open access: PLoS ONE: March 29th Integrated Analyses of microRNAs Demonstrate Their Widespread Influence on Gene Expression in High-Grade Serous Ovarian Carcinoma

PLoS ONE: Integrated Analyses of microRNAs Demonstrate Their Widespread Influence on Gene Expression in High-Grade Serous Ovarian Carcinoma

Background

The Cancer Genome Atlas (TCGA) Network recently comprehensively catalogued the molecular aberrations in 487 high-grade serous ovarian cancers, with much remaining to be elucidated regarding the microRNAs (miRNAs). Here, using TCGA ovarian data, we surveyed the miRNAs, in the context of their predicted gene targets.

Conclusions

This study establishes miRNAs as having a widespread impact on gene expression programs in ovarian cancer, further strengthening our understanding of miRNA biology as it applies to human cancer. As with gene transcripts, miRNAs exhibit high diversity reflecting the genomic heterogeneity within a clinically homogeneous disease population. Putative miRNA:mRNA interactions, as identified using integrative analysis, can be validated. TCGA data are a valuable resource for the identification of novel tumor suppressive miRNAs in ovarian as well as other cancers.

open access: Nature Reviews: Key Advances in Medicine - Ovarian Cancer/Markman page 15-16

Key Advances in Medicine (book)


Nature Reviews Clinical Oncology  (page 15)S11 ovarian cancer | Mutations and non-inferiority analyses show a way forward Maurie Markman      (page 15-16)






Highly clinically relevant ovarian cancer clinical research in 2011 focused on an increased understanding of the biology of the malignancy, limitations of strategies for early detection and screening, and the provocative reports of alternative primary and second-line management strategies.

"Although there were a number of very interesting
preliminary reports of therapeutic
advances in ovarian cancer in 2011 (for
example, bevacizumab in the first-line and
second-line management of the malignancy,
and olaparib  (Blogger's Note: links to Olaparib (parp inhibitor) - Cancer Research UK)  as maintenance therapy for
high-grade serous cancers), as of the writing
of this commentary these studies have not
appeared in the peer-reviewed oncology literature......."

Key advances
■■ There are currently no evidence-based
data supporting the clinical utility of any
ovarian cancer screening strategy in
non‑high-risk populations1
■■ Provocative data suggest there may be a
clinically meaningful difference between
the presence of a BRCA1 or a BRCA2
mutation in influencing outcome in ovarian
cancer6
■■ Under specific circumstances (for example,
neuropathy) it might be reasonable to
substitute pegylated liposomal doxorubicin
for paclitaxel in the front-line chemotherapy
management of ovarian cancer7

Markman, M. Nat. Rev. Clin. Oncol. 9, 69–70 (2012); published online 20 December 2011; doi:10.1038/nrclinonc.2011.200

                                   ~~~~~~~~~~~~~
"The articles included in Nature Reviews Key Advances in
Medicine were originally published in the February 2012
issues of the eight clinical Nature Reviews journals. The journals’
editors commissioned international experts to write a short
essay highlighting up to five key papers that made the biggest
contribution to their field in 2011."

High-Risk Ovarian Cancer Based on 126-Gene Expression Signature Is Uniquely Characterized by Downregulation of Antigen Presentation Pathway - Japan

Abstract

Purpose: 

High-grade serous ovarian cancers are heterogeneous not only in terms of clinical outcome but also at the molecular level. Our aim was to establish a novel risk classification system based on a gene expression signature for predicting overall survival, leading to suggesting novel therapeutic strategies for high-risk patients. 

Experimental Design: 

In this large-scale cross-platform study of six microarray data sets consisting of 1,054 ovarian cancer patients, we developed a gene expression signature for predicting overall survival by applying elastic net and 10-fold cross-validation to a Japanese data set A (n = 260) and evaluated the signature in five other data sets. Subsequently, we investigated differences in the biological characteristics between high- and low-risk ovarian cancer groups. 

Results: 

An elastic net analysis identified a 126-gene expression signature for predicting overall survival in patients with ovarian cancer using the Japanese data set A (multivariate analysis, P = 4 × 10⁻²⁰).. ........ Through gene ontology and pathway analyses, we identified a significant reduction in expression of immune-response–related genes, especially on the antigen presentation pathway, in high-risk ovarian cancer patients. 

Conclusions: 

This risk classification based on the 126-gene expression signature is an accurate predictor of clinical outcome in patients with advanced stage high-grade serous ovarian cancer and has the potential to develop new therapeutic strategies for high-grade serous ovarian cancer patients. 

open access: Feb 13th - PLoS ONE: Angiogenic mRNA and microRNA Gene Expression Signature Predicts a Novel Subtype of Serous Ovarian Cancer

"Advanced epithelial ovarian cancer is notable for initial sensitivity to platinum- and taxane-based chemotherapy [1], [2], but the vast majority of women will develop recurrent ovarian cancer within 12 to 24 months and will eventually die from increasingly platinum- and chemotherapy-resistant disease. One possible reason that ovarian cancer remains refractory to therapy is that there are distinct molecular subtypes, which different cellular properties, each of which may require different therapeutic approaches to effectively treat the disease."

"Our goal was to identify robust molecular subtypes of high-grade serous ovarian cancer and sets of functionally defined classification genes that might give insight into potential therapies."

"In the analysis presented here, we focused on a single histological type—high-grade serous ovarian cancer. We chose this because it is by far the most common histologic subtype of ovarian cancer and the one that is most responsive to chemotherapy. Moreover the vast majority of published gene expression data, including that from the TCGA, is from patients with high-grade serious cancer. Although there are other recognized ovarian histological subtypes, including mucinous, clear cell and endometrioid cancers, we did not have sufficient numbers of these to search for subtypes or to robustly validate their existence in independent datasets."

Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features.

Abstract

Malignant epithelial tumors (carcinomas) are the most common ovarian cancers and also the most lethal gynecological malignancies.
Based on histopathology and molecular genetic alterations, ovarian carcinomas are divided into five main types (high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous (3%), and low-grade serous carcinomas (5%)) that account for over 95% of cases.

These types are essentially distinct diseases, as indicated by differences in epidemiological and genetic risk factors, precursor lesions, patterns of spread, and molecular events during oncogenesis, response to chemotherapy, and prognosis. For a successful specific treatment, reproducible histopathological diagnosis of the tumor cell type is critical.

The five tumor types are morphologically diverse and resemble carcinomas of the uterus. Actually, recent investigations have demonstrated that a significant number of cancers, traditionally thought to be primary ovarian tumors (particularly serous, endometrioid, and clear cell carcinomas), originate in the fallopian tube and the endometrium and involve the ovary secondarily. This review summarizes recent advances in the molecular pathology which have greatly improved our understanding of the biology of ovarian carcinoma and are also relevant to patient management.

Assessment of symptomatic women for early diagnosis of ovarian cancer: results from the prospective DOvE pilot project : The Lancet Oncology

"....Seven (78%) of the HGSC in the DOvE group originated outside the ovaries and five were associated with only slightly raised CA-125 concentrations and minimal or no ovarian abnormalities on TVUS."

 

Interpretation

The proportion of HGSC that originated outside the ovaries in this study suggests that early diagnosis programmes should aim to identify low-volume disease rather than early-stage disease, and that diagnostic approaches should be modified accordingly. Although testing symptomatic women may result in earlier diagnosis of invasive ovarian cancer, large-scale implementation of this approach is premature.

abstract: Calculator for ovarian carcinoma subtype prediction : Modern Pathology

Abstract:

With the emerging evidence that the five major ovarian carcinoma subtypes (high-grade serous, clear cell, endometrioid, mucinous, and low-grade serous) are distinct disease entities, management of ovarian carcinoma will become subtype specific in the future.

In an effort to improve diagnostic accuracy, we set out to determine if an immunohistochemical panel of molecular markers could reproduce consensus subtype assignment.

Immunohistochemical expression of 22 biomarkers were examined on tissue microarrays constructed from 322 archival ovarian carcinoma samples from the British Columbia Cancer Agency archives, for the period between 1984 and 2000, and an independent set of 242 cases of ovarian carcinoma from the Gynaecologic Tissue Bank at Vancouver General Hospital from 2001 to 2008. Nominal logistic regression was used to produce a subtype prediction model for each of these sets of cases. These models were then cross-validated against the other cohort, and then both models were further validated in an independent cohort of 81 ovarian carcinoma samples from five different centers.

Starting with data for 22 markers, full model fit, backwards, nominal logistic regression identified the same nine markers (CDKN2A, DKK1, HNF1B, MDM2, PGR, TFF3, TP53, VIM, WT1) as being most predictive of ovarian carcinoma subtype in both the archival and tumor bank cohorts. These models were able to predict subtype in the respective cohort in which they were developed with a high degree of sensitivity and specificity (κ statistics of 0.88±0.02 and 0.86±0.04, respectively).

When the models were cross-validated (ie using the model developed in one case series to predict subtype in the other series), the prediction equation's performances were reduced (κ statistics of 0.70±0.04 and 0.61±0.04, respectively) due to differences in frequency of expression of some biomarkers in the two case series. Both models were then validated on the independent series of 81 cases, with very good to excellent ability to predict subtype (κ=0.85±0.06 and 0.78±0.07, respectively).

A nine-marker immunohistochemical maker panel can be used to objectively support classification into one of the five major subtypes of ovarian carcinoma.

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.

abstract: A microRNA survival signature (MiSS) for advanced ovarian cancer (serous)

 Abstract

Objectives

MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression primarily through post-transcriptional modification. We tested the hypothesis that miRNA expression is associated with overall survival in advanced ovarian cancer.

Results

Of all patients, 80% had high-grade, stage IIIC tumors and 64% underwent optimal cytoreduction. The median survival for the entire cohort was 49 ± 4 months. The training set identified 3 miRNAs associated with survival — miR-337, miR-410, and miR-645. An miRNA signature containing miR-410 and miR-645 was most strongly associated with overall survival in the training set (HR = 2.96, 95% CI: 1.51–5.78). This miRNA survival signature (MiSS) was validated in the test set (HR = 1.71, 95% CI: 1.05–2.78). The MiSS was independent of FIGO stage and surgical debulking.

Conclusions

The data suggest that an MiSS that contains miR-410 and miR-645 is negatively associated with overall survival in advanced serous ovarian cancer. This signature, when further validated, may be useful in individualizing care for the ovarian cancer patient. Pathway analyses identify biologically plausible mechanisms.

Research highlights

► A MicroRNA Survival Signature was developed in advanced ovarian carcinoma.
► The signature was independent of common clinical co-variates.

abstract: Ovarian serous surface papillary borderline tumors form sea anemone-like masses

PURPOSE: To clarify the imaging characteristics of ovarian serous surface papillary borderline tumor (SSPBT), whose prognosis is far better than that of serous surface papillary adenocarcinoma (SSPC).

abstract: (repost) Differences in tumor type in low-stage versus high-stage ovarian carcinomas

Int J Gynecol Pathol. 2010
Köbel M, Kalloger SE, Huntsman DG, Santos JL, Swenerton KD, Seidman JD, Gilks CB; Cheryl Brown (ovarian cancer survivour/deceased) Ovarian Cancer Outcomes Unit of the British Columbia Cancer Agency, Vancouver BC.
Department of Pathology, University of Calgary, Calgary AB, Canada T2N 2T9. martin.kobel@cls.ab.ca


Abstract

Although there are recognized differences in the type of ovarian carcinomas between those tumors diagnosed at low versus high stage, there is a lack of data on stage distribution of ovarian carcinomas diagnosed according to the current histopathologic criteria from large population-based cohorts. We reviewed full slide sets of 1009 cases of 2555 patients diagnosed with ovarian carcinoma that were referred to the British Columbia Cancer Agency over a 16-year period (1984 to 2000).
On the basis of the reviewed cases we extrapolated the distribution of tumor type in low-stage (I/II) and high-stage (III/IV) tumors. We then compared the frequencies with those seen in a large hospital practice.
The overall frequency of tumor types was as follows: high-grade serous-68.1%, clear-cell-12.2%, endometrioid-11.3%, mucinous-3.4%, low-grade serous-3.4%, rare types-1.6%. High-grade serous carcinomas accounted for 35.5% of stage I/II tumors and 87.7% of stage III/IV tumors.
In contrast, clear-cell (26.2% vs. 4.5%), endometrioid (26.6% vs. 2.5%), and mucinous (7.5% vs. 1.2%) carcinomas were relatively more common among the low-stage versus high-stage tumors.
This distribution was found to be very similar in 410 consecutive cases from the Washington Hospital Center. The distribution of ovarian carcinoma types differs significantly in patients with low-stage versus high-stage ovarian carcinoma when contemporary diagnostic criteria are used, with consistent results seen in 2 independent case series. These findings reflect important biological differences in the behavior of the major tumor types, with important clinical implications.

Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma - jnl Oncogene

"These data show that cisplatin resistance in HGS (high grade serous) carcinoma develops from pre-existing minor clones but that enrichment for these clones is not apparent during short-term chemotherapy treatment