AT-rich interactive domain-containing
protein 1A (ARID1A), a chromatin remodeling gene recently discovered to be a
tumor suppressor in
ovarian cancers, has been found to be mutated at low frequencies in many other
tumors including
colorectal carcinoma (CRC). An association between ARID1A alteration and DNA mismatch repair (
MMR) deficiency has been implicated; understanding this association may facilitate the understanding of the role of ARID1A in the various
tumors. In this pilot study, we analyzed the immunohistochemical expression of ARID1A in a consecutive series of 257
CRCs that fulfilled a set of relaxed criteria for
Lynch syndrome screening; 59 (23%) were MMR deficient by immunohistochemistry (44 MLH1/PMS2 deficient, 9 MSH2/MSH6 deficient, 4 MSH6 deficient, and 2 PMS2 deficient). ARID1A loss was observed in 9% (22/257) of the cohort: 24% of MMR-deficient
tumors (14/59, 13 of the 14 being MLH1/PMS2 deficient) and 4% of MMR-normal
tumors (8/198) (P < .05). MLH1 (
mutL homolog 1) promoter hypermethylation was observed in 10 of the 13 MLH1/PMS2-deficient/ARID1A-loss
tumors, indicating an association between ARID1A loss and sporadic microsatellite unstable
CRCs. Among the MMR-deficient cases, ARID1A loss correlated with old age (P = .04), poor
tumor differentiation (P < .01), medullary histology (P < .01), and an increased rate of nodal and distant
metastasis (P = .03); these patients also trended toward a worse 5-year overall survival. Among MMR-normal
tumors, no differences in clinicopathological features were detected between the groups stratified by ARID1A. In conclusion, our results suggest that ARID1A loss may be linked to a specific subset of sporadic microsatellite unstable
CRCs that may be medullary but is more likely to present with metastatic disease, warranting further investigation.