Dataset Information

Dysregulation of X chromosome inactivation in high grade ovarian serous adenocarcinoma.

ABSTRACT:

Background

One of the two copies of the X chromosome is randomly inactivated in females as a means of dosage compensation. Loss of X chromosome inactivation (XCI) is observed in breast and ovarian cancers, and is frequent in basal-like subtype and BRCA1 mutation-associated breast cancers. We investigated the clinical implications of the loss of XCI in ovarian cancer and the association between the loss of XCI and BRCA1 dysfunction.

Materials and methods

We used open source data generated by The Cancer Genome Atlas (TCGA) Genome Data Analysis Centers. Ward's hierarchical clustering method was used to classify the methylation status of the X chromosome.

Results

We grouped 584 high grade serous ovarian adenocarcinomas (HG-SOA) according to methylation status, loss of heterozygosity and deletion or gain of X chromosome into the following five groups: preserved inactivated X chromosome (Xi) group (n = 175), partial reactivation of Xi group (n = 100), p arm deletion of Xi group (n = 35), q arm deletion of Xi group (n = 44), and two copies of active X group (n = 230). We found four genes (XAGE3, ZNF711, MAGEA4, and ZDHHC15) that were up-regulated by loss of XCI. HG-SOA with loss of XCI showed aggressive behavior (overall survival of partial reactivation of Xi group: HR 1.7, 95% CI 1.1-2.5, two copies of active X group: HR 1.4, 95% CI 1.0-1.9). Mutation and hypermethylation of BRCA1 were not frequent in HG-SOA with loss of XCI.

Conclusions

Loss of XCI is common in HG-SOA and is associated with poor clinical outcome. The role of BRCA1 in loss of XCI might be limited. XCI induced aberrant expression of cancer-testis antigens, which may have a role in tumor aggressiveness.

SUBMITTER: Kang J

PROVIDER: S-EPMC4351149 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Dysregulation of X chromosome inactivation in high grade ovarian serous adenocarcinoma.

Kang Jun J Lee Hee Jin HJ Kim Jiyoung J Lee Jae Jun JJ Maeng Lee-so LS

PloS one 20150305 3

<h4>Background</h4>One of the two copies of the X chromosome is randomly inactivated in females as a means of dosage compensation. Loss of X chromosome inactivation (XCI) is observed in breast and ovarian cancers, and is frequent in basal-like subtype and BRCA1 mutation-associated breast cancers. We investigated the clinical implications of the loss of XCI in ovarian cancer and the association between the loss of XCI and BRCA1 dysfunction.<h4>Materials and methods</h4>We used open source data ge ...[more]

PMID: 25742136

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Project description:Purpose of reviewEpithelial ovarian cancer is a disease that encompasses a number of histologically and molecularly distinct entities; the most prevalent subtype being high-grade serous (HGS) carcinoma. Standard first-line treatment of advanced HGS carcinoma includes cytoreductive surgery plus intravenous paclitaxel/platinum-based chemotherapy. Despite excellent responses to initial treatment, the majority of patients develop recurrent disease within 3 years. The introduction of the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, and poly(ADP-ribose) polymerase (PARP) inhibitors into first-line management has changed the outlook for this lethal disease. In this review, we summarise the most recent clinical trials that determine current primary therapy of advanced HGS carcinoma and the ongoing trials that aim to change management in the future.Recent findingsRecent phase III clinical trials have shown that delayed primary surgery after completing neo-adjuvant chemotherapy is non-inferior to immediate primary surgery, but could provide a survival benefit in FIGO (International Federation of Gynecology and Obstetrics) stage IV disease. The use of weekly intravenous chemotherapy regimens has not been proven to be more effective than standard 3-weekly regimens in Western patient populations, and the use of intraperitoneal chemotherapy remains controversial in the first-line setting. In contrast, newer systemic anti-cancer therapies targeting angiogenesis and/or HR-deficient tumours have been successfully incorporated into front-line therapeutic regimens to treat HGS carcinoma. Recent results from randomised trials investigating the use of PARP inhibitors as monotherapy and in combination with the anti-angiogenic agent, bevacizumab, have demonstrated highly impressive efficacy when combined with traditional first-line multi-modality therapy. Management of HGS carcinoma is evolving, but further work is still required to optimise and integrate tumour and plasma biomarkers to exploit the potential of these highly efficacious targeted agents.

Dataset Information

Dysregulation of X chromosome inactivation in high grade ovarian serous adenocarcinoma.

Background

Materials and methods

Results

Conclusions

Publications

Dysregulation of X chromosome inactivation in high grade ovarian serous adenocarcinoma.

Similar Datasets

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