Inherited Genetic Variants Associated with Occurrence of Multiple Primary Melanoma

Recent studies including genome-wide association studies have identified several putative low-penetrance susceptibility loci for melanoma. We sought to determine their generalizability to genetic predisposition for multiple primary melanoma in the international population-based Genes, Environment, and Melanoma (GEM) Study. GEM is a case-control study of 1,206 incident cases of multiple primary melanoma and 2,469 incident first primary melanoma participants as the control group. We investigated the odds of developing multiple primary melanoma for 47 single nucleotide polymorphisms (SNP) from 21 distinct genetic regions previously reported to be associated with melanoma. ORs and 95% CIs were determined using logistic regression models adjusted for baseline features (age, sex, age by sex interaction, and study center). We investigated univariable models and built multivariable models to assess independent effects of SNPs. Eleven SNPs in 6 gene neighborhoods (TERT/CLPTM1L, TYRP1, MTAP, TYR, NCOA6, and MX2) and a PARP1 haplotype were associated with multiple primary melanoma. In a multivariable model that included only the most statistically significant findings from univariable modeling and adjusted for pigmentary phenotype, back nevi, and baseline features, we found TERT/CLPTM1L rs401681 (P = 0.004), TYRP1 rs2733832 (P = 0.006), MTAP rs1335510 (P = 0.0005), TYR rs10830253 (P = 0.003), and MX2 rs45430 (P = 0.008) to be significantly associated with multiple primary melanoma while NCOA6 rs4911442 approached significance (P = 0.06). The GEM study provides additional evidence for the relevance of these genetic regions to melanoma risk and estimates the magnitude of the observed genetic effect on development of subsequent primary melanoma

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Inherited Genetic Variants Associated with Occurrence of Multiple Primary Melanoma

Recent studies, including genome-wide association studies, have identified several putative low-penetrance susceptibility loci for melanoma. We sought to determine their generalizability to genetic predisposition for multiple primary melanoma in the international population-based Genes, Environment, and Melanoma (GEM) Study. GEM is a case-control study of 1,206 incident cases of multiple primary melanoma and 2,469 incident first primary melanoma participants as the control group. We investigated the odds of developing multiple primary melanoma for 47 SNPs from 21 distinct genetic regions previously reported to be associated with melanoma. ORs and 95% confidence intervals were determined using logistic regression models adjusted for baseline features (age, sex, age by sex interaction, and study center). We investigated univariable models and built multivariable models to assess independent effects of SNPs. Eleven SNPs in 6 gene neighborhoods (TERT/CLPTM1L, TYRP1, MTAP, TYR, NCOA6, and MX2) and a PARP1 haplotype were associated with multiple primary melanoma. In a multivariable model that included only the most statistically significant findings from univariable modeling and adjusted for pigmentary phenotype, back nevi, and baseline features, we found TERT/CLPTM1L rs401681 (P = 0.004), TYRP1 rs2733832 (P = 0.006), MTAP rs1335510 (P = 0.0005), TYR rs10830253 (P = 0.003), and MX2 rs45430 (P = 0.008) to be significantly associated with multiple primary melanoma, while NCOA6 rs4911442 approached significance (P = 0.06). The GEM Study provides additional evidence for the relevance of these genetic regions to melanoma risk and estimates the magnitude of the observed genetic effect on development of subsequent primary melanoma

Inherited Genetic Variants Associated with Occurrence of Multiple Primary Melanoma

Recent studies including genome-wide association studies have identified several putative low-penetrance susceptibility loci for melanoma. We sought to determine their generalizability to genetic predisposition for multiple primary melanoma in the international population-based Genes, Environment, and Melanoma (GEM) Study. GEM is a case-control study of 1,206 incident cases of multiple primary melanoma and 2,469 incident first primary melanoma participants as the control group. We investigated the odds of developing multiple primary melanoma for 47 single nucleotide polymorphisms (SNP) from 21 distinct genetic regions previously reported to be associated with melanoma. ORs and 95% CIs were determined using logistic regression models adjusted for baseline features (age, sex, age by sex interaction, and study center). We investigated univariable models and built multivariable models to assess independent effects of SNPs. Eleven SNPs in 6 gene neighborhoods (TERT/CLPTM1L, TYRP1, MTAP, TYR, NCOA6, and MX2) and a PARP1 haplotype were associated with multiple primary melanoma. In a multivariable model that included only the most statistically significant findings from univariable modeling and adjusted for pigmentary phenotype, back nevi, and baseline features, we found TERT/CLPTM1L rs401681 (P = 0.004), TYRP1 rs2733832 (P = 0.006), MTAP rs1335510 (P = 0.0005), TYR rs10830253 (P = 0.003), and MX2 rs45430 (P = 0.008) to be significantly associated with multiple primary melanoma while NCOA6 rs4911442 approached significance (P = 0.06). The GEM study provides additional evidence for the relevance of these genetic regions to melanoma risk and estimates the magnitude of the observed genetic effect on development of subsequent primary melanoma

Association of Interferon Regulatory Factor-4 Polymorphism rs12203592 With Divergent Melanoma Pathways.

Solar elastosis and neval remnants are histologic markers characteristic of divergent melanoma pathways linked to differences in age at onset, host phenotype, and sun exposure. However, the association between these pathway markers and newly identified low-penetrance melanoma susceptibility loci remains unknown. In the Genes, Environment and Melanoma (GEM) Study, 2103 Caucasian participants had first primary melanomas that underwent centralized pathology review. For 47 single-nucleotide polymorphisms (SNPs) previously identified as low-penetrant melanoma risk variants, we used multinomial logistic regression to compare melanoma with solar elastosis and melanoma with neval remnants simultaneously to melanoma with neither of these markers, excluding melanomas with both markers. All statistical tests were two-sided. IRF4 rs12203592 was the only SNP to pass the false discovery threshold in baseline models adjusted for age, sex, and study center. rs12203592*T was associated positively with melanoma with solar elastosis (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.18 to 1.82) and inversely with melanoma with neval remnants (OR = 0.65, 95% CI = 0.48 to 0.87) compared with melanoma with neither marker (P global = 3.78 x 10(-08)). Adjusting for phenotypic characteristics and total sun exposure hours did not materially affect rs12203592's associations. Distinct early- and late-onset age distributions were observed in patients with IRF4 rs12203592 [CC] and [TT] genotypes, respectively. Our findings suggest a role of IRF4 rs12203592 in pathway-specific risk for melanoma development. We hypothesize that IRF4 rs12203592 could underlie in part the bimodal age distribution reported for melanoma and linked to the divergent pathways

Association of interferon regulatory factor-4 polymorphism rs12203592 with divergent melanoma pathways

BackgroundSolar elastosis and neval remnants are histologic markers characteristic of divergent melanoma pathways linked to differences in age at onset, host phenotype, and sun exposure. However, the association between these pathway markers and newly identified low-penetrance melanoma susceptibility loci remains unknown. MethodsIn the Genes, Environment and Melanoma (GEM) Study, 2103 Caucasian participants had first primary melanomas that underwent centralized pathology review. For 47 single-nucleotide polymorphisms (SNPs) previously identified as low-penetrant melanoma risk variants, we used multinomial logistic regression to compare melanoma with solar elastosis and melanoma with neval remnants simultaneously to melanoma with neither of these markers, excluding melanomas with both markers. All statistical tests were two-sided. ResultsIRF4 rs12203592 was the only SNP to pass the false discovery threshold in baseline models adjusted for age, sex, and study center. rs12203592*T was associated positively with melanoma with solar elastosis (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.18 to 1.82) and inversely with melanoma with neval remnants (OR = 0.65, 95% CI = 0.48 to 0.87) compared with melanoma with neither marker (Pglobal = 3.78 x 10-08). Adjusting for phenotypic characteristics and total sun exposure hours did not materially affect rs12203592's associations. Distinct early- and late-onset age distributions were observed in patients with IRF4 rs12203592 [CC] and [TT] genotypes, respectively. ConclusionsOur findings suggest a role of IRF4 rs12203592 in pathway-specific risk for melanoma development. We hypothesize that IRF4 rs12203592 could underlie in part the bimodal age distribution reported for melanoma and linked to the divergent pathways.</p