insensitive to conventional chemotherapy, further clarification of the molecular mechanisms of metastasis is needed in order to develop targeted therapeutics.

Methods: We performed comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 cases of PC.

Results: We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated at a frequency of 21% (3/14) and 14% (2/14), respectively. Mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in a mutually exclusive manner in 36% (5/14). Pathway analysis of the mutated genes revealed enrichment of genes involved in mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling. RNA sequencing revealed a total of 8 novel fusion transcripts including one derived from a chromosomal translocation between the TRIB2 and PRKCE genes. All of the 8 fusion genes were detected in primary PCs that had developed metastasis after surgical resection. We identified 14 genes (DENND1B, GRID1, CLMN, DENND1B, NRP1, SEL1L3, C5orf13, TNFRSF21, TES, STK39, MTHFD2, OPN3, MET, and HIST1H3C) up-regulated in 5 PCs that had relapsed after surgical resection.

Conclusions: In this study we identified novel somatic mutations and chromosomal rearrangements in PC by examining clinically aggressive cases that had developed postsurgical metastasis. It will be essential to validate the clinical significance of these genetic changes in a larger independent patient cohort.

Keywords: Chromosomal rearrangement; MUC gene family; Next-generation sequencing; Postsurgical recurrence; Pulmonary carcinoid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Calcium-Calmodulin-Dependent Protein Kinases
Carcinoid Tumor* / genetics
Exome
Exome Sequencing
Humans
Lung Neoplasms* / genetics
Mutation
Neoplasm Recurrence, Local / genetics
Rod Opsins
Sequence Analysis, RNA

Substances

OPN3 protein, human
Rod Opsins
Calcium-Calmodulin-Dependent Protein Kinases
TRIB2 protein, human