title: SMARCA4 and SMARCA2 deficiency in non-small cell lung cancer: immunohistochemical survey of 316 consecutive specimens.
abstract: The chromatin remodeling switch sucrose nonfermentable (SWI/SNF) complex has been increasingly implicated in the pathogenesis and dedifferentiation of neoplasms from several organs with prognostic and potential therapeutic implications. We herein investigated the expression of the SWI/SNF complex catalytic subunits SMARCA4 (BRG1) and SMARCA2 (BRM) in 316 consecutive non-small cell lung cancer (NSCLC) specimens on tissue microarrays (171 adenocarcinomas [ADCAs], 130 squamous cell carcinomas [SCCs], 9 adenosquamous carcinomas, and 6 large cell carcinomas) excluding undifferentiated/giant cell or rhabdoid carcinomas. Complete loss of SMARCA4 was observed in 8 (5.5%) of 146 evaluable pulmonary ADCAs and 6 (5.2%) of 115 evaluable pulmonary SCCs, whereas 9 (6.4%) of 140 ADCAs and 2 (1.7%) of 117 SCCs showed SMARCA2 loss. Two of 6 large cell carcinomas were SMARCA2 deficient. Concurrent loss of both markers was observed in 4 cases (2 ADCAs and 2 SCCs). Of 15 ADCAs with loss of either or both markers, 12 (80%) were TTF1 negative. In conclusion, SMARCA4 and SMARCA2 deficiency is observed in 5.1% and 4.8% of NSCLC, respectively. SMARCB1 expression was intact in all cases. The presence of differentiated histology (glandular or squamous) is a novel aspect among SWI/SNF-deficient carcinomas which in other organs generally are associated with undifferentiated/rhabdoid morphology. The predominance of TTF1 negativity among SWI/SNF-deficient pulmonary ADCA (80%) underlines the need to include these 2 markers in the evaluation of TTF1-negative ADCA of putative pulmonary origin. Given the recently documented potential of SMARCA4 loss as a predictor of chemosensitivity to platinum-based chemotherapy in NSCLC, recognition of the clinicopathological features of SMARCA4-deficient NSCLC in routine surgical pathology practice is recommended.
authors.affiliation: Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.affiliation: Institute of Pathology, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Rieker
authors.affiliation: Department of Thoracic Surgery, University Hospital of Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Dienemann
authors.affiliation: Translational Research Unit, Thoraxklinik, University Hospital of Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Muley
authors.affiliation: Translational Research Unit, Thoraxklinik, University Hospital of Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Meister
authors.affiliation: Institute of Pathology, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.affiliation: Institute of Pathology, University Hospital of Erlangen, Erlangen, Germany. Electronic address: abbas.agaimy@uk-erlangen.de.
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D018287:Carcinoma, Large Cell / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D004265:DNA Helicases / Q000172:deficiency*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000172:deficiency*; D014157:Transcription Factors / Q000172:deficiency*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: Adenocarcinoma; NSCLC; SMARCA2; SMARCA4; SWI/SNF complex; Squamous cell carcinoma