Protein Expression of the SWI/SNF Chromatin Remolding Subunits in Intraductal Papillary Mucinous Neoplasm (IPMN) and Pancreatic Ductal Adenocarcinoma (PDAC)
Jason F Solus, Klaus Sahora, Daniel Shvetz, Carlos Fernandez-del-Castillo, Martha B Pitman, Mari Mino-Kenudson. Massachusetts General Hospital, Boston, MA
Background: Pancreatic adenocarcinoma remains one of the most intractable cancers to date, with an extremely high mortality rate, and IPMN is one of the precursor lesions to PDAC. An understanding of their molecular alternations may lead to therapeutic strategies. A recent study reported mutations of the genes encoding SWI/SNF complex subunits, namely ARID1A, BRG1 and PBRM1, in a minority of PDACs. Another study has found decreased protein expression of BRG1 in about half of 60 IPMN lesions, most frequently in high-grade dysplasia (HGD). However, little is known about protein expression of the other subunits in PDAC and IPMN.
Design: Our study cohort consisted of 185 IPMN lesions from 109 patients and 90 PDACs. Of the IPMNs, 86 were classified as gastric, 79 intestinal, 14 oncocytic, and 6 pancreatobiliary (PB) epithelial subtypes; 32 low-grade dysplasia, 64 intermediate-grade dysplasia, 63 HGD and 26 invasive IPMN (15 tubular, 10 colloid and 1 oncocytic carcinomas). Protein expression of BRG1, ARID1A and PBRM1 were evaluated using tissue microarrays of IPMN and PDAC by immunohistochemistry. The nuclear expression of each protein was scored using H-score (0-3 intensity and % of the positive cells) in each lesion. The cut-off for positive expression was set at the H-score of 100 or greater.
Results: Of 166 IPMN lesions available for BRG1 evaluation, 58 (35%) showed negative expression (14 with complete loss of expression). The negative BRG1 expression was more prevalent in the PB type (71%) than the gastric (33%), intestinal (33%) or oncocytic (36%) types (PB vs. others, p = 0.051). There was no significant difference in the BRG1 expression between different histological grades, including invasive IPMN. Of 90 PDACs, 30 (33%) showed negative expression of BRG1. As for PBRM1, loss of expression was seen in 11 IPMN lesions, including 4 HGD and 3 tubular carcinomas. PBRM1 expression was preserved in the PDAC cohort, and ARID1A expression was also preserved in both IPMN and PDAC lesions.
Conclusions: Decreased BRG1 expression is seen in both PDACs and IPMNs in our study, but to a lesser degree than what was reported in the previous study (∼33% vs. ∼50%). There is a significant association of negative BRG1 expression in PB-type IPMNs, which are essentially classified as HGD. Although not frequent, reduced expression of PBRM1 is also seen in IPMN, particularly in higher-grade lesions. Our results indicate that alterations of the SWI/SNF chromatin remolding complex may play a role in the progression of pancreatic ductal neoplasia.
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 168, Tuesday Afternoon