Inherited variation in the PARP1 gene and survival from melanoma

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.

The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis

“…Observed tumor immunogenicity modulates prognosis of cutaneous melanoma and varies greatly on the individual level (3, 4), suggesting that different capacities of the immune system control tumor growth (5, 6). The germline genetic factors emerge as possible novel, personalized markers of cancer outcomes, including melanoma (7–11), some exhibiting putative immunoregulatory capabilities with tumor impact and therefore representing plausible modulators of observed individual immune-response heterogeneity (12). In general, the germline associations with clinical outcome of complex disease traits found in small candidate studies are difficult to interpret and often need validation in larger cohorts.…”

PARP1 polymorphisms play opposing roles in melanoma occurrence and survival

“…However, rs3219090 is on both arrays, and this SNP is in strong linkage disequilibrium with rs2249844 (r 2 50.985 in individuals genotyped using HumanHap610 array), and has been associated with melanoma risk. 5 Neither rs3219090 nor rs2249844 exhibited deviation from Hardy-Weinberg equilibrium (p > 0.3), nor were there any differences in rs3219090 genotype frequencies by array type (Supporting Information Table 1, X 2 p 5 0.34). Survival time was defined from diagnosis date to either death due to melanoma, or date of last followup/nonmelanoma death.…”

“…3 Excitingly, a recent report has provided evidence that a single nucleotide polymorphism (SNP) previously associated with risk of melanoma in the poly(ADPribose) polymerase 1 [MIM: 173870, PARP1] gene 4 is also associated with overall survival. 5 Given the paucity of survival associated genetic variants in melanoma, the usual lack of correlation between melanoma specific and overall survival in early stage melanoma and the general requirement for replication of genetic associations, we undertook to study PARP1 variation and melanoma survival.…”

“…The orthogonal transformations of age and age 2 were used to allow modeling of each independently. Melanoma sites (trunk, head and neck, upper limb, lower limb, or unspecified) were not associated with differential survival (coxph p > 0.2); however, these were included as covariates to better replicate the analysis of Davies et al (2014). While genotyping array batch was not associated with melanoma specific survival (coxph p 5 0.91) it was included as a covariate as there were chance differences in melanoma morphological type and age by array batch (Supporting Information ); to normalize its distribution the natural log of Breslow thickness was used as a covariate.…”

“…This is in line with the report of increased PARP1 expression in ulcerated primary tumours. 5 Ulceration status was only available for 159 individuals (nine deaths) and as such was not included in primary analysis. When including ulceration status as a covariate, rs3219090 T allele was still a hazard albeit nonsignificantly, likely due to the reduced power (adjusted HR 1.77, 95% CI: 0.63-5.00, p 5 0.278).…”