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(American Journal of Pathology. 2001;159:1917-1924.)
© 2001 American Society for Investigative Pathology

Regular Articles

Cyclin D1 Polymorphism and Expression in Patients with Squamous Cell Carcinoma of the Head and Neck

Sarah L. Holley^*, Gary Parkes, Christoph Matthias, Ulrike Bockmühl, Volker Jahnke, Korinna Leder, Richard C. Strange^*, Anthony A. Fryer^* and Paul R. Hoban^*

From the Centre for Cell and Molecular Medicine,^*
University of Keele School of Postgraduate Medicine, North Staffordshire Hospital, Stoke-on-Trent, United Kingdom; the Department of Pathology,
Stafford District General Hospital, Stafford, United Kingdom; the Department of Otorhinolaryngology,
Charite-Hospital, Humboldt-University, Berlin, Germany; and the Department of Pathology,
Virchow-Hospital, Humboldt-University, Berlin, Germany

We have previously reported that the cyclin D1 (CCND1) GG⁸⁷⁰ genotype was associated with poorly differentiated tumors and reduced disease-free interval in patients with squamous cell carcinoma of the head and neck (SCCHN). We have now examined the association of this and a second CCND1 polymorphism with gene expression and outcome in SCCHN patients. Analysis of a CCND1 G/C¹⁷²² polymorphism revealed that CCND1 CC¹⁷²² genotype was associated with poorly differentiated tumors [P = 0.005; odds ratio (OR), 5.7; 95% CI, 1.7 to 19.2), and reduced disease-free interval (P = 0.003; Hazard Ratio (HR), 7.3; 95% CI, 1.1 to 27.2.) independently from the influence of CCND1 GG⁸⁷⁰ genotype. Patients whose tumors were negative for cyclin D1 were associated with reduced disease-free interval (P = 0.028; HR, 4.1; 95% CI, 1.4 to 14.2). Although G/C¹⁷²² genotypes were not associated with expression, we found a significant trend between reduced expression of cyclin D1 in patients with the CCND1 GG⁸⁷⁰ genotype (P = 0.04). Splicing of CCND1 mRNA in head and neck tissues was modulated by CCND1 A/G⁸⁷⁰ alleles, thus CCND1 transcript a was spliced equally from CCND1 A⁸⁷⁰ and G⁸⁷⁰ alleles, whereas CCND1 transcript b was spliced mainly from the CCND1 A⁸⁷⁰ allele. Our analysis has also identified differences in cyclin D1 genotype and protein expression and the pathogenesis of SCCHN in males and females. Thus, CCND1 CC¹⁷²² genotype was more common in female patients (P = 0.019; OR, 3.3; 95% CI, 1.3 to 10) and cyclin D1 expression was more frequent (chi-square₁, 3.96; P = 0.046) and at higher levels (P = 0.004) in tumors from female patients. In summary, our data show that the two CCND1 polymorphic sites are independently associated with tumor biology and clinical outcome. CCND1 A/G⁸⁷⁰ alleles affect gene expression in head and neck tissues. We also provide preliminary evidence that the molecular genetics of SCCHN development may be influenced by patient gender.

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