Oncotarget

Research Papers:

Identification and characterization of HPV-independent cervical cancers

Carolyn E. Banister, Changlong Liu, Lucia Pirisi, Kim E. Creek, Phillip J. Buckhaults _

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Oncotarget. 2017; 8:13375-13386. doi: 10.18632/oncotarget.14533

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Abstract

Carolyn E. Banister1, Changlong Liu1, Lucia Pirisi2, Kim E. Creek1, Phillip J. Buckhaults1

1University of South Carolina College of Pharmacy, Columbia, SC, USA

2University of South Carolina School of Medicine, Columbia, SC, USA

Correspondence to:

Carolyn E. Banister, email: banisterce@gmail.com

Phillip J. Buckhaults, email: phillip.buckhaults@gmail.com

Keywords: HPV, cervical cancer, TP53, CTNNB1, APOBEC

Received: September 26, 2016     Accepted: December 27, 2016     Published: January 06, 2017

ABSTRACT

Background: Human papillomavirus (HPV) initiates cervical cancer, and continuous expression of HPV oncogenes E6 and E7 is thought to be necessary to maintain malignant growth. Current therapies target proliferating cells, rather than specific pathways, and most experimental therapies specifically target E6/E7. We investigated the presence and expression of HPV in cervical cancer, to correlate HPV oncogene expression with clinical and molecular features of these tumors that may be relevant to new targeted therapies.

Results: While virtually all cervical cancers contained HPV DNA, and most expressed E6/E7 (HPV-active), a subset (8%) of HPV DNA-positive cervical cancers did not express HPV transcripts (HPV-inactive). HPV-inactive tumors occurred in older women (median 54 vs. 45 years, p = 0.02) and were associated with poorer survival (median 715 vs 3046 days, p = 0.0003). Gene expression profiles of HPV-active and -inactive tumors were distinct. HPV-active tumors expressed E2F target genes and increased AKT/MTOR signaling. HPV-inactive tumors had increased WNT/β-catenin and Sonic Hedgehog signaling. Substantial genome-wide differences in DNA methylation were observed. HPV-inactive tumors had a global decrease in DNA methylation; however, many promoter-associated CpGs were hypermethylated. Many inflammatory response genes showed promoter methylation and decreased expression. The somatic mutation landscapes were significantly different. HPV-active tumors carried few somatic mutations in driver genes, whereas HPV-inactive tumors were enriched for non-synonymous somatic mutations (p-value < 0.0000001) specifically targeting TP53, ARID, WNT, and PI3K pathways.

Materials and Methods: The Cancer Genome Atlas (TCGA) cervical cancer data were analyzed.

Conclusions: Many of the gene expression changes and somatic mutations found in HPV-inactive tumors alter pathways for which targeted therapeutics are available. Treatment strategies focused on WNT, PI3K, or TP53 mutations may be effective against HPV-inactive tumors and could improve survival for these cervical cancer patients.

Author Information

Carolyn E. Banister

Changlong Liu

Lucia Pirisi

Kim E. Creek

Phillip J. Buckhaults
Primary Contact  _


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