10780432ccr160355-sup-162074_1_supp_3593421_11n101.pptx (4.78 MB)

Supplementary Figures from Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung

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posted on 2023-03-31, 19:22 authored by Tomohiro Miyoshi, Shigeki Umemura, Yuki Matsumura, Sachiyo Mimaki, Satoshi Tada, Hideki Makinoshima, Genichiro Ishii, Hibiki Udagawa, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Hironobu Ohmatsu, Keiju Aokage, Tomoyuki Hishida, Junji Yoshida, Kanji Nagai, Koichi Goto, Masahiro Tsuboi, Katsuya Tsuchihara

Supplementary Figure 1: Representative example of tissue microarray (TMA) punched out from a combined large-cell neuroendocrine carcinoma (LCNEC) with adenocarcinoma. Supplementary Figure 2: Validation of five mutations on the PI3K/AKT/mTOR pathway by Sanger sequencing (LCNEC 68c: PIK3CA E545K, LCNEC 9c: PTEN K342*, LCNEC 13c: PTEN S59*, LCNEC 4c: RICTOR R910H, LCNEC 11p: MTOR E2419K). Supplementary Figure 3: Correlation of gene copy number, calculated using the total depth on the covered region of each of 244 targeted genes and those obtained from the Oncomine® Cancer Research Panel (OCP). Supplementary Figure 4: Validation of the copy number gains or amplifications of 13 samples (8 LCNEC samples, 1 SCLC biopsy samples and 4 SCLC surgically resected cases) for MYCL1, MYC and FGFR1 by a quantitative real-time polymerase chain reaction (qPCR). Supplementary Figure 5: Overview of the key driver alterations and other activating alterations in small cell lung cancer (SCLC). Genetic alterations in the PI3K/AKT/mTOR pathway were detected in 24 (17%) of the tumors: PIK3CA (4%), PTEN (6%), AKT2 (2%) and RICTOR (6%). Copy number gains of each MYC family member were mutually exclusive. Supplementary Figure 6: Relationship between RB1 mutation and IHC staining of RB and p16. The mutual exclusivity of the protein expression between RB and p16 was distinct. Supplementary Figure 7: Relationship between genetic alteration and protein expression in large-cell neuroendocrine carcinoma (LCNEC) of the lung. Comparison of the over expression of receptor tyrosine kinases (RTKs) with the genetic alterations in resected LCNEC specimens (51 of 65 resected cases) revealed no significant relationship between strongly positive RTKs (KIT, EGFR, IGF1R, KDR, ERBB2) expression and genetic alterations.

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ARTICLE ABSTRACT

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. Clin Cancer Res; 23(3); 757–65. ©2016 AACR.