Whole-genome characterization of chemoresistant ovarian cancer

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1

Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

BackgroundMany loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.MethodsWe carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.ResultsWe found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro.ConclusionsThe locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association.ImpactThis finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604

Systematic review on evidence of the effectiveness of cholesterol-lowering drugs

Introduction: Coronary heart disease (CHD) is the leading cause of mortality worldwide. With increasingly urbanized lifestyles in developing countries and the aging populations, the major risk factors for CHD such as obesity, diabetes mellitus, and hypercholesterolemia are likely to increase in the future. In the current report, we reviewed the evidence on the effect of cholesterol lowering using pharmacological agents. Methods: A PubMed/Medline systematic search was performed over the past 12 years (1998–2009 inclusive) and relevant papers written in the English language were selected. We used key phrases including, “risk factors for hypercholesterolemia,” “management of hypercholesterolemia,” “guidelines for management of hypercholesterolemia,” and “pharmacological management of hypercholesterolemia.” Results: There were a total of over 3500 reports. We selected key publications on the effect of cholesterol lowering using different pharmacological agents. Conclusion: Several options exist with regards to pharmacological management of hypercholesterolemia. There is a substantial body of evidence to support the effect of a population shift towards a favorable risk profile, which has huge potential in reducing the burden of CHD globally