SWI/SNF Complex-Deficient Undifferentiated Carcinoma of the Pancreas: Clinicopathologic and Genomic Analysis

IF 7.1 1区医学 Q1 PATHOLOGY

Modern Pathology Pub Date : 2024-07-31 DOI:10.1016/j.modpat.2024.100585

Aslihan Yavas , Kerem Ozcan , N. Volkan Adsay , Serdar Balci , Zeynep C. Tarcan , Jaclyn F. Hechtman , Claudio Luchini , Aldo Scarpa , Rita T. Lawlor , Andrea Mafficini , Michelle D. Reid , Yue Xue , Zhaohai Yang , Kester Haye , Andrew M. Bellizzi , Alessandro Vanoli , Jamal Benhamida , Vinod Balachandran , William Jarnagin , Wungki Park , Olca Basturk

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引用次数: 0

Abstract

Inactivating 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.

查看原文本刊更多论文

swi/snf复合体缺陷型胰腺未分化癌：临床病理学和基因组分析。

多种肿瘤类型中都描述了SWItch/蔗糖不发酵（SWI/SNF）染色质重塑复合体亚基的失活改变。最近的研究侧重于该复合体的 SMARC 亚基，以了解它们与肿瘤特征和治疗机会的关系。迄今为止，尽管有个别未分化癌病例的报道，但对存在这些改变的胰腺癌还没有进行深入研究。在此，我们利用免疫组化（IHC）和/或新一代测序（NGS）技术筛选了 59 例胰腺未分化癌，以发现 SWI/SNF 复合物相关 [SMARCB1 (BAF47/INI1)、SMARCA4 (BRG1)、SMARCA2 (BRM)]蛋白和/或基因的改变。将SWI/SNF复合体相关蛋白/基因发生改变的病例与未发生改变的病例以及96例常规胰腺导管腺癌（PDAC）进行比较。在所有肿瘤组中，还评估了MMR和PD-L1蛋白的表达。59个未分化癌中有30个（51%）出现了SWI/SNF复合体相关蛋白表达缺失或基因改变。30个SWI/SNF缺失的未分化癌中有27个（90%）呈横纹状形态[与9/29（31%）个SWI/SNF保留的未分化癌相比；p < 0.001]，所有未分化癌都表达细胞角蛋白，至少是局部表达。免疫组化结果显示，16/30（53%）的病例没有 SMARCB1 蛋白表达，4/30（13%）的病例没有 SMARCA2 蛋白表达，4/30（13%）的病例没有 SMARCA4 蛋白表达；1/30（3%）的病例没有 SMARCB1 和 SMARCA2 蛋白表达。在通过 IHC 检测发现 SMARCB1 蛋白表达缺失的 8 例 SWI/SNF 缺陷未分化癌中，有 5 例（62.5%）通过 NGS 检测发现有相应的 SMARCB1 缺失。对这些病例的PDAC典型驱动突变分析显示，KRAS（2/5）和TP53（2/5）异常。与常规PDAC相比，有/无SWI/SNF缺陷的未分化癌中PD-L1（E1L3N）的中位数CPS明显更高（p < 0.001）。SWI/SNF缺失的未分化癌体积更大（p < 0.001），患者年龄更小（p < 0.001）。与SWI/SNF缺失型未分化癌（p = 0.004）和PDAC（p < 0.001）患者相比，SWI/SNF缺失型未分化癌患者的总生存率较低。我们的研究结果表明，SWI/SNF缺失型胰腺未分化癌常以横纹状形态为特征，表现出高度侵袭性，对预后有负面影响。SMARCB1缺失的胰腺未分化癌往往是KRAS野生型。目前正在研究针对 SWI/SNF 复合物基因组基础的创新发展治疗策略，以及 EZH2 抑制剂（NCT03213665）、SMARCA2 降解剂（NCT05639751）或免疫疗法的治疗意义。

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来源期刊

Modern Pathology 医学-病理学

CiteScore

14.30

自引率

2.70%

发文量

174

审稿时长

18 days

期刊介绍： Modern Pathology, an international journal under the ownership of The United States & Canadian Academy of Pathology (USCAP), serves as an authoritative platform for publishing top-tier clinical and translational research studies in pathology. Original manuscripts are the primary focus of Modern Pathology, complemented by impactful editorials, reviews, and practice guidelines covering all facets of precision diagnostics in human pathology. The journal's scope includes advancements in molecular diagnostics and genomic classifications of diseases, breakthroughs in immune-oncology, computational science, applied bioinformatics, and digital pathology.