Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses

Allogén vérképzőőssejt-átültetés Magyarországon

INTRODUCTION AND AIM: The publication summarizes the 2548 stem cell transplantations performed in the period of 1993-2015 in Szent Laszlo Hospital, Budapest and provides a detailed discussion of the 425 allogeneic transplantations during 2007-2013. METHOD: The analysis explains the major steps of the evolution of allogeneic stem cell transplantation and compares the results of the unique Hungarian allogeneic center. RESULTS: The significant shift in the transplantation indications from chronic myeloid leukemia to myelodysplastic syndromes and the rising age of the recipients are in line with world wide tendencies. The latter one is the consequence of the introduction and improvement of the concept of reduced intensity conditioning regimens, originally arising from the idea of Endre Kelemen. The most limiting factor, the donor availability seems to be resolved with the use of a new immunomodulating regimen, the application of posttransplantation cyclophosphamide, which allows the transplantation through HLA barriers with haploidentical family donors with comparable results to the HLA matched volunteer unrelated donors. The above mentioned tendencies result the wider use of allogeneic stem cell transplantation less dependent from recipient age, comorbidities and even donor availability. CONCLUSIONS: The publication highlights the need of expanding the stem cell transplantation budget and the involvement of new centers in Hungary in allogeneic of stem cell transplantation. Orv. Hetil., 2017, 158(8), 291-297

Sex differences in oncogenic mutational processes.

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair

Chemical castration decreases Ku70 expression impairing nonhomologous end joining DNA repair and improving the radiotherapy response of prostate cancer patients.</jats:p

Supplementary Figure S1 from Deoxycytidine Kinase Expression Underpins Response to Gemcitabine in Bladder Cancer

Supplementary Figure S1. Transfection efficiency of siRNA measured with fluorescence. 50 nM Block-iT fluorescent siRNA was transfected and cells fixed 6 h later.</p

Supplementary Figure S3 from Deoxycytidine Kinase Expression Underpins Response to Gemcitabine in Bladder Cancer

Supplementary Figure S3. Inverse correlation between S phase accumulation of cells and gemcitabine IC50. Cells were treated with 10 nM gemcitabine for 24 h, prior to fixation in 70% ethanol and staining with propidium iodide. The proportion of cells in S phase was calculated using ModFit LT (Verity Software House).</p

Supplementary Table S1 from Deoxycytidine Kinase Expression Underpins Response to Gemcitabine in Bladder Cancer

Supplementary Table S1. dCK positivity of nuclei of xenograft tumour, stroma and vasculature.</p

Supplementary Figure S4 from Deoxycytidine Kinase Expression Underpins Response to Gemcitabine in Bladder Cancer

Supplementary Figure S4. Clonogenic plating efficiency of HUVECs in the presence of gemcitabine.</p