Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types

Abstract

Mutations in the chromatin remodeling gene ARID1A have recently been identified in the majority of ovarian clear cell carcinomas (OCCCs). To determine the prevalence of mutations in other tumor types, we evaluated 759 malignant neoplasms including those of the pancreas, breast, colon, stomach, lung, prostate, brain, and blood (leukemias). We identified truncating mutations in 6% of the neoplasms studied; nontruncating somatic mutations were identified in an additional 0.4% of neoplasms. Mutations were most commonly found in gastrointestinal samples with 12 of 119 (10%) colorectal and 10 of 100 (10%) gastric neoplasms, respectively, harboring changes. More than half of the mutated colorectal and gastric cancers displayed microsatellite instability (MSI) and the mutations in these tumors were out-of-frame insertions or deletions at mononucleotide repeats. Mutations were also identified in 2-8% of tumors of the pancreas, breast, brain (medulloblastomas), prostate, and lung, and none of these tumors displayed MSI. These findings suggest that the aberrant chromatin remodeling consequent to ARID1A inactivation contributes to a variety of different types of neoplasms.

Figure 1

A: Examples of truncating mutations in ARID1A in gastric, colon, breast, and pancreatic cancers. Arrows indicate the position of the mutation. Note that in the breast primary tumor (399), there were contaminating nonneoplastic cells that reduced the relative peak heights of the mutant alleles. B: Distribution and types of mutations identified in ARID1A to date. Exons are indicated in blue with the ARID (AT-rich interactive domain), DNA-binding domain shown in green, the HIC (hypermethylated in cancer) domain in purple, and the LXXLL (leucine rich) motifs in pink. Black arrows indicate the position of insertion or deletion mutations, red arrows indicate nonsense mutations, blue arrows indicate missense variants, and gray arrows indicate splice site alterations. Mutations listed above the figure represent those reported in this study; those below were identified in Jones et al. [2010] and Wiegand et al. [2010] in ovarian cancers; Gui et al. [2011] in bladder cancer; Varela et al. in renal cancer, and Birnbaum et al. in pancreatic cancer.