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PTCH codon 1315 polymorphism and risk for nonmelanoma skin cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2005 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 152, no 5, 868-873 p.Article in journal (Refereed) Published
Abstract [en]

Background  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.

Methods  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.

Results  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).

Conclusions  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.

Place, publisher, year, edition, pages
2005. Vol. 152, no 5, 868-873 p.
Keyword [en]
Carcinoma; Basal Cell/genetics, Carcinoma; Squamous Cell/genetics, Codon/genetics, Genetic Predisposition to Disease, Genotype, Hair Color/genetics, Humans, Loss of Heterozygosity, Neoplasm Proteins/*genetics, Pilot Projects, Polymerase Chain Reaction/methods, Polymorphism; Single Nucleotide, Receptors; Cell Surface/*genetics, Research Support; Non-U.S. Gov't, Research Support; U.S. Gov't; P.H.S., Skin Neoplasms/*genetics, Skin Pigmentation/genetics
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-93048DOI: 10.1111/j.1365-2133.2005.06464.xPubMedID: 15888139OAI: oai:DiVA.org:uu-93048DiVA: diva2:166406
Available from: 2005-05-11 Created: 2005-05-11 Last updated: 2013-03-21Bibliographically approved
In thesis
1. Molecular Analysis of Normal Human Skin and Basal Cell Carcinoma Using Microdissection Based Methods
Open this publication in new window or tab >>Molecular Analysis of Normal Human Skin and Basal Cell Carcinoma Using Microdissection Based Methods
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis was to gain further insight into the biology of normal human skin and basal cell carcinoma (BCC). Morphology in combination with microdissection was used as primary tool for sampling.

Using the X-chromosome inactivation assay, we found normal human skin to consist of a mosaic of cells, with either the maternal or the paternal X-chromosome inactivated. We believe that each tile is made up of several epidermal proliferative units with identical X-chromosome inactivation patterns. Using the same method, we found BCC to be a monoclonal neoplasm imbedded in polyclonal stroma. However, one tumor displayed clear evidence of being composed of two intermingled monoclonal tumors.

To better enable molecular analysis of defined cells from tissue sections, we investigated a zinc-based fixative as alternative to neutral-buffered formalin. Zinc-based fixative preserves good quality of genomic DNA, with only slight impairment of morphology. In addition, it partly abrogates the need for antigen retrieval.

The patched gene is involved in BCC development. We analyzed the distribution of a coding polymorphism (Pro/Leu) at codon 1315 in populations with different skin types. We found a reduced Pro/Pro genotype frequency in populations with lighter pigmentation. This in combination with genotype analyses of patients with multiple BCCs, showed that failure to lose the Pro allele during a shift towards lighter pigmented skin may be associated with an increased risk of developing BCC.

We compared the expression profile of BCC cells with putative progenitor cells in the basal layer of epidermis. In addition to discovering several unknown genes, we found the Wnt signaling pathway to upregulated. Furthermore, differentiation markers were downregulated together with proteins important for scavenging of oxygen radicals.

In conclusion, the combination of morphology, microdissection and subsequent molecular applications provided valid information deepening our understanding of normal skin and BCC.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 50 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 40
Pathology, skin, basal cell carcinoma, microdissection, X-chromosome inactivation, Patologi
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-5795 (URN)91-554-6249-9 (ISBN)
Public defence
2005-05-28, Rudbecksalen, Rudbecklaboratoriet C11, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Available from: 2005-05-11 Created: 2005-05-11Bibliographically approved

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