Published OnlineFirst December 3, 2012; DOI: 10.1158/2159-8290.CD-12-0361 MINI REVIEW ARID1A Mutations in Cancer: Another Epigenetic Tumor Suppressor? Jennifer N. Wu and Charles W.M. Roberts ABSTRACT Although disordered chromatin organization has long been recognized as a fea- ture of cancer, the molecular underpinnings of chromatin structure, epigenetic regulation, and their relationships to transcription are only beginning to be understood. Cancer genome sequencing studies have revealed a novel theme: frequent mutation of epigenetic regulators. Among these, the ARID1A/BAF250A subunit of the SWI/SNF (BRG1-associated factors) chromatin remod- eling complex has emerged as recurrently mutated in a broad array of tumor types. We review the genomic and functional data supporting classifi cation of ARID1A as a tumor suppressor. Signifi cance: Mutations in chromatin remodeling complex genes are increasingly recognized in many cancer types. However, the mechanisms by which chromatin remodeling complexes contribute to gene expression and the cancer phenotype are poorly understood. Understanding how mutation of chroma- tin remodelers facilitates transformation may offer the potential for development and implementation of novel therapies for cancer. Cancer Discov; 3(1); 35–43. ©2012 AACR. INTRODUCTION risk of developing malignant rhabdoid tumors at an especially young age. Epigenetic regulators impose upon the genetic code a Subsequent to these discoveries, implementation of next- chromatin structure characterized by chromatin accessibil- generation sequencing technologies have revealed frequent ity, nucleosome position, and histone modifi cations. These and recurrent mutations in a wide variety of epigenetic features of chromatin structure modulate gene expres- modulators, including mediators of DNA methylation (e.g., sion, thereby affecting both the identity and function of DNMT3a) and covalent modifi ers of histones (e.g., MLL, MLL3, cells. Sequencing of cancer genomes has revealed frequent KDM5A, KDM5C, KDM6A). Furthermore, genes encoding mutations in epigenetic regulators, particularly chromatin subunits of ATP-dependent chromatin remodelers, especially remodelers and histone modifi ers, and disordered chromatin subunits of the SWI/SNF complex, are frequently mutated in regulation has emerged as a distinct mechanism contributing a broad array of cancer types ( 3 ). to tumor development. Recently, recurrent inactivating mutations in ARID1A have The canonical example of the links between chromatin been identifi ed in a wide variety of cancers, suggesting that remodeling and cancer may well be SMARCB1/SNF5/INI1/ it too functions as a tumor suppressor in many different cell BAF47, a core component of the SWI/SNF chromatin remod- types. Here, we review the spectrum of ARID1A mutations eling complexes, of which ARID1A is also a member. In the late in cancer and what is known about ARID1A structure and 1990s, specifi c biallelic inactivating mutations of SMARCB1 function, as well as discuss potential mechanisms of tumor were identifi ed in the vast majority of rhabdoid tumors, highly suppression and clinical implications. aggressive cancers arising in kidney, brain, and soft tissues in young children ( 1, 2 ). Analogous to retinoblastoma and the Rb gene product, children having germline heterozygous inac- ARID1A MUTATIONS IN CANCER tivation of SMARCB1 are predisposed to cancer, having a high In late 2010, next-generation sequencing revealed that ARID1A mutations are present at high frequency in sub- types of ovarian ( 4, 5 ), endometrial ( 6 ), and uterine cancers Authors’ Affi liation: Department of Pediatric Oncology, Dana-Farber ( 7 ). Ovarian clear-cell carcinomas (OCC) are an uncom- Cancer Institute, Division of Hematology/Oncology, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, mon but aggressive type of ovarian cancer. More than Massachusetts 50% of OCCs carry ARID1A mutations, as do 30% of ovar- Corresponding Author: Charles W.M. Roberts, 450 Brookline Avenue, ian endometrioid carcinomas (refs. 4, 5 ; Table 1 ). These Mayer 657, Boston, MA 02215. Phone: 617-632-2072; Fax: 617-582- mutations are specific to this ovarian cancer subtype, as 8096; E-mail: [email protected] no serous ovarian carcinomas contained ARID1A muta- doi: 10.1158/2159-8290.CD-12-0361 tions. A substantial proportion of uterine endometrioid © 2012 American Association for Cancer Research. carcinomas (29%), uterine clear-cell carcinomas (26%), JANUARY 2013CANCER DISCOVERY | 35 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst December 3, 2012; DOI: 10.1158/2159-8290.CD-12-0361 MINI REVIEW Wu and Roberts Table 1. Recurrent loss or mutation of ARID1A in primary human cancers ARID1A Decreased Decreased/absent Primary cancers mutation (%) Homozygous (%) transcript (%) protein (%) Reference Ovarian clear-cell 55/119 (46%) 12/55 (22%) N/A 27/37 (73%) 5 carcinoma 24/42 (57%) 11/24 (46%) N/A N/A 4 Gastric cancer 32/109 (29%) 14/32 (44%) N/A 24/32 (75%) 8 9/110 (8%) 2/9 (22%) N/A 6/8 (75%) 9 10/100 (10%) N/A N/A N/A 15 N/A N/A N/A 26/180 (14%) 6 N/A N/A N/A 5/45 (11%) 7 N/A N/A N/A 95/657 (14%) 10 Hepatocellular carcinoma 21/125 (17%) 1/21 (5%) N/A N/A 11 14/110 (13%) N/A N/A N/A 13 12/120 (10%) N/A N/A N/A 12 N/A N/A N/A 0/41 (0%) 4 Breast cancer 90/256 (35%)a 5/90 (6%) Deletions associated with N/A 59 decreased expression 4/114 (4%) N/A N/A N/A 15 11/82 (13%)a 0/11 (0%) N/A 240/376 (64%) 14 N/A N/A 22/40 (55%) 63/112 (56%) 24 N/A N/A N/A 11/315 (3%) 6 N/A N/A N/A 1/91 (1%) 7 N/A N/A 5/50 (10%) N/A 20 Uterine endometrioid N/A N/A N/A 90/309 (29%) 6 carcinoma N/A N/A N/A 15/58 (26%) 7 Uterine clear-cell carcinoma N/A N/A N/A 6/23 (26%) 6 Pancreatic cancer 33/70 (47%)a, 2/24 (8%) N/A N/A 16 tumor + cell lines 10/119 (8%) N/A N/A N/A 15 14/39 (36%) 1/14 (7%) N/A N/A 17 N/A N/A N/A 5/85 (6%) 6 N/A N/A N/A 4/48 (8%) 7 Transitional-cell carcinoma 13/97 (13%) N/A N/A N/A 18 of bladder Waldenström 5/30 (17%) N/A N/A N/A 19 macroglobulinemia Anaplastic thyroid cancer N/A N/A N/A 5/35 (14%) 6 Renal cancer N/A N/A 6/20 (30%) N/A 20 N/A N/A N/A 1/58 (2%) 6 N/A N/A N/A 0/73 (0%) 7 Colon cancer 12/119 (10%) N/A N/A N/A 15 N/A N/A 2/30 (7%) N/A 20 N/A N/A N/A 2/49 (4%) 7 N/A N/A N/A 1/130 (0.8%) 6 Lung cancer 2/36 (6%) N/A N/A N/A 15 N/A N/A 1/21 (5%) N/A 20 N/A N/A N/A 2/52 (4%) 7 N/A N/A N/A 12/523 (2%) 6 Cervical adenocarcinoma N/A N/A N/A 1/11 (9%) 7 Bile duct cancer N/A N/A N/A 2/27 (7%) 7 Prostate cancer 2/23 (8%) N/A N/A N/A 15 Medulloblastoma 3/125 (2%) N/A N/A N/A 15 Abbreviation: N/A, not applicable. aARID1A loss via chromosomal deletion. 36 | CANCER DISCOVERYJANUARY 2013 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst December 3, 2012; DOI: 10.1158/2159-8290.CD-12-0361 ARID1A Mutations in Cancer MINI REVIEW Nature of the Somatic Mutations— KEY CONCEPTS A Haploinsuffi cient Effect? The vast majority of cancer-associated mutations in ARID1A • Epigenetic dysregulation is a common characteristic (>97%) were inactivating, with nonsense or frameshift (rather of cancer. than silent or missense) mutations detected throughout the • Inactivating mutations of ARID1A, a member of the gene. However, in only 30% of the OCCs with ARID1A muta- SWI/SNF chromatin-remodeling complex, have been tions were both alleles affected ( 4, 5 ). By IHC, 73% of the identifi ed in a variety of cancers. ARID1A-heterozygous tumors lacked protein expression, as • Mutational and functional data suggest ARID1A is a did 5% of tumors not found to have coding mutations ( 5 ). Sev- bona fi de tumor suppressor. eral mechanisms may be postulated to explain this interesting • ARID1A may contribute to tumor suppression via fi nding—loss of ARID1A protein expression in the setting of effects on the SWI/SNF complex, control of cell pro- heterozygous mutation without loss of heterozygosity. Muta- liferation and differentiation, and/or effects on his- tions affecting ARID1A expression may occur in noncoding tone ubiquitylation. regions of the genome not assayed by exome sequencing tech- niques. Alternatively, epigenetic silencing might contribute. One group has postulated that posttranscriptional and/or posttranslational mechanisms account for loss of ARID1A uterine serous carcinomas (18%), and uterine carcinosarco- protein in OCCs harboring heterozygous mutations, based on mas (14%) also have loss of ARID1A protein (also known as the fi nding that RNA sequencing detects both wild-type and BAF250A) by immunohistochemistry (IHC; ref. 6 ). In addi- mutant alleles in a small number of cases ( 5 ). tion, loss of ARID1A has been shown in patient samples Conversely, 27% of the ARID1A-heterozygous OCCs retain having atypical endometriotic lesions (thought to be pre- detectable protein expression. A similar situation occurs in cursors to OCC development) contiguous to OCC, raising gastric cancer, in which ARID1A mutations were biallelic in the possibility that ARID1A loss may be an early cancer- only 44% of ARID1A-mutant samples.