UCSF

Glioma and melanoma are rapidly-progressing malignancies that arise from neuroectodermal origin.SEER registry data indicate that melanoma patients areat significantly increased risk of developing glioma(OR=1.42, 95%CI=1.22-1.62)[1]. Although a sharedgenetic etiology is suggested by melanoma-astrocytomasyndrome, an inherited cancer predisposition due togermline CDKN2A mutation, this Mendelian disordercannot account for the increased co-occurrence ofmelanoma and glioma observed at the populationlevel[1]. Recent epidemiologic research has identifiedadditional germline variants that confer risk of bothglioma and melanoma and which implicate telomeremaintenance in the development of these cancers.Telomeres are repetitive DNA sequences that cap andprotect chromosomes and are depleted with eachsomatic cellular division. Because telomere attritioncauses replicative senescence, increased telomere lengthmay allow for prolonged cell survival, increased accrualof mutations, and greater propensity for malignanttransformation. A very large genome-wide associationstudy (GWAS) conducted by the ENGAGE Consortiumhas identified seven genes that are reproduciblyassociated with inter-individual variation in leukocytetelomere length (LTL), including single nucleotidepolymorphisms (SNPs) in: ACYP2, TERC, NAF1,TERT, OBFC1, ZNF208, and RTEL1[2]. In addition tothe effects of these genes on LTL, recent GWAS alsoidentified glioma susceptibility loci near TERT, TERC,and RTEL1[3] and melanoma susceptibility loci nearTERC, TERT, OBFC1, and RTEL1[4]. Taken together,these GWAS suggest that telomere length may be acommon link between the genetic architecture ofmelanoma and glioma predisposition