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A Genotype-Phenotype Examination of Cyclin D1 on Risk and Outcome of Squamous Cell Carcinoma of the Head and Neck

Authors' Affiliations: ¹ Department of Pathology and Laboratory Medicine and ² Center for Environmental Health and Technology, Brown University, Providence, Rhode Island; ³ Department of Pathology, Dartmouth Medical School, Hanover, New Hampshire; and ⁴ Department of Medical Oncology, Head and Neck Cancer Program, Dana-Farber Cancer Institute, Boston, Massachusetts

Requests for reprints: Carmen J. Marsit, Department of Pathology and Laboratory Medicine, Brown University, Box G-E537, Providence, RI 02912. Phone: 401-863-6508; Fax: 401-863-9008; E-mail: carmen_marsit{at}brown.edu.

Purpose: The variant allele of CCND1 G870A encodes a splice variant of the cyclin D1 protein, which possesses an increased half-life. To confirm the phenotypic effect of the variant allele, we examined the immunohistochemical staining pattern of the protein in tumors from a case population of head and neck squamous cell carcinoma (HNSCC) and compared it with the genotype of these individuals. We also examined how this genotype was associated with the risk of HNSCC and if this genotype-phenotype association was related to patient outcome.

Experimental Design: In a population-based case-control study of 698 cases and 777 controls, we both genotyped all participants for the CCND1 gene and did immunohistochemical staining of the cyclin D1 protein in the HNSCC tumors.

Results: The variant AA genotype was significantly associated with positive immunohistochemical staining (P < 0.02), and this variant genotype was associated with a significantly elevated odds ratio of 1.5 (95% confidence interval, 1.1-2.0) for HNSCC overall, with risk greatest in oral and laryngeal sites. Positive immunohistochemical staining was inversely related to human papillomavirus 16 DNA present in the tumor (P < 0.03). The AA genotype and superpositive immunohistochemical staining for cyclin D1 also had independent and significant effects on patient survival.

Conclusions: These results strongly suggest that this splice variant, when present in two copies, is a significant predictor of both the occurrence of HNSCC as well as patient survival after treatment. These data further indicate that this variant protein is an important determinant of individual response to therapy for this disease.

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