We have developed, confirmed, and now validated a pragmatic molecular classification tool (ProMisE) that provides consistent categorization of tumors and identifies four distinct prognostic molecular subtypes. ProMisE can be applied to diagnostic samples and thus could be used to inform surgical procedure(s) and/or need for adjuvant therapy. Based on the IOM guidelines this classifier is now ready for clinical evaluation through prospective clinical trials.

No abstract

No abstract

Judging the carcinogenicity of human papillomavirus (HPV) types rarely found in cervical cancer (CxCa) is hindered by lack of studies of their biological activity in cancer tissues. To asses transcriptional activity of HPV types, we have developed ultrashort amplimer, splice-site specific, E6*I mRNA RT-PCR assays for 12 high-risk (HR)-HPV (IARC Group 1) and eight probable/ possible high-risk (pHR)-HPV types (IARC Group 2A/B carcinogens). Previously unreported E6*I splice sites of the six pHR-HPV types 26, 53, 67, 70, 73 and 82 were identified by cloning and sequencing. We analyzed 97 formalin-fixed paraffin-embedded (FFPE) Mongolian CxCa biopsies for presence of HPV DNA by two sensitive genotyping assays, for E6*I transcripts of all HR-/ pHR-HPV types identified and for expression of HPV surrogate markers p16 INK4a , pRb and p53. E6*I of at least one HR-/pHR-HPV was expressed in 94 (98%) of cancer tissues including seven with pHR-HPV types 26, 66, 70 or 82 as single transcribed types. Fifty-eight of E6*I mRNA transcribing cases were analyzable by immunohistochemistry and displayed p16 INK4a overexpression in 57 (98%), pRb downregulation in 56 (97%) and p53 downregulation in 36 (62%) tissues. The newly developed E6*I mRNA RT-PCR assays appeared to be highly sensitive method to analyze HPV transcription in FFPE materials. Our finding of viral oncogene transcription of pHR-HPV types 26, 66, 70 and 82 in cervical tumors, in the absence of any other transcriptionally active HR-type and with p16 INK4a overexpression and pRb downregulation, may support a reassessment of the carcinogenicity classification of these pHR-HPV types.Human papillomaviruses (HPV) with currently more than 150 types defined are a complex group differing in tropism and carcinogenic potential. Detection of HPV DNA in 99.7% of cervical cancer (CxCa) cases has established HPV as an etiological factor for CxCa development. 1,2 Epidemiological studies have demonstrated that 20 mucosal HPV types from five phylogenetically related species of the genus alpha (a5, a6, a7, a9 and a11-termed as ''high-risk clade'') are consistently found as single HPV infections in CxCa worldwide. [3][4][5][6] Based on their frequency in CxCa and available biological data, 12 of these types, i.e., types 16,18,31,33,35,39, 45, 51, 52, 56, 58 and 59 have been defined as carcinogens (IARC Group 1A)-hereafter referred to as high-risk (HR)-HPV. For eight other types, in the high-risk clade, i.e., types 26, 53, 66, 67, 68, 70, 73 and 82, the combination of their low frequency, lack of data on their active transcription and their transforming potential in model systems, has led them to be classified as only probable/possible carcinogens (IARC Groups 2A and 2B)-hereafter referred to as possible highrisk (pHR)-HPV types. 7 In the era of HPV-based cervical cancer precursor screening and of type-specific HPV vaccination, understanding the oncogenic properties of individual

Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually exclusive ATPases of the SWI/SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high‐grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4‐negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re‐expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Many women with ovarian endometrioid carcinoma present with concurrent endometrial carcinoma. Organ-confined and low-grade synchronous endometrial and ovarian tumors (SEOs) clinically behave as independent primary tumors rather than a single advanced-stage carcinoma. We used 18 SEOs to investigate the ancestral relationship between the endometrial and ovarian components. Based on both targeted and exome sequencing, 17 of 18 patient cases of simultaneous cancer of the endometrium and ovary from our series showed evidence of a clonal relationship, ie, primary tumor and metastasis. Eleven patient cases fulfilled clinicopathological criteria that would lead to classification as independent endometrial and ovarian primary carcinomas, including being of FIGO stage T1a/1A, with organ-restricted growth and without surface involvement; 10 of 11 of these cases showed evidence of clonality. Our observations suggest that the disseminating cells amongst SEOs are restricted to physically accessible and microenvironment-compatible sites yet remain indolent, without the capacity for further dissemination.

Studies on the p53 expression and outcome for women with ovarian carcinoma have produced conflicting results. The observed heterogeneity may be due to the range of cut-offs used to define overexpression and the mix of histotypes of the study cohorts. We aimed to examine the association between p53 expression and biological properties of tumours as well as outcome in 502 pelvic high-grade serous carcinomas (HGSCs) derived from two population-based cohorts from British Columbia representing cases with or without residual tumour after initial surgery, respectively, and one clinical trial cohort from Germany (AGO-OVAR-3). p53 expression was assessed on tissue microarrays by immunohistochemistry using the DO-7 antibody. p53 expression was scored in three tiers as complete loss of expression, focal expression or overexpression (defined as more than 50% positive tumour cell nuclei) and correlated with survival using multivariate Cox regression models. p53 was completely absent in 30.3%, focally expressed in 12.0%, and overexpressed in 57.7% of HGSCs, which was an inverse pattern compared to clear cell and endometrioid types of ovarian carcinomas, where 76% and 69% of cases showed focal expression, respectively (p < 0.001, chi square test). Pelvic HGSCs show either complete absence of p53 expression or p53 overexpression in 88% of cases; thus, aberrant p53 expression is a ubiquitous feature of HGSCs. HGSCs with p53 overexpression were associated with a reduced risk of recurrence compared to cases with complete absence of p53 in the British Columbia cohort with residual tumour (HR = 0.71, 95% CI 0.51-0.99) and for a combination of all three cohorts (HR = 0.70, 95% CI 0.55-0.89) in multivariate analysis including age, stage, residual tumour, and stratification by cohort. The association of complete absence of p53 expression with unfavourable outcome suggests functional differences of TP53 mutations underlying overexpression, compared to those underlying complete absence of expression.

Intratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.