Gene expression changes in cervical squamous cell carcinoma after initiation of chemoradiation and correlation with clinical outcome.
OBJECTIVE
The purpose of this study was to investigate early gene expression changes after chemoradiation in a human solid tumor, allowing identification of chemoradiation-induced gene expression changes in the tumor as well as the tumor microenvironment. In addition we aimed to identify a gene expression profile that was associated with clinical outcome.


METHODS
Microarray experiments were performed on cervical cancer specimens obtained before and 48 h after chemoradiation from 12 patients with Stage IB2 to IIIB squamous cell carcinoma of the cervix treated between April 2001 and August 2002.


RESULTS
A total of 262 genes were identified that were significantly changed after chemoradiation. Genes involved in DNA repair were identified including DDB2, ERCC4, GADD45A, and XPC. In addition, significantly regulated cell-to-cell signaling pathways included insulin-like growth factor-1 (IGF-1), interferon, and vascular endothelial growth factor signaling. At a median follow-up of 41 months, 5 of 12 patients had experienced either local or distant failure. Supervised clustering analysis identified a 58-gene set from the pretreatment samples that were differentially expressed between patients with and without recurrence. Genes involved in integrin signaling and apoptosis pathways were identified in this gene set. Immortalization-upregulated protein (IMUP), IGF-2, and ARHD had particularly marked differences in expression between patients with and without recurrence.


CONCLUSIONS
Genetic profiling identified genes regulated by chemoradiation including DNA damage and cell-to-cell signaling pathways. Genes associated with recurrence were identified that will require validation in an independent patient data set to determine whether the 58-gene set associated with clinical outcome could be useful as a prognostic assay.
Klopp
Ann H
AH
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Jhingran
Anuja
A
Ramdas
Latha
L
Story
Michael D
MD
Broadus
Russell R
RR
Lu
Karen H
KH
Eifel
Patricia J
PJ
Buchholz
Thomas A
TA
D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D015398:Signal Transduction / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy