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Carcinogenesis Advance Access published online on April 15, 2009
Carcinogenesis, doi:10.1093/carcin/bgp096
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Nucleotide excision repair core gene polymorphisms and risk of second primary malignancy in patients with index squamous cell carcinoma of the head and neck

Mark E. Zafereo, MD1,3, Erich M. Sturgis, MD, MPH1,2, Zhensheng Liu, MD, PhD2, Li-E Wang, MD2, Qingyi Wei, MD, PhD2 and Guojun Li, MD, PhD1,2

1 Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
2 Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
3 Bobby R. Alford Department of Otolaryngology—Head and Neck Surgery, Baylor College of Medicine, Houston, Texas

Corresponding author: Guojun Li, Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 441, Houston, Texas 77030-4009. Phone: 713-792-0227. Fax: 713-794-4662. Email: gli{at}mdanderson.org

The nucleotide excision repair (NER) pathway is central in response to damage induced by environmental carcinogens. Efficiency of this pathway, likely genetically determined, may modulate individual risk of developing squamous cell carcinoma of the head and neck (SCCHN) as well as second primary malignancy (SPM) after the index tumor. We hypothesized that common nonsynonymous and regulatory single nucleotide polymorphisms (SNPs) in the NER core genes individually, and more likely, collectively are associated with risk of SPM. We genotyped for seven selected SNPs in 1,376 incident SCCHN patients who were prospectively recruited between 1995 and 2006 and followed for SPM development. We found that 110 patients (8%) developed SPM: 43 (39%) second SCCHN, 38 (35%) other tobacco-associated sites, and 29 (26%) other non-tobacco-associated sites. The associations of these SNPs with SPM risk were assessed assuming a recessive genetic model. We did not find any significant associations of each or in combination of the seven SNPs with SPM risk in the recessive models. However, when we explored the combined effect based an alternatively dominant genetic model, we found that the number of observed risk genotypes was associated with a significantly increased SPM risk in a dose-response manner (P = 0.005) and patients with 5-7 risk genotypes had a significantly 2.4-fold increased SPM risk compared to patients with 0-2 risk genotypes. These findings suggest that a profile of NER core gene polymorphisms might collectively contribute to risk of SPM not in a recessive model but in a dominant model among patients with an index primary SCCHN. These findings need to be validated in future studies with larger sample sizes and longer follow-up time.

Key Words: DNA repair • genetic polymorphisms • head and neck cancer • second primary malignancy

Received March 3, 2009; revised April 6, 2009; accepted April 12, 2009.


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