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SWI/SNF complex-deficient undifferentiated carcinoma of the pancreas: clinicopathologic and genomic analysis

dc.contributor.coauthorYavas, Aslihan
dc.contributor.coauthorOzcan, Kerem
dc.contributor.coauthorBalci, Serdar
dc.contributor.coauthorTarcan, Zeynep C.
dc.contributor.coauthorHechtman, Jaclyn F.
dc.contributor.coauthorLuchini, Claudio
dc.contributor.coauthorScarpa, Aldo
dc.contributor.coauthorLawlor, Rita T.
dc.contributor.coauthorMafficini, Andrea
dc.contributor.coauthorReid, Michelle D.
dc.contributor.coauthorXue, Yue
dc.contributor.coauthorYang, Zhaohai
dc.contributor.coauthorHaye, Kester
dc.contributor.coauthorBellizzi, Andrew M.
dc.contributor.coauthorVanoli, Alessandro
dc.contributor.coauthorBenhamida, Jamal
dc.contributor.coauthorBalachandran, Vinod
dc.contributor.coauthorJarnagin, William
dc.contributor.coauthorPark, Wungki
dc.contributor.coauthorO'Reilly, Eileen M.
dc.contributor.coauthorKlimstra, David S.
dc.contributor.coauthorBasturk, Olca
dc.contributor.departmentKUTTAM (Koç University Research Center for Translational Medicine)
dc.contributor.departmentSchool of Medicine
dc.contributor.kuauthorAdsay, Nazmi Volkan
dc.contributor.schoolcollegeinstituteResearch Center
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2024-12-29T09:38:57Z
dc.date.issued2024
dc.description.abstractInactivating alterations in the SWItch/Sucrose NonFermentable (SWI/SNF) Chromatin Remodeling Complex subunits have been described in multiple tumor types. Recent studies focused on SMARC subunits of this complex to understand their relationship with tumor characteristics and therapeutic opportunities. To date, pancreatic cancer with these alterations has not been well studied, although isolated cases of undifferentiated carcinomas have been reported. Herein, we screened 59 pancreatic undifferentiated carcinomas for alterations in SWI/SNF complex–related (SMARCB1 [BAF47/INI1], SMARCA4 [BRG1], SMARCA2 [BRM]) proteins and/or genes using immunohistochemistry and/or next-generation sequencing. Cases with alterations in SWI/SNF complex–related proteins/genes were compared with cases without alterations, as well as with 96 conventional pancreatic ductal adenocarcinomas (PDAC). In all tumor groups, mismatch repair and PD-L1 protein expression were also evaluated. Thirty of 59 (51%) undifferentiated carcinomas had a loss of SWI/SNF complex–related protein expression or gene alteration. Twenty-seven of 30 (90%) SWI-/SNF-deficient undifferentiated carcinomas had rhabdoid morphology (vs 9/29 [31%] SWI-/SNF-retained undifferentiated carcinomas; P < .001) and all expressed cytokeratin, at least focally. Immunohistochemically, SMARCB1 protein expression was absent in 16/30 (53%) cases, SMARCA2 in 4/30 (13%), and SMARCA4 in 4/30 (13%); both SMARCB1 and SMARCA2 protein expressions were absent in 1/30 (3%). Five of 8 (62.5%) SWI-/SNF-deficient undifferentiated carcinomas that displayed loss of SMARCB1 protein expression by immunohistochemistry were found to have corresponding SMARCB1 deletions by next-generation sequencing. Analysis of canonical driver mutations for PDAC in these cases showed KRAS (2/5) and TP53 (2/5) abnormalities. Median combined positive score for PD-L1 (E1L3N) was significantly higher in the undifferentiated carcinomas with/without SWI/SNF deficiency compared with the conventional PDACs (P < .001). SWI-/SNF-deficient undifferentiated carcinomas were larger (P < .001) and occurred in younger patients (P < .001). Patients with SWI-/SNF-deficient undifferentiated carcinoma had worse overall survival compared with patients with SWI-/SNF-retained undifferentiated carcinoma (P = .004) and PDAC (P < .001). Our findings demonstrate that SWI-/SNF-deficient pancreatic undifferentiated carcinomas are frequently characterized by rhabdoid morphology, exhibit highly aggressive behavior, and have a negative prognostic impact. The ones with SMARCB1 deletions appear to be frequently KRAS wild type. Innovative developmental therapeutic strategies targeting this genomic basis of the SWI/SNF complex and the therapeutic implications of EZH2 inhibition (NCT03213665), SMARCA2 degrader (NCT05639751), or immunotherapy are currently under investigation.
dc.description.indexedbyWOS
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.issue11
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuN/A
dc.description.sponsorshipThis work was partly funded by the Novogradac Family G.I. Pathology Research Fund, the Melamed Family Foundation, and the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748.
dc.description.volume37
dc.identifier.doi10.1016/j.modpat.2024.100585
dc.identifier.eissn1530-0285
dc.identifier.issn0893-3952
dc.identifier.quartileQ1
dc.identifier.scopus2-s2.0-85201687212
dc.identifier.urihttps://doi.org/10.1016/j.modpat.2024.100585
dc.identifier.urihttps://hdl.handle.net/20.500.14288/22864
dc.identifier.wos1308293800001
dc.keywordsMismatch repair
dc.keywordsPancreas
dc.keywordsPancreatic ductal adenocarcinoma
dc.keywordsSMARC
dc.keywordsSWI/SNF
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofModern Pathology
dc.subjectPathology
dc.titleSWI/SNF complex-deficient undifferentiated carcinoma of the pancreas: clinicopathologic and genomic analysis
dc.typeJournal Article
dspace.entity.typePublication
local.contributor.kuauthorAdsay, Nazmi Volkan
local.publication.orgunit1SCHOOL OF MEDICINE
local.publication.orgunit1Research Center
local.publication.orgunit2KUTTAM (Koç University Research Center for Translational Medicine)
local.publication.orgunit2School of Medicine
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