Carcinogenesis Advance Access originally published online on August 4, 2005
Carcinogenesis 2006 27(1):84-94; doi:10.1093/carcin/bgi204
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Carcinogenesis vol.27 no.1 Published by Oxford University Press 2005.
Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients
1 Basic Research Laboratory and 2 Laboratory of Cellular Oncology, CCR, NCI, Bethesda, MD, USA, 3 Armed Forces Institute of Pathology, Washington, DC, USA, 4 Department of Dermatology, Brown Medical School, Providence, RI, USA, 5 Department of Dermatology, Yüzüncüyil University Medical School, Van, Turkey, 6 Department of Biochemistry, Inönü University Medical School, Malatya, Turkey, 7 Department of Human Genetics, Tel Aviv University Medical School, Tel Aviv, Israel and 8 Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, Institute Gustave Roussy, Villejuif, France
9 Present address: Washington and Lee Law School, Lexington, VA, USA
10 Present address: Kinki University School of Medicine, Osaka, Japan
11 Present address: Georg-August-University, Goettingen, Germany
12 Present address: University of North Carolina, Chapel Hill, NC, USA
13 Present address: University of California School of Medicine, Los Angeles, CA, USA
* To whom correspondence should be addressed. Tel: +1 301 496 9033; Fax: +1 301 594 3409; Email: kraemerk{at}nih.gov
Xeroderma pigmentosum group C (XP-C) is a rare autosomal recessive disorder. Patients with two mutant alleles of the XPC DNA repair gene have sun sensitivity and a 1000-fold increase in skin cancers. Clinically normal parents of XP-C patients have one mutant allele and one normal allele. As a step toward evaluating cancer risk in these XPC heterozygotes we characterized cells from 16 XP families. We identified 15 causative mutations (5 frameshift, 6 nonsense and 4 splicing) in the XPC gene in cells from 16 XP probands. All had premature termination codons (PTC) and absence of normal XPC protein on western blotting. The cell lines from 26 parents were heterozygous for the same mutations. We employed a real-time quantitative reverse transcriptase–PCR assay as a rapid and sensitive method to measure XPC mRNA levels. The mean XPC mRNA levels in the cell lines from the XP-C probands were 24% (P < 10–7) of that in 10 normal controls. This reduced XPC mRNA level in cells from XP-C patients was caused by the PTC that induces nonsense-mediated mRNA decay. The mean XPC mRNA levels in cell lines from the heterozygous XP-C carriers were intermediate (59%, P = 10–4) between the values for the XP patients and the normal controls. This study demonstrates reduced XPC mRNA levels in XP-C patients and heterozygotes. Thus, XPC mRNA levels may be evaluated as a marker of cancer susceptibility in carriers of mutations in the XPC gene.
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