Journal Article

Molecular basis of basal cell carcinogenesis in the atomic-bomb survivor population: <i>p53</i> and <i>PTCH</i> gene alterations

Terumi Mizuno, Shoji Tokuoka, Masao Kishikawa, Eiji Nakashima, Kiyohiko Mabuchi and Keisuke S. Iwamoto

in Carcinogenesis

Volume 27, issue 11, pages 2286-2294
ISSN: 0143-3334
Published online June 2006 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgl107
Molecular basis of basal cell carcinogenesis in the atomic-bomb survivor population: p53 and PTCH gene alterations

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Epidemiological studies suggest that UV exposure from sunlight is the major etiology for skin cancers, both melanocytic and non-melanocytic. However, the radiation-related risk for skin cancer among atomic bomb survivors of Hiroshima and Nagasaki is primarily derived from the excess risk of basal cell carcinoma (BCC), with no demonstrable excess in squamous cell carcinoma or melanoma. The BCCs in this cohort are therefore unusual in being potentially attributable to two types of radiation—UV and ionizing (IR). BCCs have been associated with PTCH and/or p53 tumor suppressor gene alterations. To investigate the roles of these genes in relation to IR and UV exposures, we analyzed both genes in BCC samples from atomic bomb survivors. We examined 47 tumors, of which 70% had non-silent base-substitution p53 mutations independent of IR or UV exposure. However, the distribution of mutation type depends on UV and/or IR exposure. For example, C-to-T transitions at CpG sites adjacent to pyrimidine–pyrimidine (PyPy) sequences were more prevalent in tumors from UV-exposed than UV-shielded body areas and CpG-mutations at non-PyPy sequences were more prevalent in tumors from UV-shielded body areas with high-IR (≥1 Gy) than low-IR (<0.2 Gy) exposure. And notably, although p53 deletion-frequencies demonstrated no IR–dose associations, deletions at the PTCH locus were more frequent (79% versus 44%) in tumors with high-IR than low-IR exposure. Moreover, 60% of high-IR tumors harbored both p53 and PTCH abnormalities compared with 23% of low-IR tumors. Therefore, alteration of both genes is likely to play a role in radiation-induced basal cell carcinogenesis.

Journal Article.  7090 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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