Profiling microdissected epithelium and stroma to model genomic signatures for cervical carcinogenesis accommodating for covariates.
This study is the first comprehensive, integrated approach to examine grade-specific changes in gene expression along the entire neoplastic spectrum of cervical intraepithelial neoplasia (CIN) in the process of cervical carcinogenesis. This was accomplished by identifying gene expression signatures of disease progression using cDNA microarrays to analyze RNA from laser-captured microdissected epithelium and underlying stroma from normal cervix, graded CINs, cancer, and patient-matched normal cervical tissues. A separate set of samples were subsequently validated using a linear mixed model that is ideal to control for interpatient gene expression profile variation, such as age and race. These validated genes were ultimately used to propose a genomically based model of the early events in cervical neoplastic transformation. In this model, the CIN 1 transition coincides with a proproliferative/immunosuppression gene signature in the epithelium that probably represents the epithelial response to human papillomavirus infection. The CIN 2 transition coincides with a proangiogenic signature, suggesting a cooperative signaling interaction between stroma and tumor cells. Finally, the CIN 3 and squamous cell carcinoma antigen transition coincide with a proinvasive gene signature that may be a response to epithelial tumor cell overcrowding. This work strongly suggests that premalignant cells experience a series of microenvironmental stresses at the epithelium/stroma cell interface that must be overcome to progress into a transformed phenotype and identifies the order of these events in vivo and their association with specific CIN transitions.
Gius
David
D
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. giusd@mail.nih.gov
Funk
Margo C
MC
Chuang
Eric Y
EY
Feng
Sheng
S
Huettner
Phyllis C
PC
Nguyen
Loan
L
Bradbury
C Matthew
CM
Mishra
Mark
M
Gao
Shuping
S
Buttin
Barbara M
BM
Cohn
David E
DE
Powell
Matthew A
MA
Horowitz
Neil S
NS
Whitcomb
Bradford P
BP
Rader
Janet S
JS
D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007834:Lasers; D042282:Microdissection; D009361:Neoplasm Invasiveness / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012334:RNA, Neoplasm / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000473:pathology
D014408:Biomarkers, Tumor; D012334:RNA, Neoplasm