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

Siân Jones,Sami N Malek,Petra Kristel,Meng Li,Anirban Maitra,Xiaosong Zhang,Nickolas Papadopoulos,Kenneth W Kinzler,Jelle Wesseling,Hai Yan,Marjanka K Schmidt,Bert Vogelstein,James R Eshleman,Michael Goggins,Victor E Velculescu,Christine A Iacobuzio‐Donahue,D Williams Parsons,Ralph H Hruban,Darell D Bigner ,Steve M Powell ,Sanford D Markowitz

doi:10.1002/humu.21633

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.

Highlights

Mutations in the chromatin remodeling gene ARID1A have recently been identified in the majority of ovarian clear cell carcinomas (OCCCs)
These studies have demonstrated that the landscape of each particular tumor type is defined by a small number of genes mutated at a high frequency, called “gene mountains” and a larger number of gene “hills” that are present in a smaller proportion of cases [Wood et al, 2007]
Members of our group recently used generation sequencing to evaluate the exomes of ovarian clear cell carcinomas (OCCCs) and identified truncating mutations in ARID1A (MIM# 603024) in 57% of these tumors [Jones et al, 2010]