Role of PTCH and p53 Genes in Early-Onset Basal Cell Carcinoma

Abstract

Basal cell carcinoma (BCC) is the most common skin cancer in the Western world. Ultraviolet (UV) exposure, race, age, gender, and decreased DNA repair capacity are known risk factors for the development of BCC. Of these, UVB irradiation from sunlight is the most significant risk factor. The incidence of sporadic BCC increases in individuals older than age 55, with the greatest incidence reported in individuals who are older than 70, and is rare in individuals who are younger than 30. In this study, we analyzed 24 BCC samples from individuals who had BCC diagnosed by the age of 30. Fifteen single-stranded conformation polymorphism variants in the PTCH gene were identified in 13 BCC samples. Sequence analysis of these single-stranded conformation polymorphism variants revealed 13 single nucleotide changes, one AT insertion, and one 15-bp deletion. Most of these nucleotide changes (nine of 15) were predicted to result in truncated PTCH proteins. Fifteen p53 mutations were also found in 11 of the 24 BCC samples. Thirty-three percent (five of 15) and 60% (nine of 15) of the nucleotide changes in the PTCH and p53 genes, respectively, were UV-specific C-->T and CC-->TT nucleotide changes. Our data demonstrate that the p53 and PTCH genes are both implicated in the development of early-onset BCC. The identification of UV-specific nucleotide changes in both tumor suppressor genes suggests that UV exposure is an important risk factor in early onset of BCC.

Constitutive activation of the shh–ptc1 pathway by a patched1 mutation identified in BCC

“…Most of the mutations identified in patients with NBCCS or NBCCS-associated cancers result in premature truncation of the ptc1 protein with a significant number of mutations residing within residues 663-694, indicating a putative 'mutational hot spot'. One of the more common ptc1 mutations found within this region is the Gln688X (or Q688X) mutation (Figure 1a), which is found not only in NBCCS but also in sporadic BCC (Wicking et al, 1997a, b;Zhang et al, 2001). …”

“…Cell proliferation assays, cyclin D1 protein expression and cyclin B1 association represent pathways that ptc1-Q688X fails to inhibit, reflecting loss-of-function effects (Figures 1b-d, 2a, 3b and 4). ptc1-Q688X is a more common mutation associated with both BCC and NBCCS (Wicking et al, 1997a, b;Zhang et al, 2001). The loss of ptc1 function has been shown to underlie the developmental defects associated with NBCCS (Hahn et al, 1996a;Johnson et al, 1996;Wicking et al, 1997b).…”

“…To further investigate the role of ptc1 as a tumor suppressor, we examined a mutant of ptc1 found in patients with NBCCS and from a BCC tumor (Wicking et al, 1997a, b;Zhang et al, 2001). This mutant, ptc1-Q688X, contains a C-T point mutation at nucleotide 2050, resulting in the mutation Gln-stop at residue 688 within the large intracellular loop of ptc1 ( Figure 1a).…”

BCC and the Secret Lives of Patched: Insights from Patched Mouse Models

“…When these mice are exposed to UV or ionizing radiation, BCC-like lesions form, suggesting that additional genetic alterations, possibly caused by DNA damage, are required to promote BCC progression. Consistent with this notion, human BCC typically occur in sun-exposed areas of the skin and BCC with PTCH1 mutation are frequently associated with mutations in p53, a tumor suppressor gene that is mutated in over 50% of all human tumors (Ponten et al, 1997;Zhang et al, 2001). Furthermore, BCC formation in Ptc1 +/-mice was enhanced upon the ablation of p53 in the skin, suggesting that Ptc1 mutations synergize with the loss of p53 to promote BCC .…”

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

“…9,10 Somatic variants in PTCH1 and TP53 genes are often present in sporadic BCC cases, and are considered as the main targets for UV radiationinduced variant formation. 11 In addition to highly penetrant genes, common low-penetrance alleles that increase susceptibility to BCC have been identified through association studies of sporadic BCC cohorts. Variants in melanocortin 1 receptor (MC1R) gene, a major contributor to skin pigmentation, have been associated with risk of BCCs.…”