Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma.

 Blogger's Note: varying studies show different %'s of ARID1A gene expression in clear cell ovarian cancer
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Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma.:

Mod Pathol. 2012 Feb;25(2):282-8

Abstract
Recently, the ARID1A gene has been identified as a novel tumor suppressor in ovarian clear cell carcinoma. The prognostic significance of the loss of ARID1A expression is not known. The current study was designed to evaluate whether ARID1A was a prognostic factor for progression, survival, and chemoresistance in ovarian clear cell carcinoma.

Functional profiling of clear cell ovarian cancer. | 2012 ASCO Annual Meeting Abstracts

Functional profiling of clear cell ovarian cancer. | 2012 ASCO Annual Meeting Abstracts

Abstract:
Background: Clear cell ovarian cancer represents up to 15% of epithelial ovarian cancers. In comparison to other subtypes, clear cell ovarian carcinomas have a poorer prognosis and are relatively resistant to standard platinum based chemotherapy. Recently, loss of function mutations in the tumour suppressor gene ARID1A were identified in up to 50% of ovarian clear cell carcinomas. We have adopted an integral functional and molecular profiling approach as a route to identify new genetic dependencies and therapeutic targets for this disease.

Methods: Clear cell ovarian cancer cell lines were functionally profiled using high throughput screening with chemical and siRNA libraries. This has been integrated with molecular profiling data generated from exome and transcriptome sequencing to aid the discovery of novel targets.

Results: Using functional screens we have now identified critical gene dependencies and potential therapeutics in a series of clear cell ovarian cancer models. The comparison of functional viability profiles for models characterized by ARID1A loss of function mutations is now enabling an analysis of synthetic lethal effects that could be used to target clear cell ovarian cancers carrying these mutations.  

Conclusions: The work undertaken so far provides the framework for the discovery of therapeutic targets for clear cell ovarian cancer using an integrated approach. Revalidation of these preliminary results is now underway to characterize new genetic dependencies for this disease.

(Apr 2012) Commentary: Link between endometriosis and ovarian-cancer subtypes : The Lancet Oncology

Link between endometriosis and ovarian-cancer subtypes : The Lancet Oncology

"Previous large epidemiological studies have attempted to identify benign gynaecological disorders that predispose to the development of epithelial ovarian cancer. The only disorder that has been repeatedly1—4 (although not universally5) associated with this cancer is endometriosis. Results of some of these studies have suggested a specific link with endometrioid and clear-cell ovarian cancers, but until now none had the power to allow definitive subgroup analysis based on a contemporary definition of histological subtype.

 

In a study reported in the Lancet Oncology, Celeste Leigh Pearce and colleagues6 assessed self-reported endometriosis data from 13 pooled case—control studies in the Ovarian Cancer Association Consortium (OCAC). They confirm that a history of endometriosis is significantly associated with an increased risk of clear-cell (odds ratio 3·05, 95% CI 2·43—3·84) and endometrioid (2·04, CI 1·67—2·48) ovarian cancers, and for the first time show an association with low-grade serous ovarian cancer (2·11, 1·39—3·20). No association was noted between endometriosis and high-grade serous, mucinous, serous borderline, or mucinous borderline ovarian cancers.

 

With more than 23 000 participants (7911 with a diagnosis of ovarian cancer), the main strengths of this study are its statistical power and its robust methods. Incidences of reported endometriosis differ substantially between the pooled studies. Although clinicopathological and genetic differences between the populations could reasonably be expected, importantly there was no significant heterogeneity of the association with histological subtype in the different studies.

The main truly novel finding is an association between a history of endometriosis and low-grade serous ovarian cancer. Perhaps surprisingly, serous borderline tumours (from which invasive low-grade serous ovarian cancers are believed to arise7) are not also associated with a history of endometriosis.

open access: Does the Loss of ARID1A (BAF-250a) Expression in Endometrial Clear Cell Carcinomas Have Any Clinicopathologic Significance? A Pilot Assessment (note comments re: clear cell ovarian)

"....Accordingly, their loss of function has been associated with malignant transformation. ARID1A (the expression of whose product, BAF250a, a key complex component, is lost when mutated) has recently been identified as a tumor suppressor gene that is mutated in 46-57% of ovarian clear cell carcinoma (CCC). The purposes of this study are to assess the frequency of loss of BAF250a expression in endometrial CCC and whether this loss has any discernable clinicopathologic implications....."

"....The fact that BAF250a expression is lost in only a small percentage of endometrial CCC may suggest that ARID1A mutations plays a significant role in only a small proportion of CCC, or that these mutations represent only a small component of the genesis of this specific tumor type. It may also bolster the argument that endometrial CCC represents a phenotype that arises via a multitude of different pathways (3,7), with no one pathway being notably dominant. However, it is unclear if those clear cell carcinomas whose pathogenesis does involve ARID1A mutations, represents a clinicopathologically distinct group with definable characteristics."

Loss of ARID1A-Associated Protein Expression is a Frequent Event in Clear Cell and Endometrioid Ovarian Cancers

Abstract

Background: Inactivating somatic mutations in the ARID1A gene are described in a significant fraction of clear cell and endometrioid ovarian cancers leading to loss of the corresponding protein (BAF250a).

Conclusions:

These data confirm that loss of the ARID1A-encoded protein BAF250a is a frequent event in the genesis of clear cell and endometrioid ovarian cancers. Loss of BAF250a was not associated with clinical or epidemiologic characteristics. One explanation for these findings is that inactivation of the chromatin remodeling pathway may be a requisite event in the development of these cancers.

Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations : Modern Pathology

ARID1A is a recently identified tumor suppressor gene that is mutated in ~50% of ovarian clear-cell carcinomas. This mutation is associated with loss of ARID1A protein expression as assessed by immunohistochemistry. The present study aimed at determining the timing of the loss of ARID1A protein expression during the development of ovarian clear-cell carcinoma and assessing its relevance in correlation to PIK3CA gene mutations......

abstract: Mutation and Loss of Expression of ARID1A in Uterine Low-grade Endometrioid Carcinoma

Abstract:

ARID1A is a recently identified tumor suppressor gene that is mutated in approximately 50% of ovarian clear cell and 30% of ovarian endometrioid carcinomas. The mutation is associated with loss of protein expression as assessed by immunohistochemistry.

In this study, we evaluated ARID1A immunoreactivity in a wide variety of carcinomas to determine the prevalence of ARID1A inactivation in carcinomas. Mutational analysis of ARID1A was carried out in selected cases. Immunoreactivity was not detected (corresponding to inactivation or mutation of ARID1A) in 36 (3.6%) of 995 tumors.

Uterine low-grade endometrioid carcinomas showed a relatively high-frequency loss of ARID1A expression, as 15 (26%) of 58 cases were negative. The other tumor that had a relatively high-frequency loss of ARID1A expression was gastric carcinoma (11%). Mutational analysis showed 10 (40%) of 25 uterine endometrioid carcinomas; none of 12 uterine serous carcinomas and none of 56 ovarian serous and mucinous carcinomas harbored somatic ARID1A mutations. All mutations in endometrioid carcinomas were nonsense or insertion/deletion mutations, and tumors with ARID1A mutations showed complete loss or clonal loss of ARID1A expression.

In conclusion, this study is the first large-scale analysis of a wide variety of carcinomas showing that uterine low-grade endometrioid carcinoma is the predominant tumor type harboring ARID1A mutations and frequent loss of ARID1A expression. These findings suggest that the molecular pathogenesis of low-grade uterine endometrioid carcinoma is similar to that of ovarian low-grade endometrioid and clear cell carcinoma, tumors that have previously been shown to have a high-frequency loss of expression and mutation of ARID1A.

full free text: Targeted Epigenetic Therapies: The Next Frontier? — J. Natl. Cancer Inst. (includes discussion regarding clear cell/ARIDIa mutation

Targeted Epigenetic Therapies: The Next Frontier?

1. Rabiya S. Tuma

When researchers look for mutations associated with cancer, they often expect to come up with alterations in signaling molecules or transcription factors. But an increasing number of the mutations found are in genes that regulate the epigenome—a system that alters DNA structure and regulates gene activity without changing the nucleotide sequence itself.

On Sept. 8, investigators published two independent reports online—one in Science and one in the New England Journal of Medicine—showing that mutations in an epigenetic regulatory gene, ARID1a, were associated with approximately half of the ovarian clear-cell cancers tested.

Frequent Mutations of Chromatin Remodeling Gene ARID1A in Ovarian Clear Cell Carcinoma (note: 2nd study)

Note: this is a second study regarding clear cell ovarian cancer/ARID1A

"The nature and pattern of the mutations suggest that PPP2R1A functions as an oncogene and ARID1A as a tumor suppressor gene. In a total of 42 OCCCs, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. These results suggest that aberrant chromatin remodeling contributes to the pathogenesis of OCCC."

Medical News: Ovarian Cancer Subtype Linked to Gene Mutations (re: clear cell ovarian cancer)

Note: easier to read article

Making strides in ovarian cancer research « BC Cancer Foundation's Blog - re: clear cell ovarian cancer/endometriosis

"We were able to show that ARID1A mutated in close to 50 per cent of clear cell carcinomas of the ovary and in a slightly fewer number of the related endometrioid carcinomas.
When we studied in detail two cases where there was endometriosis attached to the tumour, we found that the mutation was present even before the cells in endometriosis looked like cancer cells. This suggests that ARID1A mutations are a very early event and likely critical to the transformation of a non-cancerous disease into cancer.
We are fully confident that this discovery marks the start of finding real treatments for clear cell carcinoma – but there is still a lot of work to do in the future...."