SMARCA2 Deficiency While Preserving SMARCA4 and SMARCB1 in Lung Neuroendocrine Carcinomas

The human BAF multiprotein complex of adenosine triphosphate-dependent nucleosome remodeler (mammalian SWItch/sucrose nonfermentable) regulates gene expression, cell proliferation and differentiation by tuning transcription factor access to chromatin. It is composed about 15 high-evolutionarily conserved proteins, which are involved in approximately 20% life-threatening malignancies at ubiquitous sites. In the thoracic domain, alterations three members such a complex, namely SMARCA2, SMARCA4, SMARCB1, have been associated with development soft tissue epithelioid appearance or undifferentiated carcinomas featuring round spindle rhabdoid cells. this regard, we read great interest comprehensive study Dagogo-Jack et al.1Dagogo-Jack I. Schrock A.B. Kem M. al.Clinicopathologic characteristics BRG1-deficient NSCLC.J Thorac Oncol. 2020; 15: 766-776Abstract Full Text PDF PubMed Scopus (27) Google Scholar published May 2020 issue Journal on SMARCA4-deficient NSCLC, congratulate authors for quality their work. Two large data sets tumors totaling 28,703 NSCLCs were thoroughly interrogated SMARCA4 using next-generation sequencing. Moreover, correlation mutation immunohistochemistry (IHC) was accomplished 64 117 SMARCA4-mutated (54.7%) sufficient residual revealing lack BRG1 expression 29 (45.3%), mainly represented adenocarcinomas nonsense frameshift mutations. Only one case high-grade neuroendocrine (NE) carcinoma (NEC) accounted study. Notably, NE markers described SMARCA4-, SMARCA2-, even SMARCB1-deficient (mainly synaptophysin, but also chromogranin A CD56), reappraising original diagnoses NEC (LCNEC) SCLC, especially biopsy samples2Agaimy A. Fuchs F. Moskalev E.A. Sirbu H. Hartmann Haller pulmonary adenocarcinoma: clinicopathological, immunohistochemical, molecular novel aggressive neoplasm consistent TTF1(neg)/CK7pos/HepPar-1pos immunophenotype.Virchows Arch. 2017; 471: 599-609Crossref (50) Scholar, 3Crombé Alberti N. Villard al.Imaging features sarcomas: multi-centric 21 patients.Eur Radiol. 2019; 29: 4730-4741Crossref (11) 4Rekhtman Montecalvo J. Chang J.C. al.SMARCA4-deficient sarcomatoid represent primarily smoking-related rather than primary sarcomas.J 231-247Abstract (83) extrapulmonary locations.5Agaimy Jain D. Uddin Rooper L.M. Bishop J.A. sinonasal carcinoma: series 10 cases expanding genetic spectrum SWI/SNF-driven malignancies.Am J Surg Pathol. 44: 703-710Crossref (38) Scholar,6Agaimy Antonescu C.R. al.SMARCB1 (INI-1)-deficient 39 morphologic clinicopathologic recently entity.Am 41: 458-471Crossref (114) From existing data, however, it not clear whether likely reflect an overwhelming deregulation cancer cells, subset lung NECs may consistently protein expression. literature, 3% 7% credited bear SMARCA2 SMARCB1 alterations,4Rekhtman Scholar,7Simbolo Mafficini Sikora K.O. al.Lung tumours: deep sequencing four World Health Organization histotypes reveals chromatin-remodelling genes as major players prognostic role TERT, RB1, MEN1 KMT2D.J 241: 488-500Crossref (127) although IHC relevant proteins these sparse incomplete. Of note, disappearance because abrogating mutations, while reversibly silenced epigenetic mechanisms potential clinical implications its forced re-expression,8Glaros S. Cirrincione G.M. Muchardt C. Kleer C.G. Michael C.W. Reisman reversible silencing BRM: targeted therapy.Oncogene. 2007; 26: 7058-7066Crossref (116) either concomitantly independently each other. Therefore, choice technique screen nonfermentable complex-deficient preserved nuclear decoration normal cells making up reliable reaction controls. Here, briefly report tripartite clinically well-annotated cohort outcome information. We selected 12 LCNECs nine SCLCs revised according current WHO classification, affecting 14 men seven women aged 59 86 years (Supplementary Table 1). Tumor samples obtained from pathology files Città della Salute University Hospital Turin (Turin, Italy), patients provided informed consent hospital admission processing personal data. All had surgically removed (stage I–III, TNM eighth edition), whereas SCLC bronchial cerebral biopsies extended diseases presentation IV). Immunostaining (clone BRM/D9E8B, rabbit, Cell Signaling Technology, Danvers, MS; ethylenediaminetetraacetic acid [EDTA] pretreatment 96°C 72 min; dilution 1:100 40 min), EPNCIR111A, Abcam, Cambridge, MA; EDTA 94°C 92 44 min) 25/BAF47, mouse, BD Biosciences, San Jose, CA; 95°C 24 1:200 32 performed automated immunostainer (BenchMark ULTRA IHC/in situ hybridization System, Ventana-Roche Group, Basel, Switzerland) Optiview Dab detection kit (Ventana-Roche Group). Results summarized Figure 1, basis unsupervised clustering analysis. Furthermore, representative example concurrently negative depicted 2A-C. None our presented morphology component and/or discohesive frequently reported tumors.4Rekhtman While always retained cohort, lost two (LCNEC-3 SCLC-3) other 19 tumors. Conversely, absent, partially seven, tumors, respectively, compared results (p = 7.3 × 10−5). (lack, partial deficiency, retention) differentially distributed between 5.7 10−3), did differ them 1.0, significant). Partial complete retention significantly longer disease-free survival 0.0163) and, marginally, overall 0.0931) Fig. 1A B).Figure 2(A–C) An (case assessed immunostaining shown. shows small-sized molding, mitoses necrosis indicative (A) where (B) (C) labeling lacking (inflammatory stromal serve internal positive controls).View Large Image ViewerDownload Hi-res image Download (PPT) To best knowledge, first studied concurrent could expand therapeutic options (e.g., SMARCA2-deficiency confer sensitivity inhibition without inactivation SMARCA4). This echoes nonrandom involvement driver tumor hence, intriguing strategy therapy intervention. screening routine practice be warranted if validated larger NECs. work dedicated memory Carlotta, extraordinarily lively girl who died untimely death owing prime her life. indebted Ms. Matilde Pelosi accurate proofreading manuscript.