Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets Journal Article

Authors: Rekhtman, N.; Pietanza, M. C.; Hellmann, M. D.; Naidoo, J.; Arora, A.; Won, H.; Halpenny, D. F.; Wang, H.; Tian, S. K.; Litvak, A. M.; Paik, P. K.; Drilon, A. E.; Socci, N.; Poirier, J. T.; Shen, R.; Berger, M. F.; Moreira, A. L.; Travis, W. D.; Rudin, C. M.; Ladanyi, M.
Article Title: Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets
Abstract: Purpose: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types. Experimental Design: LCNEC (n = 45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Genomic data were compared with MSK-IMPACT analysis of other lung carcinoma histologies (n = 242). Results: Commonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC-like tumors (P < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation. Conclusions: LCNEC is a biologically heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients. © 2016 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 22
Issue: 14
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2016-07-15
Start Page: 3618
End Page: 3629
Language: English
DOI: 10.1158/1078-0432.ccr-15-294627379806
PROVIDER: scopus
PUBMED: 26960398
PMCID: PMC4995776
Notes: Article -- Export Date: 2 August 2016 -- Source: Scopus
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MSK Authors
  1. Natasha Rekhtman
    210 Rekhtman
  2. Ronglai Shen
    127 Shen
  3. Andre L Moreira
    170 Moreira
  4. Hangjun Wang
    12 Wang
  5. Maria C Pietanza
    115 Pietanza
  6. Marc Ladanyi
    863 Ladanyi
  7. William D Travis
    548 Travis
  8. Paul K Paik
    88 Paik
  9. Nicholas D Socci
    182 Socci
  10. Michael Forman Berger
    380 Berger
  11. Alexander Edward Drilon
    136 Drilon
  12. Matthew David Hellmann
    163 Hellmann
  13. Helen Hyeong-Eun Won
    79 Won
  14. Arshi Arora
    19 Arora
  15. Anna Maria Litvak
    25 Litvak
  16. Charles Rudin
    161 Rudin
  17. Jarushka Naidoo
    31 Naidoo
  18. John Thomas Poirier
    55 Poirier
  19. Shaozhou Ken Tian
    14 Tian