| 1. |
- Davies, John R, et al.
(författare)
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Inherited variation in the PARP1 gene and survival from melanoma
- 2014
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 135:7, s. 1625-1633
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Tidskriftsartikel (refereegranskat)abstract
- We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04-1.28, p=0.005, eleven cohorts) and MSS (HR=1.20 per allele, 95% CI 1.01-1.39, p=0.03, eight cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS. What's new? Although staging systems predict outcome fairly well for melanoma, survival still varies among individual patients. In this meta-analysis, the authors found that inheritance of a rare genetic variant of PARP1 was associated with improved survival of melanoma patients. Increased expression of PARP1 has been associated with poorer outcome, and depletion of PARP1 may reduce both melanoma growth and angiogenesis. The identification of this and other germline variants that affect survival may help to identify key biological pathways active in host/tumor interactions, which may lead to the discovery of new therapeutic targets for treating advanced melanoma. Epidemiology
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| 2. |
- Nsengimana, Jérémie, et al.
(författare)
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Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort.
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:13, s. 11683-11693
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Tidskriftsartikel (refereegranskat)abstract
- Development and validation of robust molecular biomarkers has so far been limited in melanoma research. In this paper we used a large population-based cohort to replicate two published gene signatures for melanoma classification. We assessed the signatures prognostic value and explored their biological significance by correlating them with factors known to be associated with survival (vitamin D) or etiological routes (nevi, sun sensitivity and telomere length). Genomewide microarray gene expressions were profiled in 300 archived tumors (224 primaries, 76 secondaries). The two gene signatures classified up to 96% of our samples and showed strong correlation with melanoma specific survival (P=3x10-4), Breslow thickness (P=5x10-10), ulceration (P=9.x10-8) and mitotic rate (P=3x10-7), adding prognostic value over AJCC stage (adjusted hazard ratio 1.79, 95%CI 1.13-2.83), as previously reported. Furthermore, molecular subtypes were associated with season-adjusted serum vitamin D at diagnosis (P=0.04) and genetically predicted telomere length (P=0.03). Specifically, molecular high-grade tumors were more frequent in patients with lower vitamin D levels whereas high immune tumors came from patients with predicted shorter telomeres. Our data confirm the utility of molecular biomarkers in melanoma prognostic estimation using tiny archived specimens and shed light on biological mechanisms likely to impact on cancer initiation and progression.
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