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Abstract
Background and Significance: The continuous expression of HPV oncogenes is responsible for initiating and driving cervical cancer. Current treatments include radiation and Cisplatin-based chemotherapy. Targeted therapies can be directed to specific subset of tumors if they are known.
Methods: Molecular genetic data generated by The Cancer Genome Atlas (TCGA) were analyzed.
Results: We discovered and characterized a subset of HPV positive cervical cancers that do not express HPV transcripts, including the E6 and E7 oncogenes. These tumors more commonly appear in women with a median age of diagnosis 9 years later (54 vs. 45 years) (p-value = 0.023) and reveal worse survival (p-value 0.06). Gene expression profiles of HPV expressing tumors (HPV-active) are distinct from those tumors that do not express HPV (HPV-inactive). Gene Set Enrichment Analysis of the HPV-active tumors show enrichment for E2F target genes, as expected based on the activity of HPV E7. HPV-inactive tumors show enrichment for WNT/beta-catenin target genes. Additionally, this analysis reveals that the HPV-active tumors have increased AKT/MTOR signaling and HPV-inactive tumors have increased sonic hedgehog signaling indicating different potential therapeutic targets for these two classes of tumors. The majority of differentially expressed genes can be explained by DNA hyper methylation and silencing of expression. Somatic mutation landscapes are significantly different. HPV-inactive tumors are significantly enriched for non-synonymous somatic mutations (p-value <0.0000001) compared to HPV-active tumors.
Conclusions: Many of the somatic mutations found in non-expressing tumors mimic the functions of the E6 and E7 viral oncoproteins, such as TP53, CTNNB1, EGFR and KRAS somatic mutations. Unexpectedly, BRCA1 and BRCA2 somatic mutations are more frequent in the HPV-inactive tumors. Therapeutic strategies based on PARP inhibition may be effective against this category of cervical cancers. Application of therapeutics routinely used in other cancer types could be used to exploit the weaknesses we discovered in the HPV-inactive tumors and may improve survival for these cervical cancer patients.
Citation Format: Carolyn E. Banister, Lucia Pirisi, Kim E. Creek, Phillip J. Buckhaults. Integrated genomic analysis identifies two subsets of cervical cancer with potentially distinct therapeutic profiles. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B01.