Loss of Expression of ARID1A and BRG1 in Colorectal Cancer Occurs Infrequently and Is Associated with BRAF Mutation and Microsatellite Instability
Jacob R Bledsoe, Michal Kamionek, Daniel E Shvetz, Mari Mino-Kenudson. Massachusetts General Hospital, Boston, MA
Background: The ARID1A, BRG1, and PRBM1 genes encode proteins that are major components of the SWI/SNF chromatin remodeling complex. Loss of expression of these proteins has been implicated in the tumorigenesis of many human cancers including a small proportion of colorectal cancers (CRC). Microsatellite instability and epigenetic phenomena such as CpG island methylation have been postulated to play a role in the inactivation of these proteins. However, better characterization of the pathologic features, prevalence, and clinical implications seen in CRC with SWI/SNF abnormalities is necessary.
Design: Immunohistochemistry for ARID1A, BRG1, and PBRM1 was performed on tissue microarrays and tumor sections of 122 cases of CRC. Corresponding clinicopathologic data was collected including tumor mutational status as determined by multiplex PCR directed at a panel of commonly mutated genes, as well as microsatellite instability (MSI) status. Semi-quantitative determination of the level of nuclear staining for each antibody was calculated by H-score (maximum score 300) based on staining intensity and distribution. The cut-off for preserved expression was set at the score of 100.
Results: Loss of ARID1A expression was seen in three cases (2.5%) and loss of BRG1 expression was seen in nine (7.6%). Two cases showed combined loss of ARID1A and BRG1 expression and there was a significant correlation between expression level of ARID1A and BRG1 (p=0.0197). Preserved PBRM1 expression was seen in all samples. All cases with loss of ARID1A carried the BRAF V600E mutation and showed MSI. Four of nine (44%) cases with loss of BRG1 expression also carried the BRAF mutation and three showed MSI. All with ARID1A loss were poorly differentiated and had a medullary morphology with syncytial tumor growth and tumor-infiltrating lymphocytes, features characteristic of MSI. The majority (75%) of tumors with BRG1 loss were also poorly differentiated. No significant association between loss of protein expression and prognosis or other clinicopathological features was found.
Conclusions: The results confirm that loss of ARID1A and/or BRG1 expression is seen in only a minority of CRC and is most likely due to BRAF mutation in association with microsatellite instability and/or CpG island methylation. ARID1A loss is associated with medullary morphology in our cohort. The clinicopathological characteristics and clinical significance of SWI/SNF chromatin remodeling complex abnormalities need to be evaluated further in larger scale studies.
Monday, March 4, 2013 1:00 PM
Poster Session II # 125, Monday Afternoon