Common variants modify the age of onset for basal cell carcinomas in Gorlin syndrome

Abstract

Gorlin syndrome is an autosomal dominant disorder, characterized by multiple early-onset basal cell carcinomas (BCCs) and jaw keratocysts. Through association studies in cohorts of sporadic BCC, nine genetic variants have previously been identified to increase the risk of BCC. The nine SNPs were genotyped by Taqman allelic discrimination in 125 individuals with Gorlin syndrome. Kaplan-Meier survival curves and Cox proportional-Hazard regression analysis were applied to determine the association between genotypes and age of first BCC in individuals with Gorlin syndrome. The p.(Arg151Cys) variant in MC1R (rs1805007) was associated with an earlier median age of onset of BCC of 27 years (95% CI: 20-34) compared with 34 years (95% CI: 30-40) for wild-type individuals (hazard ratio (HR) ¼ 1.64, 95% CI: 1.04-2.58, P ¼ 0.034). The risk allele of the variant at the chromosome 5p15 locus encompassing TERT-CLPTM1L (rs401681) was also associated with an earlier median onset of BCC, 31 years (95% CI: 28-37) compared with 41 years (95% CI: 32-48, HR ¼ 1.44, 95% CI: 1.08-1.93, P ¼ 0.014). In individuals with a risk allele at either rs1805007 or rs401681 the median time to BCC was 31 years of age (95% CI: 28-34) compared with 44 years of age (95% CI: 38-53) in wild-type individuals (HR ¼ 2.48, 95% CI: 1.47-4.17, P ¼ 0.0002). Our findings may have implications for future personalized risk estimates and BCC screening strategies in individuals with Gorlin syndrome.

Cohort study of Gorlin syndrome with emphasis on standardised phenotyping and quality of life assessment

“…This supports evidence that modifying genes or environmental factors modify the age of onset of BCC in Gorlin syndrome. 31 Surprisingly, other than the presence of palmar/plantar pits, no other clinical features were significantly different between the PTCH1+ and PTCH1 −ve groups. It is possible that the small numbers in this study has increased the standard error of the mean and masked any differences.…”

“…In keeping with the lack of genotype phenotype correlation described with PTCH1 mutations in the literature, in our cohort, a father with a PTCH1 mutation had 9 BCC at the age of 70, whilst one of his daughters had 15 BCC at the age of 26, and the other had not developed any BCC at the age of 23. This supports evidence that modifying genes or environmental factors modify the age of onset of BCC in Gorlin syndrome . Surprisingly, other than the presence of palmar/plantar pits, no other clinical features were significantly different between the PTCH1 + and PTCH1 −ve groups.…”

Mutiple keratocystic odontogenic tumors (KCOT) in a patient with Gorlin syndrome: a case report with late presentation and absence of skin manifestations

“…This may be explained by both genetic and environmental factors. Yaser et al described nine genetic variants which modify the age of onset of basal cell carcinoma in Gorlin syndrome [ 17 ]. In addition, environmental factors like sunlight exposure and amount of skin pigmentation may also modify the age of presentation.…”

Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG)

“…The risk of BCC seems to be greatly increased by irradiation [ 9 ]. There is some evidence for modifier genes especially the ‘red hair’ MC1R variant polymorphism [ 11 ] which supports some familial clustering of features beyond the PTCH1 variant.…”