Dataset Information

Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors.

ABSTRACT: Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n?=?60) and transcriptomic (n?=?69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1^high/DLL3^high/NOTCH^low, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1^low/DLL3^low/NOTCH^high, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.

SUBMITTER: George J

PROVIDER: S-EPMC5849599 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors.

George Julie J Walter Vonn V Peifer Martin M Alexandrov Ludmil B LB Seidel Danila D Leenders Frauke F Maas Lukas L Müller Christian C Dahmen Ilona I Delhomme Tiffany M TM Ardin Maude M Leblay Noemie N Byrnes Graham G Sun Ruping R De Reynies Aurélien A McLeer-Florin Anne A Bosco Graziella G Malchers Florian F Menon Roopika R Altmüller Janine J Becker Christian C Nürnberg Peter P Achter Viktor V Lang Ulrich U Schneider Peter M PM Bogus Magdalena M Soloway Matthew G MG Wilkerson Matthew D MD Cun Yupeng Y McKay James D JD Moro-Sibilot Denis D Brambilla Christian G CG Lantuejoul Sylvie S Lemaitre Nicolas N Soltermann Alex A Weder Walter W Tischler Verena V Brustugun Odd Terje OT Lund-Iversen Marius M Helland Åslaug Å Solberg Steinar S Ansén Sascha S Wright Gavin G Solomon Benjamin B Roz Luca L Pastorino Ugo U Petersen Iver I Clement Joachim H JH Sänger Jörg J Wolf Jürgen J Vingron Martin M Zander Thomas T Perner Sven S Travis William D WD Haas Stefan A SA Olivier Magali M Foll Matthieu M Büttner Reinhard R Hayes David Neil DN Brambilla Elisabeth E Fernandez-Cuesta Lynnette L Thomas Roman K RK

Nature communications 20180313 1

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas a ...[more]

PMID: 29535388

Similar Datasets

Project description:ImportanceUse of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain.ObjectiveTo determine which patients derived the greatest degree of clinical benefit from NGS profiling.Design, setting, and participantsPatients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020.Main outcomes and measuresPatients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer.ResultsDuring the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses.Conclusions and relevanceThe high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.

Dataset Information

Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors.

Publications

Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets