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Gene Expression Profiling in Cervical Cancer: An Exploration of Intratumor Heterogeneity

Authors' Affiliations: ¹ Department of Radiation Oncology, ² Clinical Study Coordination and Biostatistics, ³ Division of Cancer Genomics and Proteomics, Princess Margaret Hospital, Toronto, Canada, ⁴ Department of Applied Molecular Oncology, ⁵ Division of Signaling Biology, Ontario Cancer Institute, Toronto, Canada, Departments of ⁶ Medical Biophysics, ⁷ Laboratory Medicine and Pathobiology, and ⁸ Computer Science, University of Toronto, Toronto, Canada, and ⁹ Department of Radiotherapy and Radiobiology, Medical University of Vienna, Vienna, Austria

Requests for reprints: Anthony Fyles, Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Canada.

Purpose: To explore intratumor heterogeneity in gene expression profiles from patients with cervical cancer.

Experimental Design: A total of 33 biopsies were obtained from 11 patients, sampling between two and five different areas for each tumor. The extracted RNA was hybridized onto the Affymetrix U133 Plus 2.0 oligonucleotide chip. The variance of expression within a patient (W), between patients (B) and the total variance (T = W + B) were calculated for each ProbeSet, and the ratio W/T was used as a measure of intratumor heterogeneity. Gene Ontology functional analysis was done to assess the function of genes that had high W/T (top 10%) and low W/T (bottom 10%) values.

Results: In total, 448 ProbeSets (2.2% of the total) had W/T < 0.10, indicating low intratumor heterogeneity, and 537 ProbeSets (2.7% of the total) had W/T > 0.90, indicating high intratumor heterogeneity. In total 14,473 ProbeSets (72.4%) had higher intertumor than intratumor heterogeneity (W/T < 0.5). Genes with low intratumor heterogeneity were characterized by a statistically significant enrichment of immune-related functions (P < 0.0001). Genes with high intratumor heterogeneity were characterized by a significant tendency towards nuclear localization and nucleic acid binding (both P < 0.0001). For genes with W/T > 0.5, more than six biopsies would be required to minimize the intratumoral heterogeneity to <0.15; if W/T is 0.3 to 0.4, four biopsies are required; and for low W/T of 0.16 to 0.3, only two to three biopsies would be needed.

Conclusion: Although the intratumor heterogeneity was low for the majority of the tested ProbeSets, for many genes, multiple biopsies are required to obtain a reliable estimate of gene expression.

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