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Supplementary Data from Novel Molecular Subtypes of Serous and Endometrioid Ovarian Cancer Linked to Clinical Outcome

Purpose: The study aim to identify novel molecular subtypes of ovarian cancer by gene expression profiling with linkage to clinical and pathologic features.Experimental Design: Microarray gene expression profiling was done on 285 serous and endometrioid tumors of the ovary, peritoneum, and fallopian tube. K-means clustering was applied to identify robust molecular subtypes. Statistical analysis identified differentially expressed genes, pathways, and gene ontologies. Laser capture microdissection, pathology review, and immunohistochemistry validated the array-based findings. Patient survival within k-means groups was evaluated using Cox proportional hazards models. Class prediction validated k-means groups in an independent dataset. A semisupervised survival analysis of the array data was used to compare against unsupervised clustering results.Results: Optimal clustering of array data identified six molecular subtypes. Two subtypes represented predominantly serous low malignant potential and low-grade endometrioid subtypes, respectively. The remaining four subtypes represented higher grade and advanced stage cancers of serous and endometrioid morphology. A novel subtype of high-grade serous cancers reflected a mesenchymal cell type, characterized by overexpression of N-cadherin and P-cadherin and low expression of differentiation markers, including CA125 and MUC1. A poor prognosis subtype was defined by a reactive stroma gene expression signature, correlating with extensive desmoplasia in such samples. A similar poor prognosis signature could be found using a semisupervised analysis. Each subtype displayed distinct levels and patterns of immune cell infiltration. Class prediction identified similar subtypes in an independent ovarian dataset with similar prognostic trends.Conclusion: Gene expression profiling identified molecular subtypes of ovarian cancer of biological and clinical importance.

ObjectiveTo review the first two years of the primary human papillomavirus (HPV) cervical screening programme in an HPV vaccinated population.DesignObservational study.SettingAustralia.Participants3 745 318 women with a primary HPV test between 1 December 2017 and 31 December 2019; most women aged InterventionsPrimary HPV screening with referral if HPV16 or HPV18 (HPV16/18) positive and triage with liquid based cytology testing (threshold atypical squamous cells-cannot exclude high grade squamous intraepithelial lesion) for women who were positive for high risk HPV types other than 16/18. A 12 month follow-up HPV test was recommended in triaged women with a negative or low grade cytology result, with referral if they tested positive for any high risk HPV type at follow-up.Main outcome measuresProportion of women who had attended for their first HPV screening test, tested positive, and were referred for colposcopy; and short term risk of detecting cervical intraepithelial neoplasia (CIN) grade 2 or worse, CIN grade 3 or worse, or cancer.Results54.6% (n=3 507 281) of an estimated 6 428 677 eligible women aged 25-69 had undergone their first HPV test by the end of 2019. Among those attending for routine screening, positivity for HPV16/18 and for HPV types not 16/18 was, respectively, 2.0% and 6.6% in women aged 25-69 (n=3 045 844) and 2.2% and 13.3% in highly vaccinated cohorts of women aged 25-34 (n=768 362). Colposcopy referral (ages 25-69 years) was 3.5%, increasing to an estimated 6.2% after accounting for women who had not yet had a 12 month repeat test. Cervical cancer was detected in 0.98% (456/46 330) of women positive for HPV16/18 at baseline, including 0.32% (89/28 003) of women with HPV16/18 and negative cytology. Women with HPV types not 16/18 and negative or low grade cytology at both baseline and 12 months were at low risk of serious disease (3.4% CIN grade 3 or worse; 0.02% cancer; n=20 019) but estimated to account for 62.0% of referrals for this screening algorithm.ConclusionsColposcopy referral thresholds need to consider underlying cancer risk; on this basis, women with HPV16/18 in the first round of HPV screening were found to be at higher risk regardless of cytology result, even in a previously well screened population. Women with HPV types not 16/18 and negative or low grade cytology showed a low risk of serious abnormalities but constitute most referrals and could be managed safely with two rounds of repeat HPV testing rather than one. HPV16/18 driven referrals were low in HPV vaccinated cohorts.

Cervical cancer is the third most common form of cancer that strikes Malaysian women. The National Cancer Registry in 2006 and 2007 reported that the age standardized incidence (ASR) of cervical cancer was 12.2 and 7.8 per 100,000 women, respectively. The cumulative risk of developing cervical cancer for a Malaysian woman is 0.9 for 74 years. Among all ethnic groups, the Chinese experienced the highest incidence rate in 2006, followed by Indians and Malays. The percentage cervical cancer detected at stage I and II was 55% (stage I: 21.0%, stage II: 34.0%, stage III: 26.0% and stage IV: 19.0%). Data from Ministry of Health Malaysia (2006) showed a 58.9% estimated coverage of pap smear screening conducted among those aged 30-49 years. Only a small percentage of women aged 50-59 and 50-65 years old were screened, 14% and 13.8% coverage, respectively. Incidence of cervical cancer was highest (71.6%) among those in the 60-65 age group (MOH, 2003). Currently, there is no organized population-based screening program available for the whole of Malaysia. A pilot project was initiated in 2006, to move from opportunistic cervical screening of women who attend antenatal and postnatal visits to a population based approach to be able to monitor the women through the screening pathway and encourage women at highest risk to be screened. The project was modelled on the screening program in Australia with some modifications to suit the Malaysian setting. Substantial challenges have been identified, particularly in relation to information systems for call and recall of women, as well as laboratory reporting and quality assurance. A cost-effective locally-specific approach to organized screening, that will provide the infrastructure for increasing participation in the cervical cancer screening program, is urgently required.

BACKGROUND: Archival Papanicolaou (Pap)-stained cervical cytology tests may be the only source of a clinical sample for the evaluation of previous human papillomavirus (HPV) infection. Pap tests are ideal because the majority of women in countries with comprehensive screening programs would have had several collected and stored. METHODS: In the current study, HPV detection and genotyping were compared in samples collected from a conventionally fixed Pap test with those collected using an endocervical brush and collected in PreservCyt (liquid-based) in 87 women undergoing management for a high-grade Pap test abnormality. Cytology slides were scanned to create high-resolution digital images before the removal of cells because the DNA extraction process resulted in the destruction of the cells from the original sample. RESULTS: All previously identified high-grade abnormalities on the Pap tests were detectable on the digital images. β-globin was detected in all extracted Pap tests, indicating the presence of recoverable, amplifiable DNA. A total of 62 (71.3%) and 59 (67.8%) tests were found to have high-risk (HR) HPV detected on PreservCyt and fixed Pap test slides, respectively, with >87% concordance for the detection of HR HPV genotypes. Complete HPV genotyping concordance was observed in 62% and was partial in 26% of sample pairs, with very good agreement for HPV types 16 and 18 (κ = 0.850 and 0.903, respectively). Only 1 Pap test slide was found to be positive whereas the PreservCyt had no detectable HPV DNA, demonstrating a low false-positive rate (1%). CONCLUSIONS: The results of the current study confirm that imaging and subsequent HPV detection and genotyping in archival cervical smears can offer accuracy in HPV detection that is comparable to endocervical brush-collected PreservCyt samples. Cancer (Cancer Cytopathol) 2010;. © 2010 American Cancer Society.

This report describes human papillomavirus (HPV) vaccine coverage data for Australian women 18-26 years of age, as notified to the National Human Papillomavirus Vaccination Program Register. A cross-sectional analysis was conducted of notifications to the Register of HPV vaccine doses delivered as part of the National HPV Vaccination Program, which provided free catch-up vaccination to women 18-26 years of age across Australia between 2007 and 2009. HPV vaccination coverage estimates were calculated by age, state or territory of residence and dose number, using the Australian Bureau of Statistics population estimates as the denominator. As at March 2011, approximately 4.49 million doses had been notified to the Register of females of all ages, and 1.7 million of these were for women aged 18-26 years in 2007. Vaccination coverage was highest for females aged 18 years and lowest in females aged 26 years. For the entire 18-26 years cohort, coverage was estimated at 55.2% for dose 1, 44.8% for dose 2 and 31.7% for dose 3. Notified dose 1 coverage rates by single year of age and state or territory ranged between 22% for females aged 26 years in the Northern Territory and 76% in females aged 18 years in Queensland, with dose 1 coverage highest across the age range in the Northern Territory, Queensland and South Australia. These data suggest that over half of Australian women aged 18-26 years commenced HPV vaccine courses and about one-third are fully vaccinated. Some of the differences in the coverage observed between states and territories likely reflect differing mechanisms for notifying to the Register.

Objective To describe the epidemiology of infection with the human immunodeficiency virus type 1 (HIV-1) in Victoria from 1980 to 1991. Design Data on HIV-1 infection in Victoria, obtained through routine laboratory-based surveillance, were entered in a database. Missing information was sought by contacting the referring doctor where possible. Setting In Victoria, the acquired immunodeficiency syndrome (AIDS) is notifiable to Health Department Victoria by diagnosing doctors, and laboratories are required to notify new diagnoses of HIV-1 infection, without identifiers. All confirmatory testing for HIV-1 has taken place at the State HIV Reference Laboratory at Fairfield Hospital. Main outcome measures Diagnoses of HIV-1 infection, as confirmed at the State HIV Reference Laboratory by western blot immunoassay, and notifications of AIDS to Health Department Victoria. Results Over six years the annual number of diagnoses of HIV-1 infection in Victoria remained constant despite a substantial increase in the number of tests performed. To the end of 1991, 2679 people had been diagnosed with HIV-1 infection, 686 of whom had developed AIDS. Information on exposure was available for 2379 (88.8%). Homosexual and bisexual men made up 75.5% (85.0% of those for whom exposure had been ascertained); 3.4% were female or heterosexual male injecting drug users; and 3.7% were heterosexuals with no history of injecting drug use. The latter two groups contributed 2.0% in 1985 to the proportion of all new diagnoses for which exposure was known, and 14.3% in 1991; for recipients of contaminated blood or blood products before 1985 this proportion fell from 12.4% to 1.0%. The cumulative incidence of HIV-1 diagnoses was highest in the age group 25-29 years, and 20% of all HIV-1 infected people were under 25 at the time of diagnosis. In 1991, 81 of the 311 people who had been diagnosed with HIV-1 infection had had previous negative or indeterminate results of tests; half of these had acquired infection in the previous year. Conclusion Most HIV-1 infections in Victoria have been acquired through male homosexual contact, with a small but increasing proportion of diagnoses occurring in heterosexuals. Laboratory-based surveillance of voluntary testing, despite its limitations, has provided valuable information on the extent of the HIV-1 epidemic in Victoria. Surveillance of all HIV-1 test results and of seroconverters now supplements routine surveillance of HIV diagnoses and will ensure a more accurate picture of the epidemic in coming years.

The purpose of this project is to identify ovarian cancer susceptibility genes involved in stromal-epithelial cross talk. We have now genotyped 2138 samples for 1536 tagging, non-synonymous and miRNA binding site SNPs in 174 genes. Following Quality Control exclusions, the final dataset comprised 1839 samples (675 cases and 1164 controls) with genotype information for 1292 SNPs in 174 genes. We are using P(trend) values to select 25-30 SNPs for independent validation in ~2000 cases and ~4000 controls from other sites. Four of these SNPs will also be genotyped by the whole of the Ovarian Cancer Association Consortium (OCAC) (~4500 case and ~6500 controls). Currently our most significant finding is for a SNP in the podocalyxin-like (PODXL) gene for which the P(trend) = 0.0001, with a Positive Predictive Value of 33 %, and a Homozygote OR = 1.75 (95% CI 1.28-3.38).