Numerous studies have tested the association between TP53 mutations in ovarian cancer and prognosis but these have been consistently confounded by limitations in study design, methodology, and/or heterogeneity in the sample cohort. High-grade serous (HGS) carcinoma is the most clinically important histological subtype of ovarian cancer. As these tumours may arise from the ovary, Fallopian tube or peritoneum, they are collectively referred to as high-grade pelvic serous carcinoma (HGPSC). To identify the true prevalence of TP53 mutations in HGPSC, we sequenced exons 2–11 and intron–exon boundaries in tumour DNA from 145 patients. HGPSC cases were defined as having histological grade 2 or 3 and FIGO stage III or IV. Surprisingly, pathogenic TP53 mutations were identified in 96.7% (n = 119/123) of HGPSC cases. Molecular and pathological review of mutation-negative cases showed evidence of p53 dysfunction associated with copy number gain of MDM2 or MDM4, or indicated the exclusion of samples as being low-grade serous tumours or carcinoma of uncertain primary site. Overall, p53 dysfunction rate approached 100% of confirmed HGPSCs. No association between TP53 mutation and progression-free or overall survival was found. From this first comprehensive mapping of TP53 mutation rate in a homogeneous group of HGPSC patients, we conclude that mutant TP53 is a driver mutation in the pathogenesis of HGPSC cancers. Because TP53 mutation is almost invariably present in HGPSC, it is not of substantial prognostic or predictive significance. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
BackgroundThe major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease.Methods and FindingsEvolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22–46 mo), censored after 26 October 2013. Outcome measures were overall survival (OS) and progression-free survival (PFS). There were marked differences in the degree of clonal expansion (CE) between patients (median 0.74, interquartile range 0.66–1.15), and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy.ConclusionsThis study demonstrates that quantitative measures of intra-tumour heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. Subclonal tumour populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse.
Cytotoxic drug resistance is a major cause of cancer treatment failure. We report an RNA interference screen to identify genes influencing sensitivity of different cancer cell types to chemotherapeutic agents. A set of genes whose targeting leads to resistance to paclitaxel is identified, many of which are involved in the spindle assembly checkpoint. Silencing these genes attenuates paclitaxel-induced mitotic arrest and induces polyploidy in the absence of drug. We also identify a ceramide transport protein, COL4A3BP or CERT, whose downregulation sensitizes cancer cells to multiple cytotoxic agents, potentiating endoplasmic reticulum stress. COL4A3BP expression is increased in drug-resistant cell lines and in residual tumor following paclitaxel treatment of ovarian cancer, suggesting that it could be a target for chemotherapy-resistant cancers.
SummaryThe extracellular matrix (ECM) can induce chemotherapy resistance via AKT-mediated inhibition of apoptosis. Here, we show that loss of the ECM protein TGFBI (transforming growth factor beta induced) is sufficient to induce specific resistance to paclitaxel and mitotic spindle abnormalities in ovarian cancer cells. Paclitaxel-resistant cells treated with recombinant TGFBI protein show integrin-dependent restoration of paclitaxel sensitivity via FAK- and Rho-dependent stabilization of microtubules. Immunohistochemical staining for TGFBI in paclitaxel-treated ovarian cancers from a prospective clinical trial showed that morphological changes of paclitaxel-induced cytotoxicity were restricted to areas of strong expression of TGFBI. These data show that ECM can mediate taxane sensitivity by modulating microtubule stability.
Resistance to chemotherapy in ovarian cancer is poorly understood. Evolutionary models of cancer predict that, following treatment, resistance emerges either due to outgrowth of an intrinsically resistant sub-clone, or evolves in residual disease under the selective pressure of treatment. To investigate genetic evolution in high-grade serous (HGS) ovarian cancers we first analysed cell line series derived from three cases of HGS carcinoma before and after platinum resistance had developed (PEO1, PEO4 and PEO6, PEA1 and PEA2, and PEO14 and PEO23). Analysis with 24-colour fluorescence in situ hybridisation and SNP array comparative genomic hybridisation (CGH) showed mutually exclusive endoreduplication and loss of heterozygosity events in clones present at different timepoints in the same individual. This implies that platinum sensitive and resistant disease was not linearly related but shared a common ancestor at an early stage of tumour development. Array CGH analysis of six paired pre- and post-neoadjuvant treatment HGS samples from the CTCR-OV01 clinical study did not show extensive copy number differences, suggesting that one clone was strongly dominant at presentation. These data show that cisplatin resistance in HGS carcinoma develops from pre-existing minor clones but that enrichment for these clones is not apparent during short-term chemotherapy treatment.
Predonation viral screening of blood donors is effective in high endemic areas, and the savings it generates may improve the safety and limit the cost of blood. Communication with deferred donors may contribute to public health. A new screening strategy associating serologic rapid test before donation and NAT on pools of 10 plasma samples after donation is proposed.
Hepatitis C virus (HCV) infection is thought to mostly become chronic and rarely resolves. HCV infection was serologically screened in 4,984 samples from Ghanaian blood donors, and 1.3% prevalence was found. At least 53% of confirmed anti-HCV carriers had no detectable viral RNA and were considered to have cleared the virus and recovered from the infection. Confirmation was authenticated by the presence of antibodies specific to at least two viral antigens, mostly NS3 and E2. Reactivity to HCV core antigens was lower in Ghanaian than United Kingdom blood donors. The minority of chronically infected donors carried a viral load significantly lower than an unselected comparative group of United Kingdom blood donors (2.5 ؋ 10 5 versus 2.9 ؋ 10 6 IU/ml; P ؍ 0.004). HCV genotype 2 was largely predominant (87%). Sequence clustering was similarly broad in the E1/E2 and NS5 regions. The phylogenetic diversity and the incapacity to distinguish subtypes within genotype 2 in our and others' West African strains suggested that West Africa may be the origin of HCV genotype 2. The genetic diversity extended to the identification of strains clearly separated from known subtypes of genotype 2 and genotype 1. One strain appears to be part of a new HCV genotype. HCV infection in Ghana is characterized by a high rate of recovery and the predominance of broadly divergent genotype 2 strains.
Occult hepatitis B virus (HBV) infection (OBI), defined as the presence of HBV DNA without detectable HBV surface antigen (HBsAg), is frequent in west Africa, where genotype E is prevalent. The prevalence of OBI in 804 blood donors and 1368 pregnant women was 1.7 and 1.5 %, respectively. Nine of 32 OBI carriers were evaluated with HBV serology, viral load and complete HBV genome sequence of two to five clones. All samples except one were anti-HBV core antigen-positive and three contained antibodies against HBsAg (anti-HBs). All strains were of genotype E and formed quasispecies with 0.20-1.28 % intra-sample sequence variation. Few uncommon mutations (absent in 23 genotype E reference sequences) were found across the entire genome. Two mutations in the core region encoded truncated or abnormal capsid protein, potentially affecting viral production, but were probably rescued by non-mutated variants, as found in one clone. No evidence of escape mutants was found in anti-HBs-carrying samples, as the 'a' region was consistently wild type. OBI carriers constitute approximately 10 % of all HBV DNA-viraemic adult Ghanaians. OBI carriers appear as a disparate group, with a very low viral load in common, but multiple origins reflecting decades of natural evolution in an area essentially devoid of human intervention.
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