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.

Medscape: Targeting the Epigenome in Ovarian Cancer: Abstract and Introduction

Targeting the Epigenome in Ovarian Cancer: Abstract and Introduction

From Future Oncology

Targeting the Epigenome in Ovarian Cancer

Susan K Murphy

Authors and Disclosures

Posted: 03/28/2012; Future Oncology. 2012;8(2):151-164. © 2012 Future Medicine Ltd.

• Abstract and Introduction
• Ovarian Cancer
• Treatment
• Potential for Epigenetic Therapies
• Epigenome Characterization & Clinical Utility
• Progress in Using Epigenetic Therapies
• Current Limitations of Epigenetic Therapy
• Conclusion
• Future Perspective

• References

press release: Bioethics gets personal with Hastings' consumer website and Hastings-NOVA special PBS March 28th

Bioethics gets personal with Hastings' consumer website and Hastings-NOVA special

The Hastings Center

Bioethics gets personal with Hastings' consumer website and Hastings-NOVA special

(Garrison, NY) Will genetic testing and personalized medicine change the way you think about your life? Should it? What can you really learn about your future from direct-to-consumer genetic tests–or even from whole genome scanning, which is becoming increasingly affordable? And what about your privacy: how well is your genetic information protected?
These and other bioethics issues are raised in Cracking Your Genetic Code, a NOVA special produced in association with The Hastings Center that airs on PBS on March 28, at 9 pm/8c. And the discussion continues at Help with Hard Questions, The Hastings Center's first website created for the general public. Help With hard Questions is an online community that aims to help people think through the ethical dimensions of dilemmas arising from advances in science and medicine–advances like genetic screening and personalized medicine, as well as reproductive technologies, children's mental health, and advanced illness.
"Advances in medicine and science hold tremendous promise," says Mary Crowley, Director of Public Affairs and Communications at The Hastings Center. "But they also raise new questions about such issues as sharing the results of genetic tests with family and balancing caretaking with other responsibilities

open access: Resolving the variable genome and epigenome in human disease - Knight - 2012 - Journal of Internal Medicine - Wiley Online Library

Resolving the variable genome and epigenome in human disease - Knight - 2012 - Journal of Internal Medicine

pdf file

Conclusions

There is no doubt that recent advances in genomics, currently driven by new high-throughput sequencing techniques, are taking us to remarkable new levels in our understanding of the human genome, and the genetic and epigenetic variation that exists, with important implications for our understanding of human disease. As this knowledge grows, our appreciation of the complexity with which we are faced is also underlined. For common multifactorial traits, GWAs have been very informative but leave much heritable risk unresolved. Rarer variants may prove important but in general, more integrated approaches are needed in which environmental risk factors are considered and combined with functional genomic analyses. Moreover, we need to derive functional genomic data in a disease-relevant setting as the consequences of underlying genetic and epigenetic diversity are increasingly recognized to be highly context specific.

Current technologies that can interrogate the whole genome carry with them significant caveats: these tools are new, and successful application to important biological problems requires careful experimental design and consideration of the limitations inherent in such approaches. The data sets involved are highly complex, and analysis remains extremely challenging with significant risks of false positive and negative results until the field matures. High-throughput sequencing is not a panacea but a critical tool in current genomics.  

Used wisely, it is resolving the individual genome and epigenome, at a structural and functional level, and will radically advance our understanding of disease. For Mendelian traits (Wiki) , the impact is already being felt. For common multifactorial diseases, this may take a little longer.

open access - Revie: Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers - Journal of Internal Medicine (references to Lynch Syndrome/Familial Melanoma)

Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers - Journal of Internal Medicine

pdf file

Genetic variants associated with breast cancer risk for BRCA1 mutations carriers

Genetic variants associated with breast cancer risk for BRCA2 mutations carriers

Patterns of association and tumour characteristics

Genetic modifiers of ovarian cancer risk

Environmental, hormonal and reproductive modifiers of risk

Common alleles and cancer risks for mutation carriers

Future challenges     "Over the past 5 years, there has been substantial progress in our understanding of genetic factors that modify breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. This was made possible to a great extent because of the availability of large numbers of mutation carriers from the CIMBA consortium and GWAS data. However, the five loci described in this review that are associated with breast cancer risk for BRCA1 mutation carriers are estimated to explain only approximately 3% of the genetic variability in breast cancer risk for BRCA1 mutation carriers. Similarly, the 11 SNPs associated with breast cancer risk for BRCA2 mutation carriers are estimated to account for approximately 6% of the genetic variability in breast cancer risk for BRCA2 mutation carriers. Therefore, the majority of the genetic variability in breast cancer risk for mutation carriers still remains unexplained. Several more breast and ovarian cancer susceptibility alleles have been identified through GWAS in the general population, but have not yet been investigated in mutation carriers [61, 63, 72, 75]. Given the observed association patterns in mutation carriers with previously identified loci, it is expected that at least a subset of these will also be associated with breast or ovarian cancer risk for mutation carriers. Additional genetic modifiers of risk may also be identified through not only the ongoing GWAS in BRCA1 and BRCA2 mutation carriers but also other GWAS from the general population or by GWAS focusing on specific cancer subtypes such as oestrogen-receptor-negative or triple-negative breast cancers, or serous ovarian cancer. However, it is likely that several of the alleles identified through population-based GWAS may be associated with modest relative risks in the range of 1.05–1.10. Despite sample sizes of approximately 15 000 BRCA1 and 10 000 BRCA2 mutation carriers, CIMBA would still be underpowered to detect modifying polymorphisms conferring such modest relative risks. Given the rarity of BRCA1 and BRCA2 mutations, increasing sample sizes is currently only possible through increased collaboration between studies and through continued recruitment of mutation carriers........

Conclusions

As more cost-effective mutation screening techniques become available, the number of identified BRCA1 and BRCA2 mutation carriers in the population is likely to increase. Therefore, it will be important that all mutation carriers are provided with accurate information on their risk of developing breast and ovarian cancer, so that informed decisions on clinical management are made. Our understanding of factors influencing cancer risk variability in mutation carriers has increased over the last few years and is likely to improve further in the near future. Therefore, we are getting closer to the goal of being able to provide more individualized clinical management. Understanding how cancer risks are modified in BRCA1 and BRCA2 mutation carriers will also provide further insights for studying the biological mechanisms of cancer development in mutation carriers. These may lead to the development of novel therapies and more accurate prediction of breast and ovarian cancer progression in mutation carriers.

Studying genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has provided useful insights in study design, analytical methodology and applications, which could be used for studying modifiers of disease in carriers of other high-risk mutations such as the mismatch repair genes MSH2, MLH1, MSH6, PMS2 in colorectal cancer (Lynch Syndrome) and CDKN2A in melanoma but also other noncancer-related diseases.

 

 

 

 

 

 

open access: Apr 2012 -Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the ovarian cancer association consortium (OCAC) - Journal of Internal Medicine (BRCA, Lynch, high/low penetrance mutations....)

Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the ovarian cancer association consortium (OCAC) -  Journal of Internal Medicine

open access pdf file


 "In this article, we review the current knowledge of the inherited genetics of epithelial ovarian cancer (EOC) susceptibility and clinical outcome. We focus on recent developments in identifying low-penetrance susceptibility genes and the role of the ovarian cancer association consortium (OCAC) in these discoveries. The OCAC was established to facilitate large-scale replication analyses for reported genetic associations for EOC. Since its inception, the OCAC has conducted both candidate gene and genome-wide association studies (GWAS); the latter has identified six established loci for EOC susceptibility, most of which showed stronger association with the serous histological subtype. Future GWAS and sequencing studies are likely to result in the discovery of additional susceptibility loci and may result in established associations with clinical outcome. Additional rare and uncommon ovarian cancer loci will likely be uncovered from high-throughput next-generation sequencing studies. Applying these novel findings to establish improved preventative and clinical intervention strategies will be one of the major challenges of future work....

Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study.

Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study.:

Study
Breast Cancer Res Treat. 2012 Mar 21;

Abstract

In spite the close association of the triple-negative breast cancer immunophenotype with hereditary breast cancers and the BRCA1 pathway, there is a lack of population studies that determine the frequency of BRCA1 mutations among triple-negative breast cancer patients. To address this, we have screened a large sample of 403 women diagnosed with triple-negative invasive breast cancer, independently of their age or family history, for germline BRCA1 mutations.

Median age at diagnosis was 50 years (range 20-83). The overall prevalence of triple-negative cases among the initial patient group with invasive breast cancer was 8 %. BRCA1 was screened by direct DNA sequencing in all patients, including all exons where a mutation was previously found in the Greek population (exons 5, 11, 12, 16, 20, 21, 22, 23, 24-77 % of the BRCA1 coding region), including diagnostic PCRs to detect the three Greek founder large genomic rearrangements. Sixty-five deleterious BRCA1 mutations were identified among the 403 triple-negative breast cancer patients (16 %).

Median age of onset for mutation carriers was 39 years. (?? Blogger's Note: screening guidelines...)  Among a total of 106 women with early-onset triple-negative breast cancer (<40 years), 38 (36 %) had a BRCA1 mutation, while 27 % of women with triple-negative breast cancer diagnosed before 50 years (56/208) had a BRCA1 mutation. A mutation was found in 48 % (50/105) of the triple-negative breast cancer patients with family history of breast or ovarian cancer.

It is noteworthy, however, that of the 65 carriers, 15 (23 %) had no reported family history of related cancers. All but one of the carriers had grade III tumors (98 %). These results indicate that women with early-onset triple-negative breast cancer, and ideally all triple-negative breast cancer patients, are candidates for BRCA1 genetic testing even in the absence of a family history of breast or ovarian cancer.

Characterization of four novel BRCA2 large genomic rearrangements in Spanish breast/ovarian cancer families: review of the literature, and reevaluation of the genetic mechanisms involved in their origin.

Characterization of four novel BRCA2 large genomic rearrangements in Spanish breast/ovarian cancer families: review of the literature, and reevaluation of the genetic mechanisms involved in their origin

Breast Cancer Res Treat. 2012 Mar 21;

Abstract

Large genomic rearrangements (LGRs) at the BRCA2 locus explain a non-negligible proportion of hereditary breast and ovarian cancer (HBOC) syndromes. The multiplex ligation and probe amplification (MLPA) assay has permitted in recent years to identify several families carrying LGRs at this locus, but very few such alterations have been fully characterized at the molecular level. Yet, molecular characterization is essential to identify recurrent alterations, to analyze the genetic mechanisms underlying such alterations, or to investigate potential genotype/phenotype relationships. We have used MLPA

ECCO: MRI screening for women with a family history of breast cancer

MRI screening for women with a family history of breast cancer

 MRI screening for women with a family history of breast cancer but no genetic predisposition is expensive but could be cost-effective for some

DNA donor rights affirmed : Nature News & Comment

DNA donor rights affirmed : Nature

NIH committee urges that genome study subjects be told of medically relevant results.

"It is a familiar scenario in genetic research: a subject's DNA is collected for one study, deposited in a database or biobank and then analysed by other researchers for separate studies. But what happens when a later study stumbles on something that could be of significance for the donor, such as an allele for familial hypercholesterolaemia — a treatable genetic disorder that causes progressive atherosclerosis — or some other health-related variation? Do researchers conducting secondary studies and biobanks have a duty to share such revelations with the original research subjects?

They do, when possible, according to a detailed consensus statement from a working group funded by the US National Institutes of Health (NIH) in Bethesda, Maryland, and published this week (S. M. Wolf et al. Gen. Med. http://dx.doi.org/10.1038/gim.2012.23; 2012). The statement's 26 signatories consulted dozens of other researchers and biobank managers over a two-year period. They conclude that biobanks “shoulder significant responsibility” for addressing how to deal with 'incidental findings' — those research results that could have medical consequences for the donors of genetic material.

Genetic testing is increasingly

coming up with 'incidental

findings'.

Genetics researchers are divided on the matter of incidental findings......"

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors.

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors.:

Abstract
Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG→GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. .........................We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes.

abstract: Clinical characteristics and outcomes of BRCA-associated ovarian cancer: genotype and survival.

Clinical characteristics and outcomes of BRCA-associated ovarian cancer: genotype and survival

Cancer Genet. 2012 Jan;205(1-2):34-41


Abstract
Previous studies have suggested that BRCA-related epithelial ovarian cancer (EOC) conveys improved survival compared with that of sporadic EOC, but few studies have evaluated differences between BRCA genotypes.

We compared characteristics and outcome by genotype in BRCA-associated EOC. Patients with BRCA-associated EOC who were diagnosed between January 30,1981, and December 30, 2008, were retrospectively identified through institutional review board-approved registry studies. We examined clinical characteristics, including event-free survival (EFS) and overall survival (OS), for BRCA1 versus BRCA2 patients. We identified 197 cases (148 BRCA1 cases; 49 BRCA2 cases); the median follow-up period was 63 months. BRCA2 patients were older (55.4 vs. 51.1 y) and had fewer poorly differentiated tumors (67% vs. 82%). No difference in EFS was observed. OS at 5 years was 75% in BRCA2 patients versus 61% in BRCA1 patients; this was not statistically significant. A non-significant trend toward improved OS was observed in BRCA2 patients with advanced-stage disease (hazard ratio = 0.59; 95% confidence interval 0.32-1.08).

Age and grade differed significantly between BRCA1 and BRCA2 carriers in our study population. Whereas no overall differences in EFS or OS were observed, there was a trend toward improved OS in BRCA2 carriers with advanced-stage disease.

This may reflect important differences between BRCA genotypes and should be validated in larger studies.

Waiting for medicine’s black swans - CMAJ

Waiting for medicine’s black swans

"Over a decade has passed since the medical world quivered with anticipation at the completion of the Human Genome Project. For the most part, though, those heady days have been replaced by the sobering realization that the path from knowledge to product is riddled with potholes.

Time, tight budgets and delivery complications have emerged as major ruts in the drive toward the pot of therapeutic gold that was promised for the end of road....."

"....One possible solution was presented by Dr. Anil K. Sood, professor of gynecologic oncology in the Division of Surgery at the University of Texas MD Anderson Cancer Center in Houston. Sood’s research with mouse models of ovarian and colorectal cancer indicated that high-density lipoprotein nanoparticles (so-called “good” cholesterol) could be used to deliver small interfering RNAs (siRNAs) to specific gene targets.....

Incidentalome: Accidental Gene Findings You May Not Want To Know | CommonHealth

Incidentalome: Accidental Gene Findings You May Not Want To Know | CommonHealth

Lynch Syndrome: Don't Miss It (Transcript including slides))

Blogger's Opinion/Note:
guidelines indicate varying ages of screening depending on organ assuming there are screening mechanisms (eg. ovarian cancer has no screening for the general population however increased surveillance is possible for those at high risk,  albeit, ineffective; generally 25 yrs +;  'averages' are not helpful and therefore the urging of family history taking by primary/family care physicians, see NCCN guidelines for Lynch Syndrome which includes gene-specific details (eg. MLH1, MSH2/6, PMS2.....)

Lynch Syndrome: Don't Miss It (Transcript)

Clinical Implications

"Lynch syndrome is a genetic defect that has significant implications on the clinical side. A patient whose genetic testing is positive for Lynch syndrome has a likelihood of developing colon cancer that approaches 70% over his or her lifetime. The risk for uterine cancer is similar or a bit higher, and the risk for ovarian cancer is13%-15%. Almost certainly, these patients will have some type of cancer during their lifetime.

Metachronous cancers occur in 7%-10% of patients with Lynch syndrome. These patients present with one cancer, and typically in the course of a short period of time, another cancer develops. In patients with Lynch syndrome who have colon cancer, if you don't perform a subtotal colectomy because you didn't recognize that it was Lynch syndrome, the likelihood that the patient will develop a repeat colon cancer over 30 years (even in patients who are being screened) approaches 65%. This is not uncommon. A lot of these diagnoses are missed, and a secondary cancer develops."

"You need to start thinking about syndromic cancers because the relative risk is quite high. You need to be thinking about this in patients with early cancers -- not just colon cancer, but in uterine cancer and ovarian cancer as well." (Blogger's Note: and others including pancreatic, stomach, ureter, renal, bilary tract, gallbladder.....see slides)

" If you look at colon cancer in Lynch syndrome, the average age of onset is earlier (45 years) and some patients may be in their 20s. For sporadic uterine cancer, the average age is approximately 60 years, but in Lynch syndrome, it is shifted by a decade, to 50 years. When you see these cancers in a younger patient, the bell should go off and you should start thinking about Lynch syndrome and doing the appropriate testing."

"It is important to think about extracolonic cancers in these patients and to start to put the dots together because we are missing the boat on a lot of these syndromic cancers. It's not a zebra; it's 2%-3% of the patients who are presenting with cancer. We need to think outside the box. Even if you are not a gastroenterologist, include the colon when you see syndromic related cancers of the uterus, ovary, small bowel, or stomach."

Access : Mutation analysis of RAD51D in non-BRCA1|[sol]|2 ovarian and breast cancer families : British Journal of Cancer

Access : Mutation analysis of RAD51D in non-BRCA1|[sol]|2 ovarian and breast cancer families : British Journal of Cancer

Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families

Abstract

Background:

Recent data show that mutations in RAD51D have an aetiological role in ovarian carcinoma, yet mutations do not appear to be associated with an increased risk for breast cancer. We studied ovarian and breast cancer families having at least one woman affected by ovarian carcinoma, to assess the importance of RAD51D mutations in such families.

Methods:

The coding region of the RAD51D gene was analysed in 175 BRCA1/2-negative families with family histories of both ovarian and breast cancer ascertained from two Canadian and two Belgian institutions.

Conclusion:

RAD51D should be included in genetic screening of ovarian cancer families that do not have BRCA1/BRCA2 mutations. We show that mutations are more likely to be found in families with two or more ovarian cancers, or in probands with first-degree relatives with ovarian cancer, and we feel testing should be preferentially offered to affected women from such families.

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(click on pdf for full paper) Gynecologic Oncology Case Reports: A Case of Endometrial Cancer in the Context of a BRCA2 Mutation and Double Heterozygosity for Lynch Syndrome

Gynecologic Oncology Case Reports | Articles in Press | ScienceDirect.com

A Case of Endometrial Cancer in the Context of a BRCA2 Mutation and Double Heterozygosity for Lynch Syndrome

In Press, Accepted Manuscript, Available online 15 March 2012
Ping Gong, Sarah Charles, Norman Rosenblum, Zoe Wang, Agnieszka K. Witkiewicz

 Show preview  |   PDF (458 K)   |   Related articles  |  Related reference work articles    

Highlights

► Endometrial cancer with BRCA2 mutation and double heterozygosity for Lynch syndrome 

► Loss of MLH1 and PMS2 by immunohistochemical stain 

► MSH1 and MSH6 gene mutations by genomic sequencing

abstract: Shared Genetic Basis for Breast Cancer and Breast Density

Shared Genetic Basis for Breast Cancer and Breast Density:

" Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants."

Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer.

Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases. (300T>G mutation)

Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases.:
Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases.
Fam Cancer. 2012 Mar 1;


Abstract
It is estimated that about 5-10% of ovarian and 2-5% of all breast cancer patients are carriers of a germline BRCA1 or BRCA2 gene mutation. Most families with detected BRCA1 or BRCA2 gene mutation are qualified for molecular testing on the basis of family history of breast or ovarian cancers. The purpose of our study was to establish the frequency of positive family history of cancer in a series of Polish consecutive breast and ovarian cancer patients in two groups, with and without the BRCA1 gene mutations. We analysed the prevalence of four of the most common BRCA1 mutations: 5382insC (c.5266dupC), 300T>G (p.181T>G), 185delAG (c.68_69delAG) and 3819del5 (c.3700_3704del5). The patient group consisted of 1,845 consecutive female breast and 363 ovarian cancer cases. 19 out of 37 (51%) of BRCA1-positive ovarian cancer patients and 21 out of 55 (39%) BRCA1-positive breast cancer had negative family history of breast and/or ovarian cancer among first- and second-degree relatives.

In ovarian cancer patients, negative family history was more frequent in those with 300T>G BRCA1 gene mutation than in 5382insC carriers. This finding indicates the necessity of searching for 300T>G mutation in families with a single diagnosis of ovarian cancer in family. The high frequency of mutations detected in breast cancer patients lacking obvious family history shows that breast cancer patients should be qualified for genetic testing on the basis of wide clinical and pathological criteria.

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."