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Carcinogenesis Advance Access published online on November 25, 2004
Carcinogenesis, doi:10.1093/carcin/bgh344
© 2004 by Oxford University Press
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Received August 28, 2004
Revised November 17, 2004
Accepted November 17, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Polymorphisms in XPD and TP53 and mutation in human lung cancer

Leah E. Mechanic 1, Aizen J. Marrogi 2, Judith A. Welsh 1, Elise D. Bowman 1, Mohammed A. Khan 1, Lindsey Enewold 3, Yun-Ling Zheng 3, Stephen Chanock 4, Peter G. Shields 3, and Curtis C. Harris 1*

1 Laboratory of Human Carcinogenesis, NCI Center for Cancer Research, Bethesda, MD
2 Laboratory of Carcinogenesis and Biomarkers, CBCP-IRC, USUHS, Bethesda, MD
3 Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC
4 Advance Technology Center, NCI, Gaithersburg, MD 20892

* To whom correspondence should be addressed.
Curtis C. Harris, E-mail: Curtis_Harris{at}nih.gov


  Abstract

The pattern of somatic mutations in TP53 is distinct for particular cancers and carcinogenic exposures, providing clues to disease etiology, e.g., G:C to T:A mutations in TP53 are more frequently observed in smoking-associated lung cancers. In order to investigate possible causes and mechanisms of lung cancer susceptibility differences, the TP53 gene was sequenced in a case-only study of lung cancers (206 men and 103 women). Our primary hypothesis was that the TP53 mutation spectrum is influenced by polymorphisms in genes involved in DNA repair and apoptosis. We observed a TP53 mutation frequency in exons 5-8 of 25%. Functional polymorphisms in XPD (Asp312Asn, rs1799793; and Lys751Gln, rs1052559), a protein required for nucleotide excision repair and with roles in p53 mediated apoptosis, were modestly associated with G:C to T:A mutations in TP53 in lung tumors [312Asp/Asn + 312Asn/Asn and/or 751Lys/Gln + 751Gln/Gln vs. 312Asp/Asp + 751Lys/Lys; Odds Ratio (OR): 2.73, 95% Confidence Interval (CI): 0.98-7.61], consistent with the role of this protein in repair of bulky carcinogen DNA-adducts. In addition, a TP53 polymorphism, Arg72Pro (rs1042522), with a known role in the efficiency of apoptosis, was also associated both with the presence of a TP53 mutation [72Pro/Arg or 72Pro/Pro vs. 72Arg/Arg; OR: 2.25, 95% CI: 1.21-4.14] or a G:C to T:A mutation in TP53 [72Pro/Arg or 72Pro/Pro vs. 72Arg/Arg OR: 2.42, 95% CI: 0.97-6.04]. An interaction between the XPD variant alleles (312Asn and 751Gln) and the TP53 72Pro allele was observed for TP53 mutations (Any TP53 mutation: pint = 0.027; G:C to T:A TP53 mutation: pint = 0.041). The statistical interaction observed in our study is consistent with the observed biological interaction for XPD and p53 in nucleotide excision repair and apoptosis. In conclusion, differences in TP53 mutation spectrum in lung tumors are associated with several genetic factors and may reflect differences in lung cancer susceptibility and carcinogenesis.

Keywords: p53 mutation; lung cancer; genetic polymorphisms.
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