Somatic Mutations in the Chromatin Remodeling Gene
ARID1A Occur in Several Tumor Types
Siˆ an Jones,1Meng Li,1D. Williams Parsons,2Xiaosong Zhang,1Jelle Wesseling,3Petra Kristel,3Marjanka K. Schmidt,3
Sanford Markowitz,4Hai Yan,5Darell Bigner,5Ralph H. Hruban,6James R. Eshleman,6Christine A. Iacobuzio-Donahue,6
Michael Goggins,6Anirban Maitra,6Sami N. Malek,7Steve Powell,8Bert Vogelstein,1∗Kenneth W. Kinzler,1
Victor E. Velculescu,1and Nickolas Papadopoulos1
1Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore,
Maryland;2Texas Children’s Cancer Center and Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine,
Houston, Texas;3Department of Pathology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital Plesmanlaan 121, Amsterdam, The
Netherlands;4Department of Medicine, and Seidman Cancer Center at Case Western Reserve University and Case Medical Center of University
Hospitals of Cleveland, Cleveland, Ohio;5Department of Pathology, Pediatric Brain Tumor Foundation, and Preston Robert Tisch Brain Tumor
Center at Duke University Medical Center, Durham, North Carolina;6Department of Pathology, The Sol Goldman Pancreatic Cancer Research
Center, Johns Hopkins Medical Institutions, Baltimore, Maryland;7Division of Hematology and Oncology, Department of Internal Medicine,
University of Michigan, Ann Arbor, Michigan;8Division of Gastroenterology, Department of Internal Medicine, University of Virginia Health
System, Charlottesville, Virginia
Communicated by Ian N.M. Day
Received 2 August 2011; accepted revised manuscript 30 September 2011.
Published online 18 October 2011 in Wiley Online Library (www.wiley.com/humanmutation).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 evalu-
ated 759 malignant neoplasms including those of the pan-
creas, breast, colon, stomach, lung, prostate, brain, and
blood (leukemias). We identified truncating mutations in
6% of the neoplasms studied; nontruncating somatic mu-
tations 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 can-
cers displayed microsatellite instability (MSI) and the mu-
tations 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
Hum Mutat 33:100–103, 2012.C ?2011 Wiley Periodicals, Inc.
KEY WORDS: ARID1A; cancer; chromatin remodeling
Additional Supporting Information may be found in the online version of this article.
∗Correspondence to: Bert Vogelstein, The Sidney Kimmel Comprehensive Cancer
Contract grant sponsor: The Virginia and D. K. Ludwig Fund for Cancer Research;
The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; The Stringer
Foundation; The Family and Friends of Dick Knox and Cliff Minor NIH grants (CA121113,
CA62924, CA57345, CA129080, CA134292, CA130938); SPORE (CA062924).
Advances in sequencing technologies and bioinformatics, cou-
pled with the identification of the sequence of the human genome,
have enabled more than a dozen tumor types to be evaluated for
mutations over their entire exomes [Meyersonet al.,2010; Stratton,
2011]. These studies have demonstrated that the landscape of each
gene “hills” that are present in a smaller proportion of cases [Wood
et al., 2007].
Members of our group recently used next 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]. Independently, Wiegand
et al.  discovered a high prevalence of ARID1A mutations
in both OCCC (45%) and endometriod carcinoma of the ovary
(30%). Combining both studies, two mutations were identified in
the same tumor in 30% of the mutated cases, which, taken together
with the inactivating nature of the mutations and their remarkable
frequency, provided unequivocal evidence that ARID1A is a tu-
mor suppressor gene in these two tumor types. In addition, loss of
ARID1A expression was observed in approximately 20% of uterine
carcinomas [Wiegand et al., 2011]. In previous studies, chromo-
somal translocations involving ARID1A were identified in a breast
challenging [Huang et al., 2007].
conserved SWI–SNF (switch/sucrose non-fermentable) chromatin
remodeling complex that uses adenosine triphosphate (ATP)-
dependent helicase activities to allow access of transcriptional ac-
tivators and repressors to DNA [Wang et al., 2004; Wilson and
Roberts, 2011]. The protein therefore appears to be involved in
regulating processes including DNA repair, differentiation, and de-
velopment [Weissman et al., 2009]. Functional studies by Nagl
et al.  have demonstrated that the SWI–SNF complex sup-
presses proliferation. The ARID1A-encoded protein, BAF250a, is
one of two mutually exclusive ARID1 subunits. BAF250a has
a DNA-binding domain that specifically binds to AT-rich DNA
C ?2011 WILEY PERIODICALS, INC.
Table 1. Mutations in the Chromatin Remodeling Gene, ARID1A
SampleTumor type Nucleotide (genomic)b
Amino acid (protein) Mutation type MSI status
aMutation previously reported.
bGenomic co-ordinates refer to hg18.
cReference sequence CCDS285.1.
MSI, microsatellite instability; MSS, microsatellite stable; ND, not determined.
sequences and is thought to confer specificity to the complex [Wu
et al., 2009].
Passenger mutations are best defined as those that do not confer
a selective growth advantage to the cells in which they occur, while
often difficult to distinguish driver mutations from passenger mu-
tations when the mutations occur at low frequency. One of the best
examples of this challenge is provided by IDH1 mutations. A single
of 11 colorectal cancers (CRCs) [Sj¨ oblom et al., 2006]. This muta-
tion was not identified in more than 200 additional CRC samples
and was presumed to be a passenger mutation. However, frequent
IDH1 mutations at the identical residue were found when brain
tumors, such as lower grade astrocytomas and oligodendrogliomas
were evaluated [Parsons et al., 2008; Yan et al., 2009]. Thus, the
IDH1 mutation in that original CRC in retrospect was undoubtedly
in the same gene in other tumors can be more reliably interpreted.
Given that, it is now known that ARID1A is a bona fide tumor
of ARID1A mutations in other tumor types. As described below, we
studied more than 700 different neoplasms of seven different types
using Sanger sequencing to determine the contribution of ARID1A
alterations to tumorigenesis in general.
HUMAN MUTATION, Vol. 33, No. 1, 100–103, 2012
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.  and Wiegand et al.  in ovarian cancers; Gui et al.  in bladder cancer; Varela et al. in renal cancer,
and Birnbaum et al. in pancreatic cancer.
A: Examples of truncating mutations in ARID1A in gastric, colon, breast, and pancreatic cancers. Arrows indicate the position of the
Somatic mutations were identified in 43 of the 759 neoplasms
studied (6%) (Table 1). Eight neoplasms contained two or three
(one case) different mutations, presumably on different alleles, so
mutations was observed in neoplasms of the colon (10%; 12/119),
stomach (10%; 10/100), and pancreas (8%; 10/119). Though only a
small number of prostate tumors was available for study, we iden-
tified two carcinomas with mutations among the 23 studied. Mu-
tations were observed in three of 125 (2%) medulloblastomas, in
four of 114 (4%) breast cancers, and in two of 36 (6%) lung car-
cinomas (Table 1; Fig. 1). No mutations were observed among 34
glioblastomas or 89 leukemias tested.
As expected for inactivating mutations of a tumor suppressor
gene, the mutations were distributed throughout the gene and in-
cluded nonsense variants, out-of-frame and in-frame small inser-
tions and deletions, as well as a small number (three) of missense
changes. Mutations were most commonly observed in a seven-base
cinomas. This G tract is the longest mononucleotide repeat in the
coding region and the probability of slippage at mononucleotide
repeats clearly increases with run length [Eshleman et al., 1996;
to be MSI high, and all carried mutations at mononucleotide tracts
in the ARID1A gene (Table 1). It is therefore possible that ARID1A,
such as TGFβRII or BAX, is associated with MSI and that the ho-
mopolymeric repeat frameshifts may result from defects in mis-
is challenging [Kern, 2002], the fact that approximately 40% of the
CRCs with ARID1A mutations did not have MSI leaves little doubt
that ARID1A plays a role in this tumor type.
The identification of mutations in ARID1A in several different
types of cancer indicates that this gene has a wider role in hu-
man tumorigenesis than previously appreciated. These findings are
supported by the demonstration of loss of the ARID1A protein,
tic thyroid carcinomas [Wiegand et al., 2011] and by the identifi-
cation of ARID1A point mutations in 3 of 48 pancreatic cancers by
tumors displaying high levels of MSI. Mutations in other members
of the SWI–SNF chromatin remodeling complex have also been
reported. For example, truncating mutations in SMARCA4/BRG1
were identified in three pancreatic cancers, in a medulloblastoma,
and in several lung cancers [Jones et al., 2008; Medina et al., 2008;
HUMAN MUTATION, Vol. 33, No. 1, 100–103, 2012
Parsons et al., 2011]. More recently, 41% of renal cancers have been Download full-text
shown to have truncating mutations in the SWI–SNF chromatin
a pattern of somatic mutation of genes involved more generally in
chromatin remodeling is starting to appear. MLL3 appears to be
involved in a small number of colon and pancreatic cancers and
medulloblastomas [Jones et al., 2008; Parsons et al., 2011; Wood
et al., 2007]; MLL2 is mutated in 14% of medulloblastomas and
a large fraction of non-Hodgkin’s lymphomas [Morin et al., 2011;
Parsons et al., 2011] and JARID1C is genetically altered in a small
proportion of kidney cancers [Dalgliesh et al., 2010]. These data
collectively link genetic alterations to epigenetic changes and pave
the way for a better understanding of both.
We thank J. Ptak, N. Silliman, Lakeshia Copeland for expert technical assis-
tance, Sten Cornelissen (NKI-AVL) for germline DNA isolation, and Evan
Brower for assistance in producing figures. N.P., B.V., K.W.K., and V.E.V are
co-founders of Inosticsand Personal Genome Diagnosticsand are members
of their Scientific Advisory Boards. N.P., B.V., K.W.K., and V.E.V. own In-
ostics and Personal Genome Diagnostics stock, which is subject to certain
restrictions under University policy. The terms of these arrangements are
managed by the Johns Hopkins University in accordance with its conflict-
Birnbaum DJ, Birnbaum D, Bertucci F. 2011. Endometriosis-associated ovarian carci-
nomas. N Engl J Med 364:483–484.
Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins
S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G,
Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin
ML, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko T,
R, Stebbings L, Stephens P, Tang G, Tarpey PS, Turrell K, Dykema KJ, Khoo SK,
Petillo D, Wondergem B, Anema J, Kahnoski RJ, Teh BT, Stratton MR, Futreal
modifying genes. Nature 463:360–363.
Eshleman JR, Markowitz SD, Donover PS, Lang EZ, Lutterbaugh JD, Li GM, Longley
M, Modrich P, Veigl ML, Sedwick WD. 1996. Diverse hypermutability of multi-
ple expressed sequence motifs present in a cancer with microsatellite instability.
Gui Y, Guo G, Huang Y, Hu X, Tang A, Gao S, Wu R, Chen C, Li X, Zhou L, He M, Li
Z, Sun X, Jia W, Chen J, Yang S, Zhou F, Zhao X, Wan S, Ye R, Liang C, Liu Z,
Huang P, Liu C, Jiang H, Wang Y, Zheng H, Sun L, Liu X, Jiang Z, Feng D, Chen
J, Wu S, Zou J, Zhang Z, Yang R, Zhao J, Xu C, Yin W, Guan Z, Ye J, Zhang H,
Li J, Kristiansen K, Nickerson ML, Theodorescu D, Li Y, Zhang X, Li S, Wang J,
Yang H, Wang J, Cai Z. 2011. Frequent mutations of chromatin remodeling genes
in transitional cell carcinoma of the bladder. Nat Genet. 43:875–878.
Huang J, Zhao YL, Li Y, Fletcher JA, Xiao S. 2007. Genomic and functional evidence
for an ARID1A tumor suppressor role. Genes Chromosomes Cancer 46:745–750.
Jones S, Wang TL, Shih IeM, Mao TL, Nakayama K, Roden R, Glas R, Slamon D, Diaz
LA Jr, Vogelstein B, Kinzler KW, Velculescu VE, Papadopoulos N. 2010. Frequent
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H,
Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M,
Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD,
Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR,
Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B,
Velculescu VE, Kinzler KW. 2008. Core signaling pathways in human pancreatic
cancers revealed by global genomic analyses. Science 321:1801–1806.
Kern SE. 2002. Quantitative selection constants. Cancer Biol Ther 1:189–194.
Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska
E, Kinzler KW, Vogelstein B, Brattain M, Wilson JKV. Inactivation of the type
II TGF-beta receptor in colon cancer cells with microsatellite instability. 1995.
Medina PP, RomeroOA, KohnoT,Montuenga LM, Pio R, YokotaJ,Sanchez-Cespedes
cell lines. Hum Mutat 29:617–622.
Meyerson M, Gabriel S, Getz G. 2010. Advances in understanding cancer genomes
through second-generation sequencing. Nat Rev Genet 11:685–696.
Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson
NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh
DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O,
Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-
Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald
Nagl NG Jr, Wang X, Patsialou A, Van Scoy M, Moran E. 2007. Distinct mammalian
SWI/SNF chromatin remodeling complexes with opposing roles in cell-cycle con-
trol. EMBO J 26:752–763.
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter
H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T,
Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg
N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. 2008. An integrated
genomic analysis of human glioblastoma multiforme. Science 321:1807–1812.
Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC, Boca SM, Carter H, Samayoa J,
Bettegowda C, Gallia GL, Jallo GI, Binder ZA, Nikolsky Y, Hartigan J, Smith DR,
Gerhard DS, Fults DW, VandenBerg S, Berger MS, Marie SK, Shinjo SM, Clara C,
Phillips PC, Minturn JE, Biegel JA, Judkins AR, Resnick AC, Storm PB, Curran T,
N, Vogelstein B, Kinzler KW, Velculescu VE. 2011. The genetic landscape of the
childhood cancer medulloblastoma. Science 331:435–439.
Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, Perucho M. 1997. Somatic
phenotype. Science 275:967–969.
Sj¨ oblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ,
J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park
BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE.
2006. The consensus coding sequences of human breast and colorectal cancers.
VarelaI,Tarpey P,RaineK, HuangD,Ong CK,Stephens P, DaviesH, JonesD,Lin ML,
Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman
C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie
L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema
J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A,
Futreal PA. 2011. Exome sequencing identifies frequent mutation of the SWI/SNF
complex gene PBRM1 in renal carcinoma. Nature 469:539–542.
Wang X, Nagl NG, Wilsker D, Van Scoy M, Pacchione S, Yaciuk P, Dallas PB, Moran
E. 2004. Two related ARID family proteins are alternative subunits of human
SWI/SNF complexes. Biochem J 383:319–325.
Weissman B, Knudsen KE. 2009. Hijacking the chromatin remodeling machinery:
impact of SWI/SNF perturbations in cancer. Cancer Res 69:8223–8230..
SM, Gascoyne RD, Gilks B, Huntsman DG. 2011. Loss of BAF250a (ARID1A) is
frequent in high grade endometrial carcinomas. J Pathol 224:328–333.
Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK,
Anglesio MS, Kalloger SE, Yang W, Heravi-Moussavi A, Giuliany R, Chow C, Fee
J, Zayed A, Prentice L, Melnyk N, Turashvili G, Delaney AD, Madore J, Yip S,
McPherson AW, Ha G, BellL, FeredayS, Tam A, Galletta L, ToninPN, Provencher
D, Miller D, Jones SJ, Moore RA, Morin GB, Oloumi A, Boyd N, Aparicio SA,
ShihIeM,Mes-MassonAM,Bowtell DD,Hirst M,GilksB,MarraMA,Huntsman
DG. 2010. ARID1A mutations in endometriosis-associated ovarian carcinomas.
N Engl J Med 363:1532–1543.
Wilson BG, Roberts CW. 2011. SWI/SNF nucleosome remodelers and cancer. Nat Rev
Wood LD, Parsons DW, Jones S, Lin J, Sj¨ oblom T, Leary RJ, Shen D, Boca SM, Barber
T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky
Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson
D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL,
B. 2007. The genomic landscapes of human breast and colorectal cancers. Science
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle
I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler
KW, Velculescu VE, Vogelstein B, Bigner DD. 2009. IDH1 and IDH2 mutations
in gliomas. N Engl J Med 360:765–773.
HUMAN MUTATION, Vol. 33, No. 1, 100–103, 2012