PTCH Mutations in Squamous Cell Carcinoma of the Skin

Abstract

Ultraviolet light exposure is the major risk factor for the development of squamous cell carcinoma in Caucasians. Mutations in the tumor suppressor gene p53 have been identified in both squamous cell carcinomas and basal cell carcinomas. The human homolog of the Drosophila patched gene, has been shown to be mutated in sporadic basal cell carcinomas; however, mutations in the patched gene have not been found in squamous cell carcinoma. In this study, we screened a total of 20 squamous cell carcinoma samples for mutations in the patched gene. Using polymerase chain reaction-single strand conformation polymorphism as an initial screening method, we identified one non-sense mutation, two mis-sense mutations and three silent mutations in five squamous cell carcinoma samples. In one squamous cell carcinoma sample, we identified a tandem GG-->AA transitional change at nucleotide 3152 in exon 18 of the patched gene that resulted in a premature stop codon at codon 1051. The three squamous cell carcinoma samples containing non-sense and mis-sense mutations were isolated from individuals with histories of multiple basal cell carcinoma. Sequence analysis of the p53 gene in these five squamous cell carcinoma samples identified one CC-->TT and three C-->T ultraviolet-specific nucleotide changes. Our study provides evidence that the patched gene is mutated in squamous cell carcinoma from individuals with a history of multiple basal cell carcinoma. The identification of ultraviolet-specific nucleotide changes in both tumor suppressor genes supports the notion that ultraviolet exposure plays an important part in the development of squamous cell carcinoma.

Differential molecular profiling between skin carcinomas reveals four newly reported genes potentially implicated in squamous cell carcinoma development

“…We compared the expression of GLI-1 by RT-PCR in all our tumor samples with normal skin (Figure 2b) and found a high expression of GLI 1 in all BCC analysed, whereas in SCC no or low GLI 1 expression level was detected. Expression of GLI 1 in some SCC has already been reported (Ping et al, 2001). Other members of the hedgehog signaling pathway, Smo and ptc, are preferentially overexpressed in BCC (Kallassy et al, 1997).…”

UV-Induced Immune Suppression that Promotes Skin Cancer Development and Progression

“…This process involves the formation of mutations at sites of DNA damage and, ultimately, results in malignant transformation after the accumulation of a sufficient number of mutations in critical genes (Runger, 2007). These mutations can occur in tumor suppressor genes such as p53 (Brash et al, 1991;Hussein et al, 2003;Rees, 1994;Ziegler et al, 1994;Ziegler et al, 1993), CDKN2/p16 (Holly et al, 1995;Saridaki et al, 2003;Soufir et al, 1999;Sparrow et al, 1998), andPTCH (D'Errico et al, 2000;Daya-Grosjean & Sarasin, 2000;de Gruijl et al, 2001;Ping et al, 2001;Zhang et al, 2001) as well as proto-oncogenes such as RAS (Chan et al, 2002;Kreimer-Erlacher et al, 2001;Spencer et al, 1995;van der Schroeff et al, 1990) and RAF (Besaratinia & Pfeifer, 2008;Gaddameedhi et al, 2010). UV-induced DNA damage also induces transcriptional activation of proto-oncogene c-fos (Ghosh et al, 1993).…”

Genomics of Basal and Squamous Cell Carcinomas

“…Although most SCC carry a mutation in the p53 gene, they have also been shown to display PTCH mutations (Ping et al, 2001,J Invest Dermatol.) and allelic loss of PTCH gene (Ahmadian et al 1998,Oncogene.)…”