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1.
Oncotarget ; 8(31): 50930-50940, 2017 Aug 01.
Article in English | MEDLINE | ID: mdl-28881617

ABSTRACT

We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8×10-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 - 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality.

2.
J Natl Cancer Inst ; 108(3)2016 Mar.
Article in English | MEDLINE | ID: mdl-26823519

ABSTRACT

Mosaic truncating mutations in the protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1D (PPM1D) gene have recently been reported with a statistically significantly greater frequency in lymphocyte DNA from ovarian cancer case patients compared with unaffected control patients. Using massively parallel sequencing (MPS) we identified truncating PPM1D mutations in 12 of 3236 epithelial ovarian cancer (EOC) case patients (0.37%) but in only one of 3431 unaffected control patients (0.03%) (P = .001). All statistical tests were two-sided. A combination of Sanger sequencing, pyrosequencing, and MPS data suggested that 12 of the 13 mutations were mosaic. All mutations were identified in post-chemotherapy treatment blood samples from case patients (n = 1827) (average 1234 days post-treatment in carriers) rather than from cases collected pretreatment (less than 14 days after diagnosis, n = 1384) (P = .002). These data suggest that PPM1D variants in EOC cases are primarily somatic mosaic mutations caused by treatment and are not associated with germline predisposition to EOC.


Subject(s)
Gene Frequency , Mosaicism , Mutation , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Phosphoprotein Phosphatases/genetics , Adult , Aged , Antineoplastic Agents/therapeutic use , Case-Control Studies , Female , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Middle Aged , Polymerase Chain Reaction , Protein Phosphatase 2C
4.
J Natl Cancer Inst ; 107(11)2015 Nov.
Article in English | MEDLINE | ID: mdl-26315354

ABSTRACT

BACKGROUND: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality. METHODS: Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided. RESULTS: We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)). CONCLUSIONS: Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.


Subject(s)
Cell Cycle Proteins/genetics , DNA-Binding Proteins/genetics , Germ-Line Mutation , Neoplasms, Glandular and Epithelial/genetics , Nuclear Proteins/genetics , Ovarian Neoplasms/genetics , RNA Helicases/genetics , Tumor Suppressor Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Adult , Aged , Carcinoma, Ovarian Epithelial , Fanconi Anemia Complementation Group N Protein , Fanconi Anemia Complementation Group Proteins , Female , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Middle Aged , Mutation, Missense , Neoplasms, Glandular and Epithelial/mortality , Ovarian Neoplasms/mortality , Predictive Value of Tests , Risk , United States/epidemiology , White People
5.
J Clin Oncol ; 33(26): 2901-7, 2015 Sep 10.
Article in English | MEDLINE | ID: mdl-26261251

ABSTRACT

PURPOSE: The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. PATIENTS AND METHODS: The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis. RESULTS: In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). CONCLUSION: These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.


Subject(s)
DNA-Binding Proteins/genetics , Germ-Line Mutation , Neoplasms, Glandular and Epithelial/genetics , Ovarian Neoplasms/genetics , Adult , Aged , Carcinoma, Ovarian Epithelial , Female , Genes, BRCA1 , Genes, BRCA2 , Genetic Predisposition to Disease , Humans , Middle Aged , Neoplasms, Glandular and Epithelial/etiology , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/etiology , Ovarian Neoplasms/pathology
6.
J Ovarian Res ; 4: 18, 2011 Oct 22.
Article in English | MEDLINE | ID: mdl-22017790

ABSTRACT

BACKGROUND: Glutathione peroxidase 3 (GPX3) is a selenocysteine-containing antioxidant enzyme that reacts with hydrogen peroxide and soluble fatty acid hydroperoxides, thereby helping to maintain redox balance within cells. Serum levels of GPX3 have been found to be reduced in various cancers including prostrate, thyroid, colorectal, breast and gastric cancers. Intriguingly, GPX3 has been reported to be upregulated in clear cell ovarian cancer tissues and thus may have implications in chemotherapeutic resistance. Since clear cell and serous subtypes of ovarian cancer represent two distinct disease entities, the aim of this study was to determine GPX3 levels in serous ovarian cancer patients and establish its potential as a biomarker for detection and/or surveillance of papillary serous ovarian cancer, the most frequent form of ovarian tumors in women. PATIENTS AND METHODS: Serum was obtained from 66 patients (median age: 62 years, range: 22-89) prior to surgery and 65 controls with a comparable age-range (median age: 53 years, range: 25-83). ELISA was used to determine the levels of serum GPX3. The Mann Whitney U test was performed to determine statistical significance between the levels of serum GPX3 in patients and controls. RESULTS: Serum levels of GPX3 were found to be significantly lower in patients than controls (p = 1 × 10-2). Furthermore, this was found to be dependent on the stage of disease. While levels in early stage (I/II) patients showed no significant difference when compared to controls, there was a significant reduction in late stage (III/IV, p = 9 × 10-4) and recurrent (p = 1 × 10-2) patients. There was a statistically significant reduction in levels of GPX3 between early and late stage (p = 5 × 10-4) as well as early and recurrent (p = 1 × 10-2) patients. Comparison of women and controls stratified to include only women at or above 50 years of age shows that the same trends were maintained and the differences became more statistically significant. CONCLUSIONS: Serum GPX3 levels are decreased in women with papillary serous ovarian cancer in a stage-dependent manner and also decreased in women with disease recurrence. Whether this decrease represents a general feature in response to the disease or a link to the progression of the cancer is unknown. Understanding this relationship may have clinical and therapeutic consequences for women with papillary serous adenocarcinoma.

7.
Int J Gynecol Pathol ; 25(2): 151-4, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16633064

ABSTRACT

We report an unusual case of a 78-year-old woman with primary ovarian tumor that consisted of primitive neurectodermal tumor and endometrioid adenocarcinoma. The patient presented with abdominal pain and weight loss and had disseminated disease at her initial presentation. She was treated with debulking surgery followed by chemotherapy. The patient was still asymptomatic at the 6-month follow-up.


Subject(s)
Carcinoma, Endometrioid , Endometrial Neoplasms , Neoplasms, Multiple Primary , Neuroectodermal Tumors, Primitive , Ovarian Neoplasms , Aged , Carcinoma, Endometrioid/diagnosis , Carcinoma, Endometrioid/pathology , Carcinoma, Endometrioid/therapy , Combined Modality Therapy , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/pathology , Endometrial Neoplasms/therapy , Female , Humans , Neoplasms, Multiple Primary/diagnosis , Neoplasms, Multiple Primary/pathology , Neoplasms, Multiple Primary/therapy , Neuroectodermal Tumors, Primitive/diagnosis , Neuroectodermal Tumors, Primitive/pathology , Neuroectodermal Tumors, Primitive/therapy , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/pathology , Ovarian Neoplasms/therapy , Prognosis
8.
J Neurosurg ; 100(2): 328-31, 2004 Feb.
Article in English | MEDLINE | ID: mdl-15086241

ABSTRACT

In this report the authors describe a woman with low-grade endometrial stromal sarcoma who was treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. After receiving megestrol acetate continuously for 19 years for chronic hormone suppression, she began to experience progressive dementia. Magnetic resonance imaging revealed 11 separate intracranial meningiomas of various sizes. The largest lesions were treated with staged angiographically guided embolization and excision. Despite discontinuation of megestrol acetate, the remaining smaller lesions grew slightly in size, requiring further treatment with a combination of excision and gamma knife stereotactic surgery. All of the excised tumors showed positive staining for progesterone receptors on immunohistochemical examination. Prolonged therapy with megestrol acetate could promote the growth of benign intracranial meningiomas in some patients.


Subject(s)
Endometrial Neoplasms/therapy , Megestrol Acetate/adverse effects , Meningeal Neoplasms/chemically induced , Meningioma/chemically induced , Progestins/adverse effects , Sarcoma, Endometrial Stromal/therapy , Dementia/etiology , Embolization, Therapeutic , Female , Gynecologic Surgical Procedures/methods , Humans , Magnetic Resonance Imaging , Meningeal Neoplasms/diagnosis , Meningeal Neoplasms/therapy , Meningioma/diagnosis , Meningioma/therapy , Middle Aged , Neurosurgical Procedures , Progesterone/agonists , Radiosurgery , Time Factors
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