Carcinogenesis Advance Access published online on June 15, 2006
Carcinogenesis, doi:10.1093/carcin/bgl107
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1 Department of Radiobiology/Molecular Epidemiology, Hiroshima, 732-0815, Japan
* To whom correspondence should be addressed. 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 depended 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 (µ1Gy) than low-IR (<0.2Gy) exposure. And notably, although p53 deletion-frequencies demonstrated no IR-dose associations, deletions at the PTCH locus were more frequent (79% vs. 44%) in tumors with high-IR than low-IR exposure. Moreover, 60% of high-IR tumors harbored both p53 and PTCH abnormalities compared to 23% of low-IR tumors. Therefore alteration of both genes is likely to play a role in radiation-induced basal cell carcinogenesis.
Received February 16, 2006
Revised May 9, 2006
Accepted May 27, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Molecular basis of basal cell carcinogenesis in the atomic-bomb survivor population: p53 and PTCH gene alterations
Terumi Mizuno 1,
Shoji Tokuoka 2,
Masao Kishikawa 3,
Eiji Nakashima 4,
Kiyohiko Mabuchi 5,
and
Keisuke S. Iwamoto 6 *
2 Department of Epidemiology, Hiroshima, 732-0815, Japan
3 Nagasaki Institute for Diagnostic Pathology, Isahaya, Japan
4 Department of Statistics at the Radiation Effects Research Foundation, Hiroshima, 732-0815, Japan
5 Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, 20892-1611, USA
6 Department of Radiobiology/Molecular Epidemiology, Hiroshima, 732-0815, Japan; Roy E. Coats Research Laboratories, Department of Radiation Oncology, University of California, Los Angeles, CA, 90095-1714, USA
Keisuke S. Iwamoto, E-mail: kiwamoto{at}mednet.ucla.edu
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