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Cyclin D1 Guanine/Adenine 870 Polymorphism With Altered Protein Expression Is Associated With Genomic Instability and Aggressive Clinical Biology of Esophageal Adenocarcinoma

Julie G. Izzo, Tsung-Teh Wu, Xifeng Wu, Joe Ensor, Rajyalakshmi Luthra, Jennifer Pan, Arlene Correa, Stephen G. Swisher, Clifford K.S. Chao, Walter N. Hittelman, Jaffer A. Ajani

From the Departments of Experimental Therapeutics, Pathology, Biostatistics and Applied Mathematics, Thoracic and Cardio-Vascular Surgery, Radiation Oncology, Epidemiology, and Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Julie G. Izzo, MD, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Unit 19, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jizzo{at}mdanderson.org

PURPOSE: Altered cyclin D1 (CD1), a cell cycle regulator, may play an important role in imparting aggressive nature to esophageal adenocarcinoma (EAC). CD1 gene single nucleotide polymorphism G/A870 results in two alternatively spliced transcripts, CD1a and CD1b. CD1b, preferentially encoded by the A870 allele, is putatively oncogenic. We hypothesized that CD1 A870 allele would be associated with higher CD1 protein expression, and increased genomic instability during EAC evolution, leading to more aggressive phenotype.

PATIENTS AND METHODS: One hundred twenty-four archival specimens of EAC, and 39 associated Barrett's esophagus (BE) specimens were examined for CD1 genotype, CD1 protein expression, and chromosome 9 polysomy (representing genomic instability). We correlated CD1 genotypes with CD1 protein expression, genomic instability, age at diagnosis of EAC, and overall survival (OS).

RESULTS: The A870 allele was associated with higher levels of CD1 protein expression in EAC (P = .032); in BE (P = .01) where it was associated with concomitant increased chromosome 9 polysomy (P = .002); and with a younger age at diagnosis (P < .001) and poor OS (P = .0003) of EAC patients.

CONCLUSION: Our data suggest that CD1 A870 background may be imparting aggressive phenotype to EAC. It provides a molecular basis to explain the clinical biology associated with CD1 polymorphism whereas aberrant nuclear accumulation of CD1 protein enhances the acquisition of genomic instability (ie, clonal diversity), thus leading to early age of EAC diagnosis and poor OS. CD1 genotyping with other biomarkers may help create a biomarker-based prognostic model for EAC and CD1 may also serve as a therapeutic target.

Supported by Grants No. NIH-NCI RO1 DE13157-04 (W.N.H.), NIH-NCI EDRN CA 86390 (M.R.S.), and CA-16672, and The University of Texas M.D. Anderson Multidisciplinary Esophageal Research Grant, Riverkreek Foundation, Dallas, Cantu, Smith, and Park Families (J.A.A.).

W.N.H. and J.A.A. have contributed equally to the performance of the study and preparation of the article.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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