Influence of Genetic Variants in TPMT and COMT Associated with Cisplatin Induced Hearing Loss in Patients with Cancer:Two New Cohorts and a Meta-Analysis Reveal Significant Heterogeneity between Cohorts

Treatment with cisplatin-containing chemotherapy regimens causes hearing loss in 40-60% of cancer patients. It has been suggested that genetic variants in the genes encoding thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) can predict the development of cisplatin-induced ototoxicity and may explain interindividual variability in sensitivity to cisplatin-induced hearing loss. Two recently published studies however, sought to validate these findings and showed inconsistent results. The aim of this study was to evaluate the role of polymorphisms in the TPMT and COMT genes in cisplatin-induced ototoxicity. Therefore we investigated two independent cohorts of 110 Dutch and 38 Spanish patients with osteosarcoma and performed a meta-analysis including all previously published studies resulting in a total population of 664 patients with cancer. With this largest meta-analysis performed to date, we show that the influence of TPMT and COMT on the development of cisplatin-induced hearing loss may be less important than previously suggested

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. Methods We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). Results We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively;P-value < 5x10(-8)) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84x10(-8)). Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. Impact Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Forest plots genetic variants in <i>COMT</i> gene.

<p>Forest plots genetic variants in <i>COMT</i> gene.</p

Demographic data of patients with ototoxicity included for meta-analysis.

<p>Demographic data of patients with ototoxicity included for meta-analysis.</p

Forest plots genetic variants in <i>TPMT</i> gene.

<p>Forest plots genetic variants in <i>TPMT</i> gene.</p

Demographic data of the Dutch and Spanish cohort.

<p>Demographic data of the Dutch and Spanish cohort.</p

Eficácia do LED vermelho no aumento da densidade capilar na alopécia androgenética - um estudo autocontrolado

A alopécia androgenética é o tipo de perda capilar mais comum com prejuízo da imagem corporal e qualidade de vida. A fototerapia segura e barata, estimula a proliferação celular e o crescimento capilar, mas não se sabe quais os parâmetros ótimos para este efeito. Avaliar a eficácia do LED de655 nm e 5 mW, durante 7 semanas, no tratamento da alopécia androgenética e compara o seu efeito relativamente ao sexo, tabagismo e presença de caspa. Estudo autocontrolado com 5 homens e 4 mulheres, saudáveis, com alopécia androgenética, com idades entre os 19 e os 54 anos, aos quais foi aplicado LED vermelho num lado do couro cabeludo, aleatório, três vezes por semana em dias não concutíveis, durante 7 semanas. Foram avaliados no momento inicial e após 7 semanas a densidade capilar total, a densidade de cabelos anágenos, terminais e velos e a densidade das diferentes unidades foliculares, através da recolha com o Dino-Lite Edge Digital Microscope AM4115ZT e DinoCapture Software 2.0 com o Software TrichoSciencepro® v.17. Analisaram-se os resultados através dos testes Wilcoxone Mann-Whitney com nível de significância de 0,05. Não se verificaram diferenças significativas nas densidades capilares após a aplicação de LED vermelho. Observou-se um aumento da densidade de cabelos terminais no lado intervencionado, não significativo; um aumento da densidade de cabelos terminais significativo nos indivíduos sem caspa comparativamente aos com caspa; não foram verificadas diferenças significativas no lado intervencionado entre sexos nem entre fumadores e não fumadores, estes últimos com um aumento das densidades de cabelos anágenos e terminais contrariamente aos fumadores. Na avaliação global do couro cabeludo não se verificaram diferenças significativas, apesar da observação de uma melhoria em mais casos no lado intervencionado, coerente com os resultados da avaliação subjetiva dos participantes. A aplicação de 1J/cm2 de LED de 655 nm e 5 mW três vezes por semana durante 7 semanas pode promover o aumento da densidade capilar apenas em alguns indivíduos com AAG, que pode ser prejudicado por fatores como caspa e tabagismo, mas não pelo sexo. São necessários estudos com amostra e duração maiores, com grupo controlo/placebo, comparando os diferentes parâmetros de aplicação da fototerapia de baixa potência