Melanoma Expression Genes Identified through Genome-Wide Association Study of Breslow Tumor Thickness.
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ABSTRACT:
SUBMITTER: Fang S
PROVIDER: S-EPMC5183500 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
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Melanoma Expression Genes Identified through Genome-Wide Association Study of Breslow Tumor Thickness.
Fang Shenying S Vaysse Amaury A Brossard Myriam M Wang Yuling Y Deng Defeng D Liu Quan Q Zhang Peter P Xu Kejing K Li Ming M Feng Runhua R Liu Huey H Dang Yifang Y Chen Wei W Prieto Victor V Gershenwald Jeffrey E JE Ross Merrick I MI Matejka Brenna B Malke Jared J Haydu Lauren E LE Reveille John D JD Sui Dawen D Bassett Roland L RL Koshkina Nadya N Avril Marie Françoise MF Lu Mason M Wei Qingyi Q Demenais Florence F Amos Christopher I CI Lee Jeffrey E JE
The Journal of investigative dermatology 20160806 1
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Project description:Breslow thickness (BT) is a major prognostic factor of cutaneous melanoma (CM), the most fatal skin cancer. The genetic component of BT has only been explored by candidate gene studies with inconsistent results. Our objective was to uncover the genetic factors underlying BT using an hypothesis-free genome-wide approach. Our analysis strategy integrated a genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) for BT followed by pathway analysis of GWAS outcomes using the gene-set enrichment analysis (GSEA) method and epistasis analysis within BT-associated pathways. This strategy was applied to two large CM datasets with Hapmap3-imputed SNP data: the French MELARISK study for discovery (966 cases) and the MD Anderson Cancer Center study (1,546 cases) for replication. While no marginal effect of individual SNPs was revealed through GWAS, three pathways, defined by gene ontology (GO) categories were significantly enriched in genes associated with BT (false discovery rate ≤5% in both studies): hormone activity, cytokine activity and myeloid cell differentiation. Epistasis analysis, within each significant GO, identified a statistically significant interaction between CDC42 and SCIN SNPs (pmeta-int =2.2 × 10(-6) , which met the overall multiple-testing corrected threshold of 2.5 × 10(-6) ). These two SNPs (and proxies) are strongly associated with CDC42 and SCIN gene expression levels and map to regulatory elements in skin cells. This interaction has important biological relevance since CDC42 and SCIN proteins have opposite effects in actin cytoskeleton organization and dynamics, a key mechanism underlying melanoma cell migration and invasion.
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Project description:BackgroundSeveral host characteristics, including pigmentary traits (hair color, sunburn susceptibility and tanning ability), number of common nevi (moles), and family history of melanoma, have been associated with risk of melanoma.MethodsWe prospectively examined the associations between host characteristics and risk of incident melanoma by Breslow thickness (≤1 mm, thin melanoma; or >1 mm, "thicker melanoma") based on the Nurses' Health Study (NHS, n = 86,380 women), NHS II (n = 104,100 women), and Health Professionals Follow-up Study (HPFS, n = 46,934 men).ResultsDuring 22-30 years' follow-up, a total of 1,813 incident melanoma cases were identified with information on Breslow thickness, 1,392 (76.8%) of which had thin melanoma. No significant differences were observed for thin and thicker melanoma in associations with hair color, sunburn susceptibility, and tanning ability. However, we found significant differences for the association with family history of melanoma, with a higher risk estimate for thicker melanoma [HR = 2.55; 95% confidence interval (CI): 1.91-3.42] than thin melanoma (HR = 1.59; 95% CI: 1.21-2.08; P heterogeneity = 0.02). Interestingly, women and men displayed differential associations between nevi count and risk of melanoma by Breslow thickness, with the association appearing stronger for thicker melanoma than thin melanoma in men (P heterogeneity = 0.01), but not in women.ConclusionsIndividuals with family history of melanoma may be more likely to develop thicker melanoma. Men with high number of common nevi may tend to develop thicker melanoma, which was not found for women.ImpactThe findings further stress the risk of thicker melanoma for individuals with a family history of melanoma and men with a high nevi count.
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Project description:BACKGROUND: Previous studies of network properties of human disease genes have mainly focused on monogenic diseases or cancers and have suffered from discovery bias. Here we investigated the network properties of complex disease genes identified by genome-wide association studies (GWAs), thereby eliminating discovery bias. PRINCIPAL FINDINGS: We derived a network of complex diseases (n = 54) and complex disease genes (n = 349) to explore the shared genetic architecture of complex diseases. We evaluated the centrality measures of complex disease genes in comparison with essential and monogenic disease genes in the human interactome. The complex disease network showed that diseases belonging to the same disease class do not always share common disease genes. A possible explanation could be that the variants with higher minor allele frequency and larger effect size identified using GWAs constitute disjoint parts of the allelic spectra of similar complex diseases. The complex disease gene network showed high modularity with the size of the largest component being smaller than expected from a randomized null-model. This is consistent with limited sharing of genes between diseases. Complex disease genes are less central than the essential and monogenic disease genes in the human interactome. Genes associated with the same disease, compared to genes associated with different diseases, more often tend to share a protein-protein interaction and a Gene Ontology Biological Process. CONCLUSIONS: This indicates that network neighbors of known disease genes form an important class of candidates for identifying novel genes for the same disease.
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Project description:BackgroundThin nodular melanoma (NM) often lacks conspicuous melanoma-specific dermatoscopic criteria and escapes clinical detection until it progresses to a thicker and more advanced tumour.ObjectiveTo investigate the dermatoscopic morphology of thin (≤2 mm Breslow thickness) vs. thick (>2 mm) NM and to identify dermatoscopic predictors of its differential diagnosis from other nodular tumours.MethodsRetrospective, morphological case-control study, conducted on behalf of the International Dermoscopy Society. Dermatoscopic images of NM and other nodular tumours from 19 skin cancer centres worldwide were collected and analysed.ResultsOverall, 254 tumours were collected (69 NM of Breslow thickness ≤2 mm, 96 NM >2 mm and 89 non-melanoma nodular lesions). Light brown coloration (50.7%) and irregular brown dots/globules (42.0%) were most frequently observed in ≤2 mm NMs. Multivariate analysis revealed that dotted vessels (3.4-fold), white shiny streaks (2.9-fold) and irregular blue structureless area (2.4-fold) were predictors for thinner NM compared to non-melanoma nodular tumours. Overall, irregular blue structureless area (3.4-fold), dotted vessels (4.6-fold) and serpentine vessels (1.9-fold) were predictors of all NM compared to non-melanoma nodular lesions.LimitationsAbsence of a centralized, consensus pathology review and cases selected form tertiary centres maybe not reflecting the broader community.ConclusionsOur study sheds light into the dermatoscopic morphology of thin NM in comparison to thicker NM and could provide useful clues for its differential diagnosis from other non-melanoma nodular tumours.
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Project description:ObjectiveTo investigate the influence of socioeconomic status (SES) on Breslow thickness, disease-free survival, and overall survival in patients with stage I-II primary cutaneous melanoma (PCM).Patients and methodsThe study consists of all consecutive patients who were diagnosed as having PCM and were treated and followed up at our hospital between November 1, 1998, and July 31, 2009. Pathologic and sociodemographic characteristics of the patients were obtained. We categorized SES into 3 levels: low (manual employees and skilled/unskilled workers, including farmers, with primary education level), middle (nonmanual employees and clerks with middle education level), and high (professionals, executives, administrators, and entrepreneurs with tertiary education).ResultsA total of 1443 consecutive patients were evaluated. In a multivariate logistic regression analysis, sex (female vs male: odds ratio [OR], 1.37; 95% confidence interval [CI], 1.08-1.75), SES (high vs middle: OR, 1.27; 95% CI, 0.96-1.69; high vs low: OR, 1.73; 95% CI, 1.26-2.38), age (<60 vs ≥60 years: OR, 1.35; 95% CI, 1.03-1.78), and family context (single vs living with relatives: OR, 1.37; 95% CI, 0.97-1.94) were the strongest correlates of Breslow thickness. Compared with high SES, the risk of melanoma-related death, adjusted for age and sex, was 7 times higher (hazard ratio, 7.44; 95% CI, 3.27-16.93) and almost 2 times higher (hazard ratio, 1.88; 95% CI, 1.04-3.39) in patients with low SES living alone or living with relatives, respectively.ConclusionIn patients with PCM, low SES is associated with thicker melanoma and a poorer clinical outcome.
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Project description:Epidemiological evidence shows that people with thicker, or higher stage, melanomas have lower vitamin D status compared to those with thinner tumours. Evidence from experimental studies is inconsistent, but some suggest that administration of vitamin D metabolites can decrease tumour aggressiveness.Determine the relationship between vitamin D status at diagnosis and melanoma thickness (as an indicator of prognosis), in a subtropical setting with high melanoma incidence.We recruited 100 melanoma patients in Brisbane, Australia within days of their diagnosis. Data on factors previously associated with melanoma risk or prognosis were collected by questionnaire and physical examination. Serum for 25-hydroxyvitamin D3 [25(OH)D] levels was collected prior to wider excision biopsy; histological indicators of prognosis were obtained from pathology reports. We used multivariable logistic regression models to analyse the association between Breslow thickness (≥0.75 mm compared to <0.75 mm), Clark level (2-5 compared to 1) and presence of mitoses, and vitamin D status.Serum 25(OH)D <50 nmol/L (versus ≥50 nmol/L) was associated with a nearly four-fold increase in risk of having a thicker tumour (Adjusted OR = 3.82, 95% CI: 1.03, 14.14; p = 0.04, adjusted for age, sex, skin phototype, body mass index and season at diagnosis). There was no significant association with Clark level or presence of mitosis. Serum 25(OH)D levels in the highest quartile (≥69.8 nmol/L) were not associated with a more favourable prognosis.Vitamin D deficiency at the time of melanoma diagnosis is associated with thicker tumours that are likely to have a poorer prognosis. Ensuring vitamin D levels of 50 nmol/L or higher in this population could potentially result in 18% of melanomas having Breslow thickness of <0.75 mm rather than ≥0.75 mm.
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