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Glutathione S-Transferase Polymorphisms and Risk of Second Primary Malignancy after Index Squamous Cell Carcinoma of the Head and Neck

Authors' Affiliations: Departments of ¹ Head and Neck Surgery and ² Epidemiology, The University of Texas M. D. Anderson Cancer Center; ³ Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas; ⁴ Louisiana State University School of Medicine, New Orleans, Louisiana; and ⁵ Northwestern University School of Medicine, Chicago, Illinois

Requests for reprints: Guojun Li, Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Unit 1445, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: 713-792-0227; Fax: 713-794-4662; E-mail: gli{at}mdanderson.org.

Glutathione S-transferases (GST) detoxify carcinogens in tobacco smoke, which plays a major role in development of not only squamous cell carcinoma of the head and neck (SCCHN) but also second primary malignancy (SPM) after index SCCHN.

We hypothesized that GSTM1 null, GSTT1 null, GSTP1 Ile¹⁰⁵Val, and GSTP1 Ala¹¹⁴Val polymorphisms would individually and, more likely, collectively show an association with risk of SPM after index SCCHN. One thousand three hundred seventy-six incident SCCHN patients were prospectively recruited between May 1996 and December 2006, genotyped, and followed for SPM development.

One hundred ten patients (8%) developed SPM: 43 (39%) second SCCHN, 38 (35%) other tobacco-associated sites, and 29 (26%) other non–tobacco-associated sites. Patients with GSTP1 Ile¹⁰⁵Val polymorphism had a statistically significant association with risk of SPM development (adjusted hazard ratio, 1.7; 95% confidence interval, 1.1-2.5). However, no statistically significant associations were observed with GSTM1, GSTT1, or GSTP1 Ala¹¹⁴Val polymorphisms. After combining risk genotypes for all four polymorphisms, rates of SPM development with 0 to 1, 2, 3, and 4 risk genotypes were 6.4%, 8.4%, 10.9%, and 15.1%, respectively, and a stepwise increase in SPM risk was observed with increasing number of risk genotypes (P = 0.004 for trend). Patients with 3 to 4 risk genotypes had a 1.7-fold increased risk for SPM compared with patients with 0 to 2 risk genotypes (hazard ratio, 1.70; 95% confidence interval, 1.2-2.5).

This large prospective cohort study supports a modestly increased risk of SPM after index SCCHN with GSTP1 Ile¹⁰⁵Val polymorphism and an even greater risk of SPM with multiple combined GST risk genotypes.

Key Words: Glutathione S-transferase • Polymorphisms • Squamous cell carcinoma of the head and neck • Second primary malignancy