TY - JOUR
T1 - Genomic profiling of large-cell neuroendocrine carcinoma of the lung
AU - Miyoshi, Tomohiro
AU - Umemura, Shigeki
AU - Matsumura, Yuki
AU - Mimaki, Sachiyo
AU - Tada, Satoshi
AU - Makinoshima, Hideki
AU - Ishii, Genichiro
AU - Udagawa, Hibiki
AU - Matsumoto, Shingo
AU - Yoh, Kiyotaka
AU - Niho, Seiji
AU - Ohmatsu, Hironobu
AU - Aokage, Keiju
AU - Hishida, Tomoyuki
AU - Yoshida, Junji
AU - Nagai, Kanji
AU - Goto, Koichi
AU - Tsuboi, Masahiro
AU - Tsuchihara, Katsuya
N1 - Funding Information:
This study was performed as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), Japan Agency for Medical Research and Development (AMED), and was supported by JSPS KAKENHI grant numbers 24300346 and 26870876 and the National Cancer Center Research and Development Fund (25-A-6). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations. Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases). Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%-100%). Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies.
AB - Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations. Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases). Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%-100%). Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies.
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U2 - 10.1158/1078-0432.CCR-16-0355
DO - 10.1158/1078-0432.CCR-16-0355
M3 - Article
C2 - 27507618
AN - SCOPUS:85012239743
VL - 23
SP - 757
EP - 765
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 3
ER -