Showing papers by "Yon-Dschun Ko published in 2013"
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Max Planck Society1, University of Cologne2, ASTRON3, University of Melbourne4, University of Göttingen5, Vanderbilt University6, Massachusetts Institute of Technology7, University of North Carolina at Chapel Hill8, VU University Amsterdam9, Memorial Sloan Kettering Cancer Center10, University of Bonn11, University of Zurich12, University of Oslo13, Heidelberg University14, University of Jena15, Drug Abuse Resistance Education16, Praxis17, French Institute of Health and Medical Research18, University of Bologna19, University of Liverpool20, Institut Gustave Roussy21
TL;DR: Support is provided for broad implementation of genome-based diagnosis of lung cancer by demonstrating the correlation between lung tumor subtype and its predominant mutations, and the benefit of genetic testing and targeted therapy in these patients.
Abstract: We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.
449 citations
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German Cancer Research Center1, National Institutes of Health2, University of Cologne3, Mayo Clinic4, University of Erlangen-Nuremberg5, Radboud University Nijmegen6, American Cancer Society7, Karolinska Institutet8, QIMR Berghofer Medical Research Institute9, University of California, Los Angeles10, University of Melbourne11, University of London12, University of Cambridge13, University of Copenhagen14, University of California, Irvine15, City of Hope National Medical Center16, Cancer Prevention Institute of California17, Stanford University18, University of Tübingen19, Bosch20, Ruhr University Bochum21, University of Hamburg22, Saarland University23, University of Eastern Finland24, Katholieke Universiteit Leuven25, University of Ulm26, Cancer Council Victoria27, Memorial Sloan Kettering Cancer Center28, Harvard University29, University of Toronto30, Curie Institute31, Agency for Science, Technology and Research32, University of Sheffield33, University of Wisconsin-Madison34, Fred Hutchinson Cancer Research Center35, Dartmouth College36, University of South Florida37, Netherlands Cancer Institute38, Carlos III Health Institute39, University of Bonn40, Peter MacCallum Cancer Centre41
TL;DR: Evidence is provided that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors, as well as potential interactions between LSP1-rs3817198 and parity and CASP8 and alcohol consumption.
Abstract: Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (P-interaction = 2.4 x 10(-6)) and between CASP8-rs17468277 and alcohol consumption (P-interaction = 3.1 x 10(-4)). Overall, the perallele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of = 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (P-interaction = 5.3 x 10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.
152 citations
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TL;DR: A needs-based approach helps to use available resources for adherence management efficiently and is associated with enhanced adherence of initially non-adherent patients, whereas initially adherent patients remain adherent for at least six cycles without specific support.
Abstract: Objective To develop and evaluate a multiprofessional modular medication management to assure adherence to capecitabine. Methods The study was conducted as a prospective, multicentred observational cohort study. All participants received pharmaceutical care consisting of oral and written information. Daily adherence was defined as percentage of days with correctly administered capecitabine doses and assessed using medication event monitoring. According to their daily adherence during the first cycle, patients were identified as initially non-adherent ( Results Seventy-three patients with various tumour entities were enrolled, 58 were initially adherent and 15 non-adherent. Median daily adherence of initially non-adherent patients increased from 85.7% to 97.6% during the observation period of six cycles. Throughout all cycles, median daily adherence of initially adherent patients was 100.0%. Daily adherence was not associated with sociodemographic and disease-related factors. No patient was non-persistent. Conclusions An early adherence screening effectively distinguishes between patients adhering and non-adhering to capecitabine. The provision of specific adherence support is associated with enhanced adherence of initially non-adherent patients, whereas initially adherent patients remain adherent for at least six cycles without specific support. Our needs-based approach helps to use available resources for adherence management efficiently.
46 citations
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TL;DR: The present study illustrates the contribution of multiple imputation of genotypes using public data repositories to standard genotyping laboratory and may facilitate the design of independent studies to validate the association between USPL1 rs7984952 and risk of Grade 3 breast tumors.
Abstract: Small ubiquitin-like modifier (SUMO) proteins are covalently attached to target proteins to modify their function. SUMO conjugation participates in processes tightly linked to tumorigenesis. Recently USPL1 (ubiquitin-specific peptidase-like (1) was identified as a SUMO isopeptidase. We report here on the first exploratory study investigating the relationship between genetic variability in USPL1 and breast cancer. Three potentially functional nonsynonymous coding SNPs (rs3742303, rs17609459, rs7984952) were genotyped in 1,021 breast cancer cases and 1,015 controls from the population-based GENICA study. We took advantage of multiple genotype imputation based on HapMap and the 1000 Genomes Project data to refine the association screening in the investigated region. Public genetic databases were also used to investigate the relationship with USPL1 expression in lymphoblastoid cell lines and breast tissue. Women homozygous for the minor C allele of rs7984952 showed a lower risk of Grade 3 breast tumors compared to TT homozygotes (OR 0.50, 95% CI 0.30-0.81). Case-only analyses confirmed the association between rs7984952 and tumor grade (OR 0.60, 95% CI 0.39-0.93). Imputation results in a 238 kb region around rs7984952 based on HapMap and the 1000 Genomes Project data were similar. No imputed variant showed an association signal stronger than rs7984952. USPL1 expression in tumor breast tissue increased with the number of C alleles. The present study illustrates the contribution of multiple imputation of genotypes using public data repositories to standard genotyping laboratory. The provided information may facilitate the design of independent studies to validate the association between USPL1 rs7984952 and risk of Grade 3 breast tumors.
16 citations
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TL;DR: The hypothesis that a HSD17B1-mediated decreased conversion of estrone to the more potent 17β-estradiol may reduce the estrogenic effects, thereby reducing the risk of developing breast cancer during long-term HRT use is supported.
Abstract: 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1) plays an important role in the biosynthesis of 17β-estradiol. The current study aimed at confirming the reduced risk of breast cancer in carriers of the non-synonymous HSD17B1_937_A>G (rs605059) polymorphism who used any hormone replacement therapy (HRT) for 10 years or longer. We performed an independent association study using four breast cancer case-control studies from Australia, Germany, and Sweden. In all, 5,777 cases and 8,189 age-matched controls of European descent were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and TaqMan. Risk estimates were calculated by interaction analysis and main effect analysis adjusted for age and study. Main effect analyses for women using any HRT for 10 years or longer (1,428 cases versus 1,724 controls) revealed a protective effect of the HSD17B1_937_G allele on breast cancer risk (OR 0.86, 95 % CI: 0.73-0.99; p = 0.048). Thus, our previous finding of a protective effect of the HSD17B1_937_G allele on HRT-associated breast cancer risk has now been confirmed both in independent large patient cohorts and a comprehensive pooled analysis supporting the hypothesis that a HSD17B1-mediated decreased conversion of estrone to the more potent 17β-estradiol may reduce the estrogenic effects, thereby reducing the risk of developing breast cancer during long-term HRT use.
8 citations
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TL;DR: The dose-dense induction S-HAM was highly feasible in patients up to the age of 80 and the duration of critical neutropenia was highly significantly reduced by more than 2 weeks from 45 days (standard) to 29 days (S-HAM) counted from day 1 of treatment.
8 citations
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TL;DR: The association of UGT1A6_19_GG with increased overall breast cancer risk is confirmed and the result from a well powered multi-stage study adds a novel candidate to the panel of validated breast cancer susceptibility loci.
Abstract: Validation of an association between the UGT1A6_19_T>G (rs6759892) polymorphism and overall breast cancer risk. A pilot study included two population-based case-control studies from Germany (MARIE-GENICA). An independent validation study comprised four independent breast cancer case-control studies from Finland (KBCP, OBCS), Germany (BBCC) and Sweden (SASBAC). The pooled analysis included 7,418 cases and 8,720 controls from all six studies. Participants were of European descent. Genotyping was done by MALDI-TOF MS and statistical analysis was performed by logistic regression adjusted for age and study. The increased overall breast cancer risk for women with the UGT1A6_19_GG genotype which was observed in the pilot study was confirmed in the set of four independent study collections (OR 1.13, 95% CI 1.05-1.22; p = 0.001). The pooled study showed a similar effect (OR 1.09, 95% CI 1.04-1.14; p = 0.001). We confirmed the association of UGT1A6_19_GG with increased overall breast cancer risk and conclude that our result from a well powered multi-stage study adds a novel candidate to the panel of validated breast cancer susceptibility loci.
8 citations