CUL2 and STK11 as novel response-predictive genes for neoadjuvant radiochemotherapy in esophageal cancer.
OBJECTIVE
Neoadjuvant treatment strategies have been developed to improve the survival of patients with locally advanced esophageal cancer. Since only patients with major histopathological response benefit from multimodality treatment, we profiled the genome of patients with esophageal cancer for markers indicating response or nonresponse.


METHODS
Pretreatment biopsies of responding and nonresponding patients with locally advanced esophageal cancer, as well as the corresponding normal epithelium, were analyzed by human genome microarrays. Differential gene expression was associated with histomorphological tumor regression. Quantitative real-time reverse transcriptase-PCR was applied for verification of the predictive value of a panel of the identified marker genes, including 66 patients.


RESULTS
We detected differentially expressed candidate genes with regard to response and nonresponse to neoadjuvant radiochemotherapy. The response-predictive impact of the novel markers, CUL2 and STK11, was confirmed by the verification study including 66 patients. Whereas CUL2 mRNA expression levels of greater than 1.7 was predictive for major response (p = 0.02) in adeno- and squamous cell carcinoma, STK11 was predominantly response predictive for adenocarcinomas. Downregulation of CUL2 (p = 0.04) and STK11 (p = 0.02) mRNA also correlated with a more favorable prognosis.


CONCLUSIONS
We identified two novel markers, CUL2 and STK11, for response prediction in esophageal cancer. They will be applied to complement our panel of response-predictive markers to further individualize therapy.
Metzger
Ralf
R
Department of General, Visceral & Cancer Surgery, Center for Integrated Oncology Köln Bonn, University Hospital of Cologne, Kerpener Strasse 62, Köln, Germany.
Heukamp
Lukas
L
Drebber
Uta
U
Bollschweiler
Elfriede
E
Zander
Thomas
T
Hoelscher
Arnulf H
AH
Warnecke-Eberz
Ute
U
D000091162:AMP-Activated Protein Kinase Kinases; D044842:Cullin Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020360:Neoadjuvant Therapy / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D011379:Prognosis; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C105153:CUL2 protein, human; D044842:Cullin Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases