From Surviving to Thriving: Evaluation of the International Diabetes Federation Life for a Child Program

IDF-LFAC aims to provide: (1) insulin and syringes; (2) blood glucose monitoring (BGM) equipment; (3) appropriate clinical care; (4) HbA1c testing; (5) diabetes education; and (6) technical support and training for health professionals, as well as 7) facilitating relevant clinical research, and where possible 8) assisting with capacity building. IDF-LFAC receives financial and in-kind support from private foundations, individuals, and corporations. Insulin and blood glucose monitoring equipment distribution is made possible by donations of insulin and the purchase of blood glucose monitors and strips at a reduced price from large pharmaceutical companies.The goal of this evaluation is to assess IDF-LFAC's organizational structure, strategic framework, processes, program impact, and potential to catalyze longterm sustainable improvements to T1D care delivery systems in its partner countries. LSHTM were commissioned to undertake the evaluation in 2014 when IDF-LFAC had active programs in 45 countries

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis

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

Antitumour Activity of the Poly(Adp-Ribose) Polymerase (Parp) Inhibitor Olaparib in Unselected Sporadic Castration Resistant Prostate Cancer (Crpc) in the Toparp Trial

Background: Next generation sequencing (NGS) has identified genomic aberrations causing homologous recombination (HR) DNA repair defects in sporadic, metastatic CRPC. These aberrations sensitize tumours to PARP inhibitors (PARPi) and platinum treatment. To date very little is known about these cancers. We hypothesize that single agent olaparib would be active in a subset of unselected metastatic CRPC patients and that NGS could discover putative biomarkers of response. Methods: We designed TOPARP, an open-label, investigator-initiated adaptive biomarker phase II study (CRUK/11/029) with a two-stage design to assess antitumour activity of olaparib (po = 0.05; p1 = 0.20; α = 0.02; β = 0.10; n1 = 30, n2 = 15). TOPARP-A involved recruitment of unselected sporadic, metastatic CRPC patients with retrospective evaluation of putative biomarkers of response and TOPARP-B will involve the prospective validation of predictive biomarkers to enable co-development of therapeutics and predictive biomarkers. The primary endpoint was response rate, defined as either objective response by RECIST 1.1 and/or PSA decline ≥50% and/or confirmed circulating tumour cell (CTC) count falls from ≥5 to 50%, prolonged CTC count falls and with confirmed partial response per RECIST in 5/33 patients with measurable disease. Notably, 3 responders remained on treatment for >1 year. NGS fresh biopsy analyses have identified aberrations in DNA repair genes among the responding patients including BRCA2 and ATM loss. Sequencing results, correlation with response to PARPi as well as multicolour immunofluorescence pharmacodynamics studies evaluating RAD51, 53BP1 and γH2AX will be presented. Consistent with prior studies of olaparib, anemia (9/50, 18%) and fatigue(5/50, 10%) were the most common grade >3 adverse events, with 13 (26%) patients requiring a dose reduction. Conclusions: Olaparib has antitumour activity in heavily pre-treated patients with sporadic metastatic CRPC with a 32.7% response rate and prolonged responses lasting >6 months. Several patients remain on treatment beyond 1 year. The predefined criteria for seeking a biomarker definedsubgroup were met. Exome and transcriptome studies indicate that defects in DNA repair genes including BRCA2 and ATM loss associate with olaparib sensitivity in sporadic metastatic CRPC. The identified biomarkers are being prospectively evaluated in a validation cohort (TOPARP-B)

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.

Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.)

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.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.Peer reviewe