Funding sources, acknowledgements, consortia involved in study and bioinformatics tools used

Table S2: Odds ratio and 95% confidence limits for cancers associated with variants with pleiotropic associations. Figure S1: Flowchart showing analysis steps. Figure S2. Manhattan plots by chromosome for individual cancer sites. Figure S3. Results for rs11571833. Figure S4: Conditional QQ-plots.

PDF file - 197K, Table S1. Discovery set study populations. Table S2. Distribution of discovery set subjects by site, case-control status and chip. Table S3. Discovery set quality control summary. Table S4. SNPs with score-based P-values < 4 X 10-8 among 58016 SNPs for which Plink aborted the logistic regressions. Table S5. Replication set study populations. Table S6. Distribution of replication set subjects by site, case-control status and

Variants selected for replication

Purpose The pivotal trials for stroke prevention in non-valvular atrial fibrillation (NVAF) compared rivaroxaban, dabigatran, and apixaban with warfarin, as did most claims-based studies. Comparisons with phenprocoumon, the most frequently used vitamin K antagonist (VKA) in Germany, are scarce. Methods Risk of bleeding, ischemic stroke, and all-cause mortality in patients with NVAF were analyzed using data for 2010 to 2014 from a large German claims database. New users of oral anticoagulants from January 2012 to December 2013 were included and observed over 1 year. Baseline characteristics were adjusted using propensity score matching and logistic regression. Several sensitivity analyses were carried out. Results Fifty-nine thousand four hundred forty-nine rivaroxaban, 23,654 dabigatran, 4894 apixaban, and 87,997 matched phenprocoumon users were included. Adjusted hazard ratios (95% confidence intervals) compared with phenprocoumon were as follows: hospitalized bleedings: rivaroxaban 1.04 (0.97; 1.11), dabigatran 0.87 (0.77; 0.98), and apixaban 0.65 (0.50; 0.86); ischemic stroke: rivaroxaban 1.05 (0.94; 1.17), dabigatran 1.14 (0.96; 1.35), and apixaban 1.84 (1.20; 2.84); all-cause mortality: rivaroxaban 1.17 (1.11; 1.22), dabigatran 1.04 (0.95; 1.13), and apixaban 1.14 (0.97; 1.34). Conclusions With rivaroxaban, no significant differences were observed compared to phenprocoumon with regard to hospitalized bleedings or ischemic strokes. Dabigatran was associated with fewer bleedings and a similar risk of ischemic strokes compared to phenprocoumon. Apixaban was also associated with fewer bleedings but was unexpectedly associated with more ischemic strokes, possibly reflecting selective prescribing. The association of rivaroxaban with higher all-cause mortality unrelated to bleedings or strokes has been described previously but remains to be explained.

INTRODUCTION:Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes. METHODS:Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients. RESULTS:We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds. CONCLUSION:KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design.

Abstract Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.

CONTEXT:Episodic breathlessness is a frequent and burdensome symptom in cancer patients but pharmacological treatment is limited. OBJECTIVES:To determine time to onset, efficacy, feasibility, and safety of transmucosal fentanyl in comparison to immediate-release morphine for the relief of episodic breathlessness. METHODS:Phase II, investigator-initiated, multicenter, open-label, randomized, morphine-controlled, crossover trial with open-label titration of fentanyl buccal tablet (FBT) in inpatients with incurable cancer. The primary outcome was time to onset of meaningful breathlessness relief. Secondary outcomes were efficacy (breathlessness intensity difference at 10 and 30 minutes; sum of breathlessness intensity difference at 15 and 60 minutes), feasibility, and safety. Study was approved by local ethics committees. RESULTS:Twenty-five of 1341 patients were eligible, 10 patients agreed to participate (four female, mean age 58 ± 11, mean Karnofsky score 67 ± 11). Two patients died before final visits and two patients dropped-out because of disease progression leaving six patients for analysis with 61 episodes of breathlessness. Mean time to onset was for FBT 12.7 ± 10.0 and for immediate-release morphine 23.6 ± 15.1 minutes with a mean difference of -10.9 minutes (95% CI = -24.5 to 2.7, P = 0.094). Efficacy measures were predominately in favor for FBT. Both interventions were safe. Feasibility failed because of too much study demands for a very ill patient group. CONCLUSION:The description of a faster and greater relief of episodic breathlessness by transmucosal fentanyl versus morphine justifies further evaluation by a full-powered trial.

9018 Background: KRAS mutations in non-small cell lung cancer (NSCLC) still remain therapeutically untargetable. Assuming that these mutations are not mutually exclusive with other driver aberrations, we set out this study in order to describe and analyze co-occurring mutations and their potential therapeutic impact. In a subset of patients with co-occuring driver mutations, we performed additionally whole-exome sequencing (WES) to define clonal and evolutional status of the mutations. Results were compared with data from The Cancer Genome Atlas' (TCGA) for NSCLC. Methods: In a timeframe of 20 months, 4507 patients of a local screening initiative (Network Genomic Medicine Lung Cancer) were analyzed using next-generation parallel sequencing (NGS). The NGS panel consisted of 102 amplicons and 14 genes: KRAS, PIK3CA, BRAF, EGFR, ERBB2, NRAS, DDR2, TP53, ALK, CTNNB1, MET, AKT1, PTEN and MAP2K1. In subsets of patients, fluorescence in-situ hybridization (FISH) was performed for MET, FGFR1, and HER2 amplification and for RET, ALK and ROS1rearrangements. Clinical parameters, therapy, survival and smoking status were also collected. Results: We identified 1207 patients (26.8%) harboring a KRAS mutation, whereof 1080 patients (89.5%) underwent the complete diagnostic panel. The most common mutation was G12C accounting for 41.2%. In a total of 308 patients (28.8%) additional aberrations could be detected, including MET (prevalence 15.3%), FGFR1 (5.0%) and HER2 (12.7%) amplification and mutations in PIK3CA (3.4%), DDR2 (4.4%), PTEN (1.9%), CTNNB1 (1.7%), BRAF (1.3%) and EGFR (1.4%). Less frequently, mutations within NRAS, AKT1, ALK, MET, and MAP2K1 could be detected. 459 patients (42.9%) had co-occurring TP53mutations.. WES on selected cases confirmed the presence of these mutations. Conclusions: To our knowlege our data represent the largest analysis of co-occuring mutations in KRAS- mutated NSCLC. They show that KRAS-mutated NSCLC represents a heterogenous group of tumors with a substantial portion harboring a wide spectrum of additional targetable mutations. Further studies will show whether these findings translate into new therapeutic options in KRAS-mutated NSCLC.

INTRODUCTION:Rearrangements of RET are rare oncogenic events in patients with non-small cell lung cancer (NSCLC). While the characterization of Asian patients suggests a predominance of nonsmokers of young age in this genetically defined lung cancer subgroup, little is known about the characteristics of non-Asian patients. We present the results of an analysis of a European cohort of patients with RET rearranged NSCLC. METHODS:Nine hundred ninety-seven patients with KRAS/EGFR/ALK wildtype lung adenocarcinomas were analyzed using fluorescence in situ hybridization for RET fusions. Tumor specimens were molecularly profiled and clinicopathological characteristics of the patients were collected. RESULTS:Rearrangements of RET were identified in 22 patients, with a prevalence of 2.2% in the KRAS/EGFR/ALK wildtype subgroup. Co-occurring genetic aberrations were detected in 10 patients, and the majority had mutations in TP53. The median age at diagnosis was 62 years (range, 39-80 years; mean ± SD, 61 ± 11.7 years) with a higher proportion of men (59% versus 41%). There was only a slight predominance of nonsmokers (54.5%) compared to current or former smokers (45.5%). CONCLUSIONS:Patients with RET rearranged adenocarcinomas represent a rare and heterogeneous NSCLC subgroup. In some contrast to published data, we see a high prevalence of current and former smokers in our white RET cohort. The significance of co-occurring aberrations, so far, is unclear.

Nat. Genet. 42, 880–884 (2010); published online 19 September 2010; corrected after print 7 December 2015 In the version of this article initially published, the name of author Angela Brooks-Wilson was spelled incorrectly in the author list. The error has been corrected in the HTML and PDF versions of the article.

The goal of this study was to compare two types of rehabilitation for geriatric patients with femoral fracture in Germany, i.e. care in geriatric hospital departments (A 109 SGB V) and care in geriatric out-of-hospital rehabilitation facilities (A 111 SGB V). Based on claims data of the AOK ("Allgemeine Ortskrankenkasse" = local insurance fund) insurants with a documented hospital stay with discharge diagnosis fracture of the femur in 2007 (n = 25,954) were included and allocated to the respective form of rehabilitative health care via the OPS (German procedure classification for inpatient procedures) procedure 8-550 (A 109, n = 2028) or via admission to a geriatric rehabilitation unit (A 111, n = 4061). Excess costs (costs in the first year after fracture -aEuro parts per thousand costs in the previous year), risk of rehospitalization due to femoral fracture, and risk of death during the 1-year follow-up were compared using multivariate regression analyses. No significant differences were observed related to the outcomes rehospitalization due to femoral fracture and death. However, slight but significantly higher excess costs were observed in the health care type A 109 (compared to A 111) in patients with low excess costs. Moreover, insured members treated according to health care type A 109 were more often receiving long-term care. Further analyses including qualitative endpoints, e.g., achievements of rehabilitation aims, are warranted.

This study evaluated the impact of preenrichment on the detection of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) in clinical stool samples. ESBL-E were detected in 41 of 343 patients (12.0%). As 31.7% of the ESBL-E carriers were identified by preenrichment, only this additional diagnostic step significantly improved the detection of ESBL-E.

Diese Studie vergleicht die rehabilitative Behandlung von Patienten mit Femurfraktur zwischen geriatrischer frührehabilitativer Komplexbehandlung (§109 SGB V) und geriatrischer Anschlussrehabilitation (§111 SGB V).

Gordon Fehringer, Peter Kraft, Christopher A. Haiman , Paul Pharoah, Rosalind Eeles, Nilanjan Chatterjee, Fred Schumacher, Joellen Schildkraut, Paul Brennan, Heike Bickeböller, Richard Houlston, Maria Teresa Landi, Neil Caporaso, Angela Risch, Ali Amin Al Olama, Sonja I Berndt, Edward Giovannucci, Henrik Grönberg, Zsofia Kote-Jarai, Jing Ma, Kenneth Muir, Meir Stampfer, Victoria L. Stevens, Fredrik Wiklund, Walter Willett, Ellen L. Goode, Jenny Permuth-Wey, Harvey Risch, Brett M. Reid, Stephane Bezieau, Hermann Brenner, Andrew T. Chan, Thomas J. Hudson, Jonathan K Kocarnik, Polly A. Newcomb, Robert E. Schoen, Martha L. Slattery, Emily White, Muriel Adank on behalf of Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Habibul Ahsan , Kristiina Aittomäki, Laura Baglietto, Sonja Berndt, Carl Blomquist, Federico Canzian, Kamila Czene , Isabel dos-Santos-Silva , A. Heather Eliassen, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Montserrat Garcia-Closas, Mia M. Gaudet, Nichola Johnson, Per Hall , Aditi Hazra, Rebecca Hein , Albert Hofman, John L. Hopper, Astrid Irwanto, Mattias Johansson, Rudolf Kaaks, Muhammad G. Kibriya, Peter Lichtner, Sara Lindström, Jianjun Liu, Eiliv Lund, Enes Makalic, Alfons Meindl, Bertram Müller-Myhsok, Taru A. Muranen, Heli Nevanlinna, Petra H. Peeters, Julian Peto, Ross L. Prentice, Nazneen Rahman, Maria Jose Sanchez, Daniel F. Schmidt, Rita K. Schmutzler, Melissa C. Southey, Rulla Tamimi, Ruth C. Travis, Clare Turnbull, Andre G. Uitterlinden, Zhaoming Wang, Alice S. Whittemore, Rose Yang, Wei Zheng , Thorunn Rafnar, Julius Gudmundsson, Simon N Stacey, Kari Stefansson, Patrick Sulem, The PRACTICAL Consortium, Ovarian Cancer Association Consortium (OCAC), Y. Ann Chen, Jonathan P. Tyrer, David C. Christiani, Yongyue Wei, African American Breast Cancer Consortium (AABC), African Ancestry Prostate Cancer Consortium (AAPC), Japanese American Prostate Cancer Consortium (JAPC), Latino American Breast Cancer Consortium (LABC), Latino American Prostate Cancer Consortium (LAPC), Hongbing Shen, Dr Zhibin Hu , Xiao-Ou Shu, Kouya Shiraishi, Atsushi Takahashi, Yohan Bossé, Ma'en Obeidat, David Nickle, Wim Timens, Matthew L. Freedman, Qiyuan Li, Daniela Seminara, Stephen J. Chanock, Jian Gong, Ulrike Peters, Stephen Gruber on behalf of Colorectal Transdisciplinary (CORECT) Study, Christopher I. Amos, Thomas A. Sellers, Douglas Easton, David J Hunter, Brian E. Henderson, Rayjean J Hung.

AbstractEarly-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10−8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10−4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10−6. In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658–69. ©2014 AACR.