@article{d512649667b445b484797b3373cbeb02,
title = "In-depth molecular analysis of combined and co-primary pulmonary large cell neuroendocrine carcinoma and adenocarcinoma",
abstract = "Up to 14% of large cell neuroendocrine carcinomas (LCNECs) are diagnosed in continuity with nonsmall cell lung carcinoma. In addition to these combined lesions, 1% to 7% of lung tumors present as co-primary tumors with multiple synchronous lesions. We evaluated molecular and clinicopathological characteristics of combined and co-primary LCNEC-adenocarcinoma (ADC) tumors. Ten patients with LCNEC-ADC (combined) and five patients with multiple synchronous ipsilateral LCNEC and ADC tumors (co-primary) were included. DNA was isolated from distinct tumor parts, and 65 cancer genes were analyzed by next generation sequencing. Immunohistochemistry was performed including neuroendocrine markers, pRb, Ascl1 and Rest. Pure ADC (N = 37) and LCNEC (N = 17) cases were used for reference. At least 1 shared mutation, indicating tumor clonality, was found in LCNEC- and ADC-parts of 10/10 combined tumors but only in 1/5 co-primary tumors. A range of identical mutations was observed in both parts of combined tumors: 8/10 contained ADC-related (EGFR/KRAS/STK11 and/or KEAP1), 4/10 RB1 and 9/10 TP53 mutations. Loss of pRb IHC was observed in 6/10 LCNEC- and 4/10 ADC-parts. The number and intensity of expression of Ascl1 and neuroendocrine markers increased from pure ADC (low) to combined ADC (intermediate) and combined and pure LCNEC (high). The opposite was true for Rest expression. In conclusion, all combined LCNEC-ADC tumors were clonally related indicating a common origin. A relatively high frequency of pRb inactivation was observed in both LCNEC- and ADC-parts, suggesting an underlying role in LCNEC-ADC development. Furthermore, neuroendocrine differentiation might be modulated by Ascl1(+) and Rest(-) expression.",
keywords = "Ascl1, LCNEC, pRb, RB1, Rest, PRIMARY LUNG CANCERS, ACQUIRED-RESISTANCE, TRANSFORMATION, EXPRESSION, MUTATION, TUMORS, ASCL1, INACTIVATION, NETHERLANDS, MECHANISM",
author = "B.C.M. Hermans and J.L. Derks and Hillen, {Lisa M.} and {van der Baan}, I. and {van den Broek}, E.C. and {von der Thusen}, J.H. and {Van Suylen}, R.J. and P.N. Atmodimedjo and {den Toom}, T.D. and C. Coumans-Stallinga and W. Timens and W.N.M. Dinjens and H.J. Dubbink and E.J.M. Speel and A.M.C. Dingemans and {PALGA Group}",
note = "Funding Information: All conflicts disclosed are outside the study. Bregtje C. M. Hermans reports grants from Bristol‐Myers Squibb, nonfinancial support from Abbvie; Jules L. Derks reports grants from Bristol‐Myers Squibb, nonfinancial support from Abbvie, personal fees from BMS, personal fees from Pfizer, personal fees from Boehringer‐Ingelheim, personal fees from Novartis, personal fees from Ipsen; Jan H. von der Th{\"u}sen reports personal fees from Roche, Roche Diagnostics, Bristol‐Myers Squibb, Eli Lily, MSD and grants from Bristol‐Myers Squibb and AstraZeneca; Wim Timens reports fees to Institution (UMCG) from Roche Diagnostics/Ventana, Merck Sharp Dohme, Bristol‐Myers Squibb and AbbVie; Winand N. M. Dinjens reports personal fees from Amgen, Bayer, Bristol‐Myers Squibb, Novartis and Roche, laboratory research fees from AstraZeneca, Bristol‐Myers Squibb and Abbvie; Hendrikus J. Dubbink reports grants, personal fees and nonfinancial support from AstraZeneca, personal fees from AbbVie, Bayer, Janssen, Pfizer and Lilly, nonfinancial support from Illumina, grants from Merck; Ernst‐Jan M. Speel reports grants from AstraZeneca, Pfizer, Novartis and Bayer, personal fees from Amgen, Lilly and Novartis, nonfinancial support from Abbvie and Biocartis; Anne‐Marie C. Dingemans attended advisory boards and/or provided lectures for Roche, BMS, Eli Lillly, Takeda, Boehringer Ingelheim, Astra Zeneca, Pfizer, BMS, Amgen, Novartis, MSD and Pharmamar. She received research support from Amgen. All paid to the institute. The other authors did not report conflicts of interest. Publisher Copyright: {\textcopyright} 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.",
year = "2022",
month = mar,
day = "1",
doi = "10.1002/ijc.33853",
language = "English",
volume = "150",
pages = "802--815",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley",
number = "5",
}