Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Downregulation of histone H2A and H2B pathways is associated with anthracycline sensitivity in breast cancer

Abstract Background Drug resistance in breast cancer is the major obstacle to effective treatment with chemotherapy. While upregulation of multidrug resistance genes is an important component of drug resistance mechanisms in vitro, their clinical relevance remains to be determined. Therefore, identifying pathways that could be targeted in the clinic to eliminate anthracycline-resistant breast cancer remains a major challenge. Methods We generated paired native and epirubicin-resistant MDA-MB-231, MCF7, SKBR3 and ZR-75-1 epirubicin-resistant breast cancer cell lines to identify pathways contributing to anthracycline resistance. Native cell lines were exposed to increasing concentrations of epirubicin until resistant cells were generated. To identify mechanisms driving epirubicin resistance, we used a complementary approach including gene expression analyses to identify molecular pathways involved in resistance, and small-molecule inhibitors to reverse resistance. In addition, we tested its clinical relevance in a BR9601 adjuvant clinical trial. Results Characterisation of epirubicin-resistant cells revealed that they were cross-resistant to doxorubicin and SN-38 and had alterations in apoptosis and cell-cycle profiles. Gene expression analysis identified deregulation of histone H2A and H2B genes in all four cell lines. Histone deacetylase small-molecule inhibitors reversed resistance and were cytotoxic for epirubicin-resistant cell lines, confirming that histone pathways are associated with epirubicin resistance. Gene expression of a novel 18-gene histone pathway module analysis of the BR9601 adjuvant clinical trial revealed that patients with low expression of the 18-gene histone module benefited from anthracycline treatment more than those with high expression (hazard ratio 0.35, 95 % confidence interval 0.13–0.96, p = 0.042). Conclusions This study revealed a key pathway that contributes to anthracycline resistance and established model systems for investigating drug resistance in all four major breast cancer subtypes. As the histone modification can be targeted with small-molecule inhibitors, it represents a possible means of reversing clinical anthracycline resistance. Trial registration ClinicalTrials.gov identifier NCT00003012 . Registered on 1 November 1999

Effects of continuous versus bolus infusion of enteral nutrition in critical patients Efeitos da administração contínua versus intermitente da nutrição enteral em pacientes críticos

PURPOSE: Enteral alimentation is the preferred modality of support in critical patients who have acceptable digestive function and are unable to eat orally, but the advantages of continuous versus intermittent administration are surrounded by controversy. With the purpose of identifying the benefits and complications of each technique, a prospective controlled study with matched subjects was conducted. PATIENTS AND METHODS: Twenty-eight consecutive candidates for enteral feeding were divided into 2 groups (n = 14 each) that were matched for diagnosis and APACHE II score. A commercial immune-stimulating polymeric diet was administered via nasogastric tube by electronic pump in the proportion of 25 kcal/kg/day, either as a 1-hour bolus every 3 hours (Group I), or continuously for 24 hours (Group II), over a 3-day period. Anthropometrics, biochemical measurements, recording of administered drugs and other therapies, thorax X-ray, measurement of abdominal circumference, monitoring of gastric residue, and clinical and nutritional assessments were performed at least once daily. The principal measured outcomes of this protocol were frequency of abdominal distention and pulmonary aspiration, and efficacy in supplying the desired amount of nutrients. RESULTS: Nearly half of the total population (46.4%) exhibited high gastric residues on at least 1 occasion, but only 1 confirmed episode of pulmonary aspiration occurred (3.6%). Both groups displayed a moderate number of complications, without differences. Food input during the first day was greater in Group II (approximately 20% difference), but by the third day, both groups displayed similarly small deficits in total furnished volume of about 10%, when compared with the prescribed diet. CONCLUSIONS: Both administration modalities permitted practical and effective administration of the diet with frequent registered abnormalities but few clinically significant problems. The two groups were similar in this regard, without statistical differences, probably because of meticulous technique, careful monitoring, strict patient matching, and conservative amounts of diet employed in both situations. Further studies with additional populations, diagnostic groups, and dietetic prescriptions should be performed in order to elucidate the differences between these commonly used feeding modalities.<br>ANTECEDENTES: A alimentação enteral é a modalidade preferida de suporte em pacientes graves com função digestiva aceitável porém incapazes de se alimentar por via oral, entretanto as vantagens da oferta contínua em contraste com a intermitente são rodeadas de controvérsias. Tendo como objetivo identificar os benefícios e as complicações destas técnicas, realizou-se um estudo prospectivo e controlado com casos pareados. PACIENTES E MÉTODOS: Vinte e oito pacientes consecutivos candidatos a alimentação enteral foram divididos em dois Grupos (n= 14), pareados segundo diagnóstico e índice APACHE II.Uma dieta polimérica comercial imuno-estimulante foi administrada por sonda nasogástrica e bomba de infusão na proporção de 25 kcal/kg/dia, em forma de bolo por uma hora a cada três horas (Grupo I), ou continuamente nas 24 horas (Grupo II), durante três dias. Os métodos incluiram antropometria, dosagens bioquímicas, registro de uso de drogas e outras terapêuticas, RX de tórax, circunferência abdominal, resíduo gástrico, e avaliação clínica e nutricional, efetuada no mínimo uma vez por dia. Os principais desfechos colimados neste estudo foram frequência de distensão abdominal e aspiração pulmonar, e capacidade de atingir a meta calórica pretendida. RESULTADOS: Quase metade da população total (46,4%) apresentou resíduos gástricos elevados em pelo menos uma ocasião, porém somente foi registrado um episódio confirmado de aspiração pulmonar (3,6%). Ambos os grupos padeceram de um número moderado de complicações, sem diferenças. O ganho de dieta no Grupo II foi maior no primeiro dia, porém no terceiro dia ambos os grupos exibiam déficits pequenos e semelhantes no ganho dietético, quando comparados com o volume prescrito. CONCLUSÕES: Ambas as modalidades de oferta permitiram a administração prática e eficiente da dieta, com freqüentes anormalidades registradas porém escassas complicações clinicamente significativas. Os dois grupos se comportaram analogamente, com poucas diferenças nos resultados, provavelmente devido à técnica meticulosa, monitorização cuidadosa, rígido pareamento dos pacientes, e volumes modestos da dieta empregados nas duas circunstâncias. Investigações subseqüentes deveriam ser elaboradas com populações, grupos diagnósticos e prescrições dietéticas adicionais, a fim de elucidar as diferenças entre estas modalidades de alimentação comumente usadas