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Invasive cervical tumors with high and low HPV titer represent molecular subgroups with different disease etiology
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2019 (English)In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 40, no 2, p. 269-278Article in journal (Refereed) Published
Abstract [en]

Invasive cervical cancer (ICC) with very low titer of high-risk human papillomavirus (HPV) has worse clinical outcome than cases with high titer, indicating a difference in molecular etiology. Fresh-frozen ICC tumors (n=49) were classified into high and low HPV titer cases using real-time PCR-based HPV genotyping. The mutation spectra were studied using the AmpliSeq Comprehensive Cancer Panel and the expression profiles using total RNA-sequencing, and the results validated using the AmpliSeq Transcriptome assay. HPV DNA genotyping and RNA sequencing showed that 16.6% of ICC tumors contained very low levels of HPV DNA and HPV transcripts. Tumors with low HPV levels had more mutations with a high allele frequency and fewer mutations with low allele frequency relative to tumors with high HPV titer. A number of genes showed significant expression differences between HPV titer groups, including genes with somatic mutations. Gene ontology and pathway analyses implicated the enrichment of genes involved in DNA replication, cell cycle control and extracellular matrix in tumors with low HPV titer. The results indicate that in low titer tumors, HPV act as trigger of cancer development while somatic mutations are clonally selected and become drivers of the tumor development process. In contrast, in tumors with high HPV titer the expression of HPV oncoproteins play a major role in tumor development and the many low frequency somatic mutations represent passengers. This putative subdivision of invasive cervical tumors may explain the higher radiosensitivity of ICC tumors with high HPV titer and thereby have consequences for clinical management.

Place, publisher, year, edition, pages
Oxford University Press, 2019. Vol. 40, no 2, p. 269-278
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Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-156661DOI: 10.1093/carcin/bgy183ISI: 000472792800012PubMedID: 30596972Scopus ID: 2-s2.0-85065471065OAI: oai:DiVA.org:umu-156661DiVA, id: diva2:1290916
Funder
Swedish Cancer Society, CF23560Swedish Research Council, 2012-2884Knut and Alice Wallenberg Foundation, KAW2011.0205Available from: 2019-02-21 Created: 2019-02-21 Last updated: 2019-07-12Bibliographically approved

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Lindquist, David

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CiteExportLink to record
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