[780] ARID1A in Colorectal Carcinoma: Loss of Expression Is Associated with DNA Mismatch Repair Protein Deficiency

Jiqing Ye, Yi Zhou, Deborah DeLair, Robert Soslow, Jinru Shia. Memorial Sloan-Kettering Cancer Center, New York, NY

Background: ARID1A is a subunit of the SWI/SNF chromatin remodeling complex, and is believed to provide specificity to this complex in the regulation of gene expression by binding to AT-rich DNA sequences. Recent data indicate that ARID1A is frequently mutated in ovarian clear cell carcinoma and behaves as a tumor suppressor. This gene has also been shown to be mutated in several other tumors including 10% colorectal carcinomas (CRCs) by DNA sequencing. Intriguingly, ARID1A mutations frequently involve a seven base G tract; thus, it has been hypothesized that the mutations may result from defects in the DNA mismatch repair (MMR) system. The aim of this study was to evaluate the prevalence of loss of ARID1A expression in CRC by utilizing immunohistochemistry (IHC), and to explore the relationship between ARID1A and MMR protein in these tumors.
Design: A consecutive series of 302 CRCs from patients fulfilling the Bethesda guidelines for microsatellite instability testing was included. IHC for MLH1, MSH2, MSH6 and PMS2 was performed on whole sections in all cases. Tissue microarray (TMA) was constructed. IHC using a polyclonal antibody against ARID1A (Sigma-Aldrich HPA005456) was performed on TMA sections and the results were correlated with MMR IHC and tumor pathologic characteristics.
Results: The rate of TMA tissue loss was 13%, yielding 263 analyzable tumor samples, 67 of which (25%) showed MMR protein loss (76% lost MLH1 and/or PMS2, and 24% lost MSH2 and/or MSH6). Overall, loss of ARID1A expression was detected in 22 of the 263 (8.4%) tumors. It was detected in 14 of 67 (21%) MMR-deficient tumors, but only in 8 of 196 (4%) MMR-proficient tumors (p<0.001). Among the 22 ARID1A negative tumors, 12 of the 14 (86%) that were also deficient in MMR occurred in the right colon and 8 of the 8 that were MMR proficient occurred in the left colon/rectum. Furthermore, 13 of the 14 (93%) ARID1A negative/MMR deficient tumors were deficient in MLH1/PMS2 and the 14th case was deficient in MSH6. We did not detect a significant difference in tumor staging between ARID1A positive and negative groups either among the entire cohort or upon stratification by MMR protein status.
Conclusions: Loss of ARID1A as detected by IHC is significantly more common in MMR protein-deficient CRCs when compared with MMR protein-proficient tumors (21% vs 4%). There appears to be a tendency for tumors deficient in both MMR and ARID1A to occur in the right colon and to be associated with MLH1/PMS2 abnormality. Further studies are warranted to better understand the biologic implication of ARID1A deregulation in CRC.
Category: Gastrointestinal

Monday, March 4, 2013 1:00 PM

Poster Session II # 127, Monday Afternoon

 

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