TY - JOUR
T1 - Whole-exome and RNA sequencing of pulmonary carcinoid reveals chromosomal rearrangements associated with recurrence
AU - Miyanaga, Akihiko
AU - Masuda, Mari
AU - Motoi, Noriko
AU - Tsuta, Koji
AU - Nakamura, Yuka
AU - Nishijima, Nobuhiko
AU - Watanabe, Shun ichi
AU - Asamura, Hisao
AU - Tsuchida, Akihiko
AU - Seike, Masahiro
AU - Gemma, Akihiko
AU - Yamada, Tesshi
N1 - Funding Information:
This study was supported by the National Cancer Center Research and Development Fund ( 26-A-13 and 26-A-5 to T. Yamada and 30-A-2 to M. Masuda), the Acceleration Transformative Research for Medical Innovation (ACT-MS) program of the Japan Agency for Medical Research and Development (AMED) ( 16im0210804h0001 to T. Yamada), the Kobayashi Foundation for Cancer Research (to T. Yamada), a K AKENHI Grant-in-Aid for Scientific Research ( 26461168 to A. Miyanaga), a KAKENHI Grant-in-Aid for Challenging Exploratory Research ( 19H05566 to T. Yamada and 16K14627 to M. Masuda), a Grant-in Aid for Scientific Research (B) ( 17H03603 to M. Masuda) from the Japan Society for the Promotion of Science (JSPS) , a cancer research grant from the Foundation for Promotion of Cancer Research in Japan (to M. Masuda), the P roject Mirai Cancer Research Grant from the Japan Cancer Society (to M. Masuda), and a research grant from the P rincess Takamatsu Cancer Research Fund (to M. Masuda). The authors would like to thank K. Hayashi M.S. for technical assistance and the Fundamental Innovative Oncology Core (FIOC) of the National Cancer Center Research Institute (Tokyo, Japan) for sequence data analysis.
Funding Information:
This study was supported by the National Cancer Center Research and Development Fund (26-A-13 and26-A-5to T. Yamada and 30-A-2 to M. Masuda), the Acceleration Transformative Research for Medical Innovation (ACT-MS) program of the Japan Agency for Medical Research and Development (AMED) (16im0210804h0001 to T. Yamada), the Kobayashi Foundation for Cancer Research (to T. Yamada), a KAKENHI Grant-in-Aid for Scientific Research (26461168 to A. Miyanaga), a KAKENHI Grant-in-Aid for Challenging Exploratory Research (19H05566 to T. Yamada and 16K14627 to M. Masuda), a Grant-in Aid for Scientific Research (B) (17H03603 to M. Masuda) from the Japan Society for the Promotion of Science (JSPS), a cancer research grant from the Foundation for Promotion of Cancer Research in Japan (to M. Masuda), the Project Mirai Cancer Research Grant from the Japan Cancer Society(to M. Masuda), and a research grant from the Princess Takamatsu Cancer Research Fund (to M. Masuda). The authors would like to thank K. Hayashi M.S. for technical assistance and the Fundamental Innovative Oncology Core (FIOC) of the National Cancer Center Research Institute (Tokyo, Japan) for sequence data analysis.
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
KW - Chromosomal rearrangement
KW - MUC gene family
KW - Next-generation sequencing
KW - Postsurgical recurrence
KW - Pulmonary carcinoid
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U2 - 10.1016/j.lungcan.2020.03.027
DO - 10.1016/j.lungcan.2020.03.027
M3 - Article
C2 - 32417679
AN - SCOPUS:85084488193
VL - 145
SP - 85
EP - 94
JO - Lung Cancer
JF - Lung Cancer
SN - 0169-5002
ER -
