Common variants in breast cancer risk loci predispose to distinct tumor subtypes.

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.NovartisEli Lilly and CompanyAstraZenecaAbbViePfizer UKCelgeneEisaiGenentechMerck Sharp and DohmeRocheCancer Research UKGovernment of CanadaArray BioPharmaGenome CanadaNational Institutes of HealthEuropean CommissionMinistère de l'Économie, de l’Innovation et des Exportations du QuébecSeventh Framework ProgrammeCanadian Institutes of Health Researc

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

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

Lactated Ringer versus albumin in early sepsis therapy (the RASP study): a randomized clinical trial

Introdução: Nos últimos anos, o uso de albumina para ressuscitação nos pacientes com sepse tem se mostrado controverso. O objetivo deste estudo foi avaliar os efeitos da administração de uma solução de albumina em cristaloide (Ringer lactato comparada a uma solução cristaloide (Ringer lactato) em pacientes com câncer e sepse. Local: Unidade de Terapia Intensiva do Instituto do Câncer do Estado de São Paulo, Brasil. Métodos: Estudo unicêntrico, randomizado, duplo-cego, controlado, entre outubro de 2014 e dezembro de 2016. Pacientes com câncer e sepse grave ou choque séptico foram aleatoriamente alocados para receber infusão intravenosa de bolus de 500 mL de albumina a 4% ou solução de cristaloide (Ringer lactato) durante as 6 primeiras horas da ressuscitação volêmica. O desfecho primário foi definido como morte por qualquer causa em 7 dias. Desfecho primário: taxa de mortalidade em 7 dias. Desfechos secundários: morte por qualquer causa em 28 dias, escore de SOFA (sequence organ failur eassessment) em 7 dias, necessidade de ventilação mecânica, uso de agentes vasopressores e necessidade de terapia de substituição renal durante a internação na Unidade de Terapia Intensiva (UTI), tempo de internação na UTI e tempo de internação hospitalar. Resultados: Foi incluído na análise final o total de 360 pacientes, sendo 180 alocados no grupo albumina e 180 no grupo cristaloide. Em 7 dias, 46 dos 180 pacientes (25,6%) do grupo albumina e 40 dos 180 pacientes do grupo cristaloide (22,2%) morreram (diferença absoluta 3,4%; intervalo de confiança [IC] 95% -5,5 a 12,1%; P=0,458). Em 28 dias, 96 dos 180 pacientes do grupo albumina (53,3%) e 83 dos 180 pacientes do grupo cristaloide (46,1%) morreram (diferença absoluta 7,2%; IC95% -3,1 a 17,3%; P=0,171). Não houve diferença nos desfechos secundários entre os grupos. Conclusões: a utilização da solução de albumina com cristaloide comparada com a solução de cristaloide pura, durante a fase aguda de ressuscitação volêmica da sepse em pacientes com câncer não melhorou a taxa de sobrevida em 7 ou 28 dias. ClinicalTrials: NCT01337934Background: In the last years, the use of albumin to resuscitate septic patients became highly controversial. The aim of his study was to investigate the effects of the administration of albumin and crystalloids, as compared with crystalloids alone, in a population of cancer patients with sepsis. Methods: We performed a single center, randomized, double-blind, controlled-parallel trial between October 2014 and December 2016 at the Cancer Institute of the University of Sao Paulo, Brazil. Cancer patients with severe sepsis or septic shock were randomly assigned to receive either bolus of 500 mL of 4% albumin on crystalloid solution or crystalloid solution alone during the first 6 hours of fluid resuscitation. Primary outcome was defined as death from any cause at 7 days. Secondary outcomes were death from any cause at 28 days, the Sequence Organ Failure Assessment (SOFA) in 7 days, requirements of invasive mechanical ventilation, vasopressor therapy and renal replacement therapy during ICU stay, and length of stay in the ICU and in the hospital. Results: A total of 360 patients were included. At 7 days, 46 of 180 patients (25.6%) in the albumin group and 40 of 180 patients (22.2%) in the crystalloid group had died (absolute difference 3.4%; 95% confidence interval [CI], -5.5 to 12.1%; P=0.458). At 28 days, 96 of 180 patients (53.3%) in the albumin group and 83 of 180 patients (46.1%) in the crystalloid group had died (absolute difference 7.2%; 95%CI -3.1 to 17.3%; P=0.171). No significant differences in other secondary outcomes were observed between groups. Conclusions: The use of albumin replacement in addition to crystalloids, as compared with crystalloids alone, during the early phase of fluid resuscitation of cancer patients with sepsis did not improve the rate of survival at 7 and 28 days. Trial Registration: NCT0133793

Ten-year follow-up of kidney transplantation with living unrelated donor

INTRODUÇÃO: No contexto atual da elevada escassez de órgãos para o transplante renal e do reconhecimento cada vez maior da rejeição crônica mediada por anticorpos anti-HLA como uma importante causa de perda do enxerto, uma contínua demonstração da boa evolução a longo prazo de transplantes renais com doadores vivos não aparentados (DVNA) é de suma importância. OBJETIVOS: Analisar a sobrevida do enxerto e dos pacientes transplantados com DVNA, e compará-la com doadores vivos aparentados (DVA). MÉTODOS: Foram analisados 389 primeiros transplantes renais com doador vivo realizados em um único centro, entre janeiro de 1998 e dezembro de 2007, 281 com DVA e 108 com DVNA. RESULTADOS: Não houve diferença significativa na sobrevida dos pacientes (89,1% vs. 84,7%, p = 0,40) e do enxerto (81,1% vs. 68,9%, p = 0,77), em 10 anos de seguimento, entre DVA e DVNA, respectivamente. Na análise multivariada do modelo de regressão proporcional de Cox, a reatividade contra painel (PRA) &gt; 10% e a ocorrência de rejeição aguda no 1º ano após o transplante foram os únicos preditores independentes de perda do enxerto (OR 2,54, IC 95% 1,35 - 4,78; p < 0,05 e OR 4,1, IC 95% 2,04 -4,78; p < 0,05, respectivamente). CONCLUSÃO: Transplantes renais com DVNA representam uma importante fonte de órgãos para suprir uma crescente demanda, com resultados semelhantes aos transplantes com DVA, independente da compatibilidade HLA.INTRODUCTION: In the current era of scarcity of kidneys available for transplantation, and chronic anti-HLA-mediated rejection as a main cause of graft loss, continuous demonstration of the long-term survival of grafts from living unrelated kidney donors (LURD) is paramount. OBJECTIVE: Analyze long-term kidney graft and patient outcomes using LURD, and compare them with living related donors (LRD). METHODS: We analyzed the 389 first renal transplantations performed with a living donor (281 LRD and 108 LURD), in a single center, from January 1998 through December 2007. RESULTS: There were no significant differences between LRD and LURD as refers to patient survival (89.1% vs. 84.7%, p = 0.40, respectively) and graft survival (81.1% vs. 68.9%, p = 0.77, respectively), 10 years post-transplantation. On Cox proportional regression model of multivariate analysis, panel reactive antibodies (PRA) &gt; 10% and the occurrence of acute rejection in the first year posttransplantation were the only independent predictors of graft loss (HR 2.54, 95% CI 1.35 -4.78; p < 0.05 and HR 4.1, 95% CI 2.04 - 4.78; p < 0.05, respectively). CONCLUSION: LURD are an important source of organs for renal transplantation, with results similar to those obtained with LRD, regardless of HLA matching