PTCH codon 1315 polymorphism and risk for nonmelanoma skin cancer
- 1 May 2005
- journal article
- research article
- Published by Oxford University Press (OUP) in British Journal of Dermatology
- Vol. 152 (5), 868-873
- https://doi.org/10.1111/j.1365-2133.2005.06464.x
Abstract
The PTCH tumour suppressor gene is involved in the development of nearly all basal cell carcinomas (BCCs) of the skin and a fraction of squamous cell carcinomas (SCCs). A nonconservative Pro/Leu nucleotide polymorphism within PTCH exon 23 at codon 1315 was recently reported to be potentially important for the development of breast epithelial cell cancers. Objectives Accordingly, the status of PTCH codon 1315 was analysed for a possible association with the development of nonmelanoma skin cancers (NMSCs) in a pilot study. Because skin cancer risk is affected by specific population-dependent phenotypes such as skin and hair colour, codon 1315 was also analysed for normal allele frequency variation in human populations having differing extents of eumelanin vs. phaeomelanin. The single nucleotide polymorphism in codon 1315 of the human PTCH gene was analysed in genomic DNA from six different populations comprising 472 blood samples and from 170 patients in four different categories with NMSC. Polymerase chain reaction and pyrosequencing were used to determine the allele frequencies. Allelic loss was furthermore determined in tumours following microdissection. The Pro/Pro genotype frequency ranged from 30% to 65% between populations, with a significant trend for a reduced frequency of the Pro/Pro genotype in populations having lighter pigmentation (P = 0.020). Pro/Pro frequency showed an increasing trend with increasing tumour case severity (P = 0.027). In 260 samples from 180 Swedish patients with NMSC and a control group of 96 healthy ethnically matched volunteers, no statistically significant pairwise differences between groups were detected in the PTCH codon 1315 allelic distribution, neither was a difference seen for multiple or early onset cases of BCC in the Swedish population. In Swedish patients with single tumours, allelic loss (loss of heterozygosity) was observed in 20 of 30 (67%) patients with BCC and four of 22 (18%) patients with SCC, with no preference in the allele lost. In contrast, the Pro/Pro genotype was frequent in seven U.S. patients having multiple independent BCCs. One of these patients was heterozygous, enabling allelic loss studies. Of 20 independent tumours, 11 had lost an allele; 10 of the 11 had lost Leu, suggesting nonrandom loss that favoured retention of Pro (P = 0.0059). Our results indicate an association between the eumelanin-to-phaeomelanin shift and a shift from the Pro/Pro genotype to Leu-containing genotypes. Failure to lose Pro during the shift to phaeomelanin may be associated with an increased population risk for BCC and increased individual risk for multiple BCC. During development of a tumour, the effect of Pro may be magnified by loss of the Leu allele.Keywords
This publication has 30 references indexed in Scilit:
- Several PATCHED1 Missense Mutations Display Activity in patched1-Deficient FibroblastsPublished by Elsevier BV ,2002
- Analysis of thePTCH coding region in human rhabdomyosarcomaHuman Mutation, 2002
- Introduction of wild-type patched gene suppresses the oncogenic potential of human squamous cell carcinoma cell lines including A431Oncogene, 2002
- Melanocortin-1 Receptor Genotype is a Risk Factor for Basal and Squamous Cell CarcinomaJournal of Investigative Dermatology, 2001
- In Vivo Functions of the Patched ProteinMolecular Cell, 2000
- Sonic Hedgehog Opposes Epithelial Cell Cycle ArrestThe Journal of cell biology, 1999
- Genetic instability in the 9q22.3 region is a late event in the development of squamous cell carcinomaOncogene, 1998
- Melanin: A Two Edged Sword?Pigment Cell Research, 1997
- Increased risk of skin cancer: Another Celtic myth?: A review of Celtic ancestry and other risk factors for malignant melanoma and nonmelanoma skin cancerJournal of the American Academy of Dermatology, 1995
- Prediction of Protein Secondary Structure at Better than 70% AccuracyJournal of Molecular Biology, 1993