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Sökning: WFRF:(Hoiom Veronica)

  • Resultat 1-10 av 27
  • [1]23Nästa
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1.
  • Tuominen, Rainer, et al. (författare)
  • Investigation of a putative melanoma susceptibility locus at chromosome 3q29
  • 2014
  • Ingår i: Cancer Genetics. - : Elsevier. - 2210-7762 .- 2210-7770. ; 207:3, s. 70-74
  • Tidskriftsartikel (refereegranskat)abstract
    • Malignant melanoma, the most fatal form of skin cancer, is currently increasing in incidence in many populations. Approximately 10% of all cases occur in families with an inherited predisposition for melanoma. In Sweden, only a minor portion of such melanoma families carry a mutation in the known melanoma gene CDKN2A, and there is a need to identify additional melanoma susceptibility genes. In a recently performed genome-wide linkage screen, novel loci with suggestive evidence of linkage to melanoma were detected. In this study, we have further analyzed one region on chromosome 3q29. In all, 89 affected and 15 nonaffected family members from 42 melanoma-prone families were genotyped for 34 genetic markers. In a pooled linkage analysis of all 42 families, we detected significant evidence of linkage, with a maximum heterogeneity logarithm of odds (HLOD) score of 3.1 with 83% of the families contributing to the linkage score. The minimum critical region of linkage (defined by a 1LOD score support interval) maps to chromosome 3q29, spans 3.5 Mb of genomic sequence, and harbors 44 identified genes. Sequence variants within this region have previously been associated with cancer susceptibility. This study reports the presence of a putative novel melanoma susceptibility locus in the Swedish population, a finding that needs to be replicated in an independent study on other individuals with familial melanoma. Sequencing of genes in the region may identify novel melanoma-associated mutations.
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2.
  • Barrett, Jennifer H., et al. (författare)
  • Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions
  • 2015
  • Ingår i: International Journal of Cancer. - : John Wiley and Sons Inc.. - 0020-7136 .- 1097-0215. ; 136:6, s. 1351-1360
  • Tidskriftsartikel (refereegranskat)abstract
    • At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps toward accounting for some of the missing heritability. What's new? In genome-wide association studies, researchers identify genetic variants that frequently associate with a particular disease, though the variants identified may not contribute to the molecular cause of the disease. This study took a closer look at 17 regions associated with melanoma, fine mapping the regions both in people with melanoma and in healthy controls. Though single SNPs account for the association in some regions, they found that in a few regions, several SNPs - and possibly multiple genes - contributed to the association signal. These findings illustrate the importance of not overlooking the interaction between multiple genetic markers when conducting such studies.
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3.
  • Bishop, D. Timothy, et al. (författare)
  • Genome-wide association study identifies three loci associated with melanoma risk
  • 2009
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 41:8, s. 920-925
  • Tidskriftsartikel (refereegranskat)abstract
    • We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317K tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional two cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genome-wide screen identified five loci with genotyped or imputed SNPs reaching P < 5 x 10(-7). Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 x 10(-27) for rs258322), 11q14-q21 encompassing TYR (P = 2.41 x 10(-14) for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 x 10(-7) for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognized melanoma risk factors. Common variants within the 9p21 locus have not previously been associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.
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4.
  • Helgadottir, H., et al. (författare)
  • Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations
  • 2020
  • Ingår i: Journal of Medical Genetics. - : BMJ Publishing Group. - 0022-2593 .- 1468-6244. ; 57:5, s. 316-321
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated. Methods CDKN2A mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers' responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic CDKN2A mutation were analysed for association with tumour mutational load. Results Eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic CDKN2A mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without CDKN2A mutation (Wilcoxon test, p<0.001). Conclusion Patients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.
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5.
  • Hoiom, Veronica, et al. (författare)
  • MC1R variation and melanoma risk in the Swedish population in relation to clinical and pathological parameters
  • 2009
  • Ingår i: Pigment Cell & Melanoma Research. - : Wiley-Blackwell. - 1755-148X .- 1755-1471. ; 22:2, s. 196-204
  • Tidskriftsartikel (refereegranskat)abstract
    • The genetic background of cutaneous malignant melanoma (CMM) includes both germ line aberrations in high-penetrance genes, like CDKN2A, and allelic variation in low-penetrance genes like the melanocortin-1 receptor gene, MC1R. Red-hair colour associated MC1R alleles (RHC) have been associated with red hair, fair skin and risk of CMM. We investigated MC1R and CDKN2A variation in relation to phenotype, clinical factors and CMM risk in the Swedish population. The study cohort consisted of sporadic primary melanoma patients, familial melanoma patients and a control group. An allele-dose dependent increase in melanoma risk for carriers of variant MC1R alleles (after adjusting for phenotype), with an elevated risk among familial CMM patients, was observed. This elevated risk was found to be significantly associated with an increased frequency of dysplastic nevi (DN) among familial patients compared to sporadic patients. MC1R variation was found to be less frequent among acral lentiginous melanomas (ALM) and dependent on tumour localisation. No association was found between CDKN2A gene variants and general melanoma risk. Two new variants in the POMC gene were identified in red haired individuals without RHC alleles.
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6.
  • Iles, Mark M., et al. (författare)
  • A variant in FTO shows association with melanoma risk not due to BMI
  • 2013
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 45:4, s. 428-432
  • Tidskriftsartikel (refereegranskat)abstract
    • We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 x 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanomasusceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
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7.
  • Iles, Mark M., et al. (författare)
  • The Effect on Melanoma Risk of Genes Previously Associated With Telomere Length
  • 2014
  • Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 1460-2105. ; 106:10, s. 267-267
  • Tidskriftsartikel (refereegranskat)abstract
    • Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11 108 case patients and 13 933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.
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8.
  • Tuominen, Rainer, et al. (författare)
  • The Role of Germline Alterations in the DNA Damage Response Genes BRIP1 and BRCA2 in Melanoma Susceptibility
  • 2016
  • Ingår i: Genes, Chromosomes and Cancer. - : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 55:7, s. 601-611
  • Tidskriftsartikel (refereegranskat)abstract
    • We applied a targeted sequencing approach to identify germline mutations conferring a moderately to highly increased risk of cutaneous and uveal melanoma. Ninety-two high-risk melanoma patients were screened for inherited variation in 120 melanoma candidate genes. Observed gene variants were filtered based on frequency in reference populations, cosegregation with melanoma in families and predicted functional effect. Several novel or rare genetic variants in genes involved in DNA damage response, cell-cycle regulation and transcriptional control were identified in melanoma patients. Among identified genetic alterations was an extremely rare variant (minor allele frequency of 0.00008) in the BRIP1 gene that was found to cosegregate with the melanoma phenotype. We also found a rare nonsense variant in the BRCA2 gene (rs11571833), previously associated with cancer susceptibility but not with melanoma, which showed weak association with melanoma susceptibility in the Swedish population. Our results add to the growing knowledge about genetic factors associated with melanoma susceptibility and also emphasize the role of DNA damage response as an important factor in melanoma etiology. (C) 2016 Wiley Periodicals, Inc.
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9.
  • Vikingsson, Svante, et al. (författare)
  • Simple and cost-effective liquid chromatography-mass spectrometry method to measure dabrafenib quantitatively and six metabolites semi-quantitatively in human plasma
  • 2017
  • Ingår i: Analytical and Bioanalytical Chemistry. - : SPRINGER HEIDELBERG. - 1618-2642 .- 1618-2650. ; 409:15, s. 3749-3756
  • Tidskriftsartikel (refereegranskat)abstract
    • Dabrafenib is an inhibitor of BRAF V600E used for treating metastatic melanoma but a majority of patients experience adverse effects. Methods to measure the levels of dabrafenib and major metabolites during treatment are needed to allow development of individualized dosing strategies to reduce the burden of such adverse events. In this study, an LC-MS/MS method capable of measuring dabrafenib quantitatively and six metabolites semi-quantitatively is presented. The method is fully validated with regard to dabrafenib in human plasma in the range 5-5000 ng/mL. The analytes were separated on a C18 column after protein precipitation and detected in positive electrospray ionization mode using a Xevo TQ triple quadrupole mass spectrometer. As no commercial reference standards are available, the calibration curve of dabrafenib was used for semi-quantification of dabrafenib metabolites. Compared to earlier methods the presented method represents a simpler and more cost-effective approach suitable for clinical studies.
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10.
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  • Resultat 1-10 av 27
  • [1]23Nästa
 
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