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The aim of this study was to assess trends in the age-specific incidence of vulvar cancer in 13 high-income countries satisfying a priori conditions regarding the availability of cancer registry data over a 20-year period; these were Canada, the United States, nine European countries, Australia and Japan. Five-yearly incidence and population at risk were obtained from the International Agency for Research on Cancer's Cancer Incidence in Five Continents for the years 1988-1992 (Volume 7) to 2003-2007 (Volume 10). The 5-yearly average percent change (AvPC) over the period and standardised rate ratios (SRRs) for 2003-2007 versus 1988-1992 were used to assess changes in the age-standardised incidence rates of vulvar cancer for all ages, and for

Several single nucleotide polymorphisms (SNPs) in candidate genes of DNA repair and hormone pathways have been reported to be associated with endometrial cancer risk. We sought to confirm these associations in two endometrial cancer case-control sample sets and used additional data from an existing genome-wide association study to prioritize an additional SNP for further study. Five SNPs from the CHEK2, MGMT, SULT1E1 and SULT1A1 genes, genotyped in a total of 1597 cases and 1507 controls from two case-control studies, the Australian National Endometrial Cancer Study and the Polish Endometrial Cancer Study, were assessed for association with endometrial cancer risk using logistic regression analysis. Imputed data was drawn for CHEK2 rs8135424 for 666 cases from the Study of Epidemiology and Risk factors in Cancer Heredity study and 5190 controls from the Wellcome Trust Case Control Consortium. We observed no association between SNPs in the MGMT, SULT1E1 and SULT1A1 genes and endometrial cancer risk. The A allele of the rs8135424 CHEK2 SNP was associated with decreased risk of endometrial cancer (adjusted per-allele OR 0.83; 95%CI 0.70-0.98; p = .03) however this finding was opposite to that previously published. Imputed data for CHEK2 rs8135424 supported the direction of effect reported in this study (OR 0.85; 95% CI 0.65–1.10). Previously reported endometrial cancer risk associations with SNPs from in genes involved in estrogen metabolism and DNA repair were not replicated in our larger study population. This study highlights the need for replication of candidate gene SNP studies using large sample groups, to confirm risk associations and better prioritize downstream studies to assess the causal relationship between genetic variants and cancer risk. Our findings suggest that the CHEK2 SNP rs8135424 be prioritized for further study as a genetic factor associated with risk of endometrial cancer.

Different subtypes of ovarian cancer appear to have different causes; however, the association between body mass index (BMI) and the different subtypes is unclear. We examined the associations between body-mass index (BMI) and weight gain and risk of the different histological subtypes of epithelial ovarian cancer in a case-control study in Australia. Cases aged 18-79 with a new diagnosis of invasive epithelial ovarian cancer (n = 1,269) or borderline tumor (n = 311) were identified through a network of clinics and cancer registries throughout Australia. Controls (n = 1,509) were selected from the Electoral Roll. Height and weight (1 year previously, at age 20 and maximum weight) and other risk factor information were ascertained via a self-administered questionnaire. Obesity was positively associated with clear cell tumors (Odds Ratio 2.3; 95% confidence interval 1.2-4.2) but not invasive endometrioid or mucinous tumors. Although there was no association with invasive serous tumors overall (0.9; 0.7-1.2), we did see an increased risk of serous peritoneal tumors (2.9; 1.7-4.9), but not of serous tumors of the ovary and fallopian tube. Of the borderline subtypes, obesity was positively associated with serous (1.8; 1.1-2.8) but not mucinous tumors (1.1; 0.7-1.7). Overweight was not associated with any subtype overall. There was no association with BMI at age 20, or weight gain for any of the histological subtypes. These results add to the current evidence that obesity increases a woman's risk of developing distinct histological subtypes of ovarian cancer.

Chronic inflammation has been proposed as the possible causal mechanism that explains the observed association between certain risk factors, such as the use of talcum powder (talc) in the pelvic region and epithelial ovarian cancer. To address this issue we evaluated the potential role of chronic local ovarian inflammation in the development of the major subtypes of epithelial ovarian cancer. Factors potentially linked to ovarian inflammation were examined in an Australia-wide case-control study comprising 1,576 women with invasive and low malignant potential (LMP) ovarian tumours and 1,509 population-based controls. We confirmed a statistically significant increase in ovarian cancer risk associated with use of talc in the pelvic region (adjusted odds ratio 1.17, 95% CI: 1.01-1.36) that was strongest for the serous and endometrioid subtypes although the latter was not statistically significant (adjusted odds ratios 1.21, 95% CI 1.03-1.44 and 1.18, 95% CI 0.81-1.70, respectively). Other factors potentially associated with ovarian inflammation (pelvic inflammatory disease, human papilloma virus infection and mumps) were not associated with risk but, like others, we found an increased risk of endometrioid and clear cell ovarian cancer only among women with a history of endometriosis. Regular use of aspirin and other nonsteroidal anti-inflammatory drugs was inversely associated with risk of LMP mucinous ovarian tumours only. We conclude that on balance chronic inflammation does not play a major role in the development of ovarian cancer.

Whilst next generation sequencing can report point mutations in fixed tissue tumour samples reliably, the accurate determination of copy number is more challenging. The conventional Multiplex Ligation-dependent Probe Amplification (MLPA) assay is an effective tool for measurement of gene dosage, but is restricted to around 50 targets due to size resolution of the MLPA probes. By switching from a size-resolved format, to a sequence-resolved format we developed a scalable, high-throughput, quantitative assay. MLPA-seq is capable of detecting deletions, duplications, and amplifications in as little as 5ng of genomic DNA, including from formalin-fixed paraffin-embedded (FFPE) tumour samples. We show that this method can detect BRCA1, BRCA2, ERBB2 and CCNE1 copy number changes in DNA extracted from snap-frozen and FFPE tumour tissue, with 100% sensitivity and >99.5% specificity.

ABCB1 (adenosine triphosphate-binding cassette transporter B1) mediates cellular elimination of many chemotherapeutic agents including paclitaxel, which is commonly used to treat ovarian cancer. A significant association between common single nucleotide polymorphisms (SNPs) in ABCB1 and progression-free survival has been reported in patients with ovarian cancer. Variable paclitaxel clearance due to genotype specific differences in ABCB1 activity in cancer cells and/or normal tissues may underlie the association. Using cell-based models, we evaluated the correlations between ABCB1 expression, polymorphisms, transporter activity and paclitaxel sensitivity in ovarian cancer (n = 10) and lymphoblastoid (n = 19) cell lines. Close associations between ABCB1 expression, transporter function and paclitaxel sensitivity were found in lymphoblastoid cell lines, although we could not demonstrate an association with common SNPs. In ovarian cancer cell lines, ABCB1 expression was low and the association between expression and function was lost. These results suggest that ABCB1 related survival difference in ovarian cancer patients is more likely to be due to differential whole body paclitaxel clearance mediated by normal cells rather than a direct effect on cancer cells.

Background: X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects. Methods: We assessed the pattern of X chromosome inactivation using methylation-specific polymerase chain reaction amplification of the exon 1 microsatellite region of the X-linked androgen receptor (AR) gene in DNA from blood samples obtained from control subjects without a personal history of breast or ovarian cancer (n = 735), ovarian cancer patients (n = 313), familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2 (n = 235), and affected and unaffected carriers of mutations in BRCA1 (n = 260) or BRCA2 (n = 63). We defined the pattern of X chromosome inactivation as skewed when the same X chromosome was active in at least 90% of cells. The association between skewed X inactivation and disease and/or BRCA mutation status was assessed by logistic regression analysis. The association between skewed X inactivation and age at cancer diagnosis was assessed by Cox proportional hazards regression analysis. All statistical tests were two-sided. Results: The age-adjusted frequency of skewed X inactivation was not statistically significantly higher in ovarian cancer or familial breast cancer case subjects compared with control subjects. Skewed X inactivation was higher in BRCA1 mutation carriers than in control subjects (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.1 to 6.2; P = .02), particularly among unaffected women (OR = 6.1, 95% CI = 1.5 to 31.8; P = .005). Among BRCA1 mutation carriers, those with skewed X inactivation were older at diagnosis of breast or ovarian cancer than those without skewed X inactivation (hazard ratio [HR] of breast or ovarian cancer = 0.37, 95% CI = 0.14 to 0.95; P = .04). Among BRCA2 mutation carriers, skewed X inactivation also occurred more frequently in unaffected carriers than in those diagnosed with breast or ovarian cancer (OR = 5.2, 95% CI = 0.5 to 28.9; P = .08) and was associated with delayed age at onset (HR = 0.59, 95% CI = 0.37 to 0.94; P = .03). Conclusions: Skewed X inactivation occurs at an increased frequency in BRCA1 (and possibly BRCA2) mutation carriers compared with control subjects and is associated with a statistically significant increase in age at diagnosis of breast and ovarian cancer. © The Author 2008

Although some high-risk ovarian cancer genes have been identified, it is likely that common low penetrance alleles exist that confer some increase in ovarian cancer risk. We have genotyped nine putative functional single-nucleotide polymorphisms (SNP) in genes involved in steroid hormone synthesis (SRD5A2, CYP19A1, HSB17B1, and HSD17B4) and DNA repair (XRCC2, XRCC3, BRCA2, and RAD52) using two Australian ovarian cancer case-control studies, comprising a total of 1,466 cases and 1,821 controls of Caucasian origin. Genotype frequencies in cases and controls were compared using logistic regression. The only SNP we found to be associated with ovarian cancer risk in both of these two studies was SRD5A2 V89L (rs523349), which showed a significant trend of increasing risk per rare allele (P = 0.00002). We then genotyped another SNP in this gene (rs632148; r2 = 0.945 with V89L) in an attempt to validate this finding in an independent set of 1,479 cases and 2,452 controls from United Kingdom, United States, and Denmark. There was no association between rs632148 and ovarian cancer risk in the validation samples, and overall, there was no significant heterogeneity between the results of the five studies. Further analyses of SNPs in this gene are therefore warranted to determine whether SRD5A2 plays a role in ovarian cancer predisposition. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2557–9)

It remains unclear whether physical activity is associated with epithelial ovarian cancer risk. We therefore examined the association between recreational physical activity and risk of ovarian cancer in a national population-based case-control study in Australia. We also systematically reviewed all the available evidence linking physical activity with ovarian cancer to provide the best summary estimate of the association. The case-control study included women ages 18 to 79 years with a new diagnosis of invasive (n = 1,269) or borderline (n = 311) epithelial ovarian cancer identified through a network of clinics, physicians, and state cancer registries throughout Australia. Controls (n = 1,509) were randomly selected from the national electoral roll and were frequency matched to cases by age and state. For the systematic review, we identified eligible studies using Medline, the ISI Science Citation Index, and manual review of retrieved references, and included all case-control or cohort studies that permitted assessment of an association between physical activity (recreational/occupational/sedentary behavior) and histologically confirmed ovarian cancer. Meta-analysis was restricted to the subset of these studies that reported on recreational physical activity. In our case-control study, we observed weakly inverse or null associations between recreational physical activity and risk of epithelial ovarian cancer overall. There was no evidence that the effects varied by tumor behavior or histologic subtype. Twelve studies were included in the meta-analysis, which gave summary estimates of 0.79 (95% confidence interval, 0.70-0.85) for case-control studies and 0.81 (95% confidence interval, 0.57-1.17) for cohort studies for the risk of ovarian cancer associated with highest versus lowest levels of recreational physical activity. Thus, pooled results from observational studies suggest that a modest inverse association exists between level of recreational physical activity and the risk of ovarian cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2321–30)

Over the past quarter of a century, several scientific developments have challenged traditional concepts in ovarian cancer. First, it was recognized that ovarian cancer is not a homogeneous disease, but rather a group of diseases-each with different morphology and biological behavior. Approximately 90% of ovarian cancers are carcinomas (malignant epithelial tumors) and, based on histopathology, immunohistochemistry, and molecular genetic analysis, at least five main types are currently distinguished: high-grade serous carcinoma (HGSC, 70%); endometrioid carcinoma (EC,10%); clear-cell carcinoma (CCC,10%); mucinous carcinoma (MC, 3%); and low-grade serous carcinoma (LGSC

Families with hereditary nonpolyposis colorectal cancer (HNPCC) have an increased lifetime risk of endometrial (40%) and ovarian (10%) carcinomas. Endometrial and ovarian carcinomas from members of these families frequently display a mutator phenotype as manifest by high levels of microsatellite instability (MSI-H). Microsatellite instability (MSI) occurs in 17-32% of sporadic endometrial carcinomas and 3-17% of sporadic ovarian carcinomas. We hypothesized that there might be a higher rate of MSI in tumors from women with synchronous primary carcinomas of the ovary and endometrium.We identified 52 cases of synchronous tumors of the ovary and endometrium from the databases of four gynecological oncology units. Archival material and clinical data were available on 45 of these patients. We examined DNA extracted from ovarian and endometrial tumor tissue for MSI using DNA extracted from normal tissue of that patient as a germ-line DNA control. MSI was assessed using a panel of five standard microsatellite markers: D2S123, D5S346, D17S250, BAT25, and BAT26. MSI-H was defined by more than two markers being positive. Low-level MSI (MSI-L) was defined as one or two markers positive and microsatellite stable (MSS) was defined as no markers positive.The 45 patients had a median age at diagnosis of 53 years. Of a total of 134 samples analyzed, only three samples (3.3%) were MSI-H. No patient had high levels of MSI in both ovarian and endometrial tumors. One ovarian carcinoma had five of five markers positive with the corresponding endometrial carcinoma being MSI-L. Two endometrial carcinomas were MSI-H, and the corresponding ovarian carcinomas were MSI-L and MSS, respectively. Seven ovarian tumors and seven endometrial tumors were MSI-L. The majority of patients had early-stage ovarian carcinoma [International Federation of Gynecology and Obstetrics (FIGO) stage I, 44.4%; stage II, 26.7%; and stage III, 26.6%]. Eighty-two % of the endometrial primaries were FIGO stage I. Progression-free survival was significantly better for patients with synchronous primaries than those presenting with ovarian carcinoma alone [adjusted hazards ratio, 1.94; P = 0.023; 95% confidence interval, 1.096-3.44].Synchronous primary carcinomas of the ovary and endometrium are unlikely to be part of the HNPCC syndrome unless the family history is in keeping with the modified Amsterdam criteria.

Cancer sufferers are a subfertile group, and most treatments have the potential to adversely affect gonadal function. As cancer treatment becomes more effective and survival rates improve there are more cancer survivors in the reproductive age group for whom parenting is an important consideration.This article outlines the effects on fertility of cancer treatments and techniques to minimise the risk of infertility.The overall prospects for younger cancer sufferers to either retain their fertility or have genetic offspring is now better than ever before, due to advances in assisted reproductive technology, the appropriate use of fertility sparing surgery and other techniques to reduce the toxicity of therapy on the reproductive organs. These advances raise new moral and ethical concerns that must be considered before advising cancer sufferers of the options for preserving reproductive capacity.

This study is a literature review of papers in the English language dealing with quality control for ovarian cancer surgery. Quality control in surgery has long been a neglected area of medicine. Initial attempts were limited to cardiac surgery, but only very recently has there been any attempt to look at quality control in ovarian cancer surgery. Investigators from Hesse, Germany were the first to document the surgical quality of patients with ovarian cancer. Subsequently, investigators in the United States and other European countries have demonstrated that patients treated by gynaecological oncologists in large-volume tertiary institutions had the best outcomes. The Gynaecological Cancer Group of the European Organisation for Research and Treatment of Cancer has developed a series of process quality indicators for ovarian cancer surgery that could be used by surgeons or units to audit and improve their practice. These and or other initiatives are important, because pressure is coming from consumers, government, health care insurers and medical risk insurers for surgeons and hospitals to provide transparent patient outcome data. If the profession does not institute adequate internal regulation of the quality of ovarian cancer surgery, regulation is likely to be imposed by government.