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The n e w e ng l a n d j o u r na l of m e dic i n e

The Origin of Ovarian Cancer Is It Getting Clearer?


Michael J. Birrer, M.D., Ph.D.

The association of endometriosis and ovarian ment of these tumors, during transformation of
cancer was first reported by Sampson in 1925.1 endometriosis. This is the second important
Transitional areas of endometriosis, ranging from study from this group related to the molecular
benign to atypical, adjacent to ovarian cancer origins of ovarian tumors5 and attests to the
have been well documented.2 The risk of ovarian power of whole-transcriptome sequencing.
cancer among women with endometriosis is Molecular analysis has provided additional
higher, by 30 to 40%, than among women with- evidence of a causal relationship between endo-
out endometriosis. The vast majority of ovarian metriosis and certain ovarian cancers. The loss
cancers associated with endometriosis are clear- of p53 and PTEN (the phosphatase and tensin
cell or endometrioid carcinomas. The early devel- homologue protein) and loss-of-heterozygosity
opment of ovarian cancer remains poorly defined. patterns have been documented in endometriotic
Historically, most attention has been focused on lesions adjacent to ovarian cancers.6,7 Further
serous adenocarcinoma, the most common and mechanistic evidence for this causal association
lethal histologic type. These tumors have been comes from a mouse model in which forced ex-
thought to arise from the surface of the ovary or pression of KRAS (the v-Ki-ras2 Kirsten rat sar-
from inclusion cysts. Recent work has proposed coma viral oncogene homologue gene) and dele-
an alternative hypothesis: that a subgroup of tion of PTEN in ovarian surface epithelium gave
these tumors arises from the fallopian tube.3 Re- rise to endometriosis and endometrioid ovarian
gardless of the site of origin, the loss or inactiva- cancer.8
tion of the tumor-suppressor protein p53 and Despite these data, clear evidence of causality
BRCA proteins are early and important events in remained to be established, and Wiegand and
the development of serous tumors. The origin colleagues may have found a definitive link.
of rarer carcinomas (clear-cell, endometrioid, or ARID1A mutations are common in clear-cell and
mucinous) is less well defined and is presumed endometrioid ovarian cancers but not in serous
to be the ovary or possibly other gynecologic carcinoma; the mutations were also found in
precursor lesions. The initiating molecular events adjacent endometriotic lesions but not in distant
are also unclear and include a broader number endometriosis in the same patient. This suggests
of genes. that the cancers arose from the endometriosis and
In this issue of the Journal, Wiegand and col- that mutation of ARID1A is important in this pro-
leagues used whole-transcriptome sequencing of cess. However, this conclusion is based on only
18 ovarian clear-cell cancers to identify a new two observations, necessitating extensive valida-
putative tumor-suppressor gene.4 Nearly half the tion involving endometriotic lesions from patients
clear-cell and endometrioid ovarian cancers an- with ovarian cancer (including serous cancers) and
alyzed in this study carried truncating muta- patients without cancer.
tions in ARID1A (the AT-rich interactive domain Previous clues suggested a potential for tumor-
1A [SWI-like] gene), whereas none were identi- suppressor activity by ARID1A. The strongest hint
fied in serous cancers. Immunohistochemical was the identification of the gene in a screening
analyses confirmed the loss of expression of the assay for transforming sequences found in can-
BAF250 protein, encoded by ARID1A, and its cor- cer. The transforming ARID1A sequence consist-
relation with ARID1A mutation status. More im- ed of antisense complementary DNA, the product
portant, in two cases, endometriotic lesions ad- of a genomic rearrangement in a primary breast
jacent to the tumor (and not distant lesions) had carcinoma.9 Furthermore, immunohistochemical
the same mutations as were found in the can- staining for BAF250 revealed a loss of expres-
cer. These exciting results provide convincing sion in various types of cancer but not adjacent
evidence for the inactivation of ARID1A in the normal tissue.10 These results are consistent
development of clear-cell and endometrioid ovar- with the behavior of a tumor-suppressor gene.
ian cancers. Furthermore, the data suggest that The mechanism of action of ARID1A is inter-
ARID1A inactivation occurs early in the develop- esting to consider. It has been described as a

1574 n engl j med 363;16 nejm.org october 14, 2010

The New England Journal of Medicine


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Copyright 2010 Massachusetts Medical Society. All rights reserved.
editorials

component of the SWISNF-A complex.11 The high risk for the development of clear-cell or en-
SWISNF complex is a large, multiprotein chro- dometrioid ovarian cancers? Much work remains
matin remodeling complex that is known to both to be done to define the role of ARID1A in the ori-
enhance and repress transcription. The a and b gin of ovarian cancer. Nonetheless, the discovery
isoforms of BAF250 are thought to target SWI by Wiegand and colleagues has provided a step
SNF to different genes and therefore provide spec- forward, which will undoubtedly have clinical val-
ificity to the remodeling process. Furthermore, ue over the next few years. It is safe to say that the
BAF250b has been shown to associate with other origin of ovarian cancer is becoming clearer.
proteins to function as an E3 ubiquitin ligase that Disclosure forms provided by the author are available with the
participates in ubiquitination of histone H2B.12 full text of this article at NEJM.org.

This places BAF250 squarely in the center of the From the Department of Medicine, Massachusetts General
chromatin remodeling complex. BAF250 also Hospital, Boston.
functions as a substrate adapter, much as the
1. Sampson J. Endometrial carcinoma of the ovary, arising in
von HippelLindau protein (a known tumor sup- endometrial tissue in that organ. Arch Surg 1925;10:1-72.
pressor) does. 2. Sainz de la Cuesta R, Eichhorn JH, Rice LW, Fuller AF Jr,
How ARID1A might contribute to the develop- Nikrui N, Goff BA. Histologic transformation of benign endo-
metriosis to early epithelial ovarian cancer. Gynecol Oncol 1996;
ment of clear-cell and endometrioid cancers re- 60:238-44.
mains to be determined. Clear-cell ovarian can- 3. Levanon K, Crum C, Drapkin R. New insights into the
cer and, to a lesser extent, endometrioid ovarian pathogenesis of serous ovarian cancer and its clinical impact.
J Clin Oncol 2008;26:5284-93.
cancer have been noted to have a stress-resis- 4. Wiegand KC, Shah SP, Al-Agha OM, et al. ARID1A mutations
tant phenotype. Clear-cell ovarian cancers in in endometriosis-associated ovarian carcinomas. N Engl J Med
particular have gene-expression signatures asso- 2010;363:1532-43.
5. Shah SP, Kobel M, Senz J, et al. Mutation of FOXL2 in granu-
ciated with stress, angiogenesis, and hypoxia losa-cell tumors of the ovary. N Engl J Med 2009;360:2719-29.
pathways (unpublished data). It is possible that 6. Obata K, Hoshiai H. Common genetic changes between en-
these stress-resistant pathways evolve under con- dometriosis and ovarian cancer. Gynecol Obstet Invest 2000;50:
Suppl 1:39-43.
ditions such as those in endometriosis. The 7. Vigan P, Somigliana E, Chiodo I, Abbiati A, Vercellini P.
switch from a normal-stress-response phenotype Molecular mechanisms and biological plausibility underlying
to a stress-resistant phenotype may involve the the malignant transformation of endometriosis: a critical analy-
sis. Hum Reprod Update 2006;12:77-89.
loss of ARID1A. This event may involve the altera- 8. Dinulescu DM, Ince TA, Quade BJ, Shafer SA, Crowley D,
tion of transcriptional signatures mediated in Jacks T. Role of K-ras and Pten in the development of mouse
part by changes in chromatin due to disruption models of endometriosis and endometrioid ovarian cancer. Nat
Med 2005;11:63-70.
of ARID1A. 9. Huang J, Zhao YL, Li Y, Fletcher JA, Xiao S. Genomic and
At present, the clinical application of this dis- functional evidence for an ARID1A tumor suppressor role.
covery is conjectural. However, it is certainly pos- Genes Chromosomes Cancer 2007;46:745-50.
10. Wang X, Nagl NG Jr, Flowers S, Zweitzig D, Dallas PB,
sible that the loss of ARID1A activates transcrip- Moran E. Expression of p270 (ARID1A), a component of human
tional events that could be targeted by therapy. SWI/SNF complexes, in human tumors. Int J Cancer 2004;
Furthermore, if the loss of ARID1A is an early 112:636.
11. Lemon B, Inouye C, King DS, Tjian R. Selectivity of chro-
event, then perhaps this intervention would serve matin-remodelling cofactors for ligand-activated transcription.
better as a prevention strategy. Should endometri- Nature 2001;414:924-8.
otic lesions be analyzed for expression of BAF250? 12. Li XS, Trojer P, Matsumura T, Treisman JE, Tanese N. Mam-
malian SWI/SNF a subunit BAF250/ARID1 is an E3 ubiquitin
Should patients with endometriotic lesions that ligase that targets histone H2B. Mol Cell Biol 2010;30:1673-88.
show loss of expression be viewed as being at Copyright 2010 Massachusetts Medical Society.

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Copyright 2010 Massachusetts Medical Society. All rights reserved.