Cyclin D1 guanine/adenine 870 polymorphism with altered protein expression is associated with genomic instability and aggressive clinical biology of esophageal adenocarcinoma.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Izzo
Julie G
JG
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. jizzo@mdanderson.org
Wu
Tsung-Teh
TT
Wu
Xifeng
X
Ensor
Joe
J
Luthra
Rajyalakshmi
R
Pan
Jennifer
J
Correa
Arlene
A
Swisher
Stephen G
SG
Chao
Clifford K S
CK
Hittelman
Walter N
WN
Ajani
Jaffer A
JA
D000225:Adenine / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D001707:Biopsy, Needle; D015331:Cohort Studies; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D016629:Esophagectomy / Q000379:methods; D004945:Esophagoscopy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006147:Guanine / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011336:Probability; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D019938:Cyclin D1; D006147:Guanine; D000225:Adenine