Genetic variations in human papillomavirus and cervical cancer outcomes

Janet S Rader; Shirng-Wern Tsaih; Daniel Fullin; Miriam W Murray; Marissa Iden; Michael T Zimmermann; Michael J Flister

doi:10.1002/ijc.32038

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Genetic variations in human papillomavirus and cervical cancer outcomes

Journal article

Open access

Peer reviewed

Genetic variations in human papillomavirus and cervical cancer outcomes

Janet S Rader, Shirng-Wern Tsaih, Daniel Fullin, Miriam W Murray, Marissa Iden, Michael T Zimmermann and Michael J Flister

International journal of cancer, Vol.144(9), pp.2206-2214

05/01/2019

DOI: 10.1002/ijc.32038

PMCID: PMC6450540

PMID: 30515767

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https://doi.org/10.1002/ijc.32038View

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Abstract

Cervical cancer is driven by persistent infection of human papillomavirus (HPV), which is influenced by HPV type and intratypic variants, yet the impact of HPV type and intratypic variants on patient outcomes is far less understood. Here, we examined the association of cervical cancer stage and survival with HPV type, clade, lineage, and intratypic variants within the HPV E6 locus. Of 1,028 HPV-positive cases recruited through the CerGE study, 301 were in-situ and 727 were invasive cervical cancer (ICC), with an average post-diagnosis follow-up of 4.8 years. HPV sequencing was performed using tumor-isolated DNA to assign HPV type, HPV 16 lineage, clade, and intratypic variants within the HPV 16 E6 locus, of which nonsynonomous variants were functionally annotated by molecular modeling. HPV 18-related types were more prevalent in ICC compared to in-situ disease and associated with significantly worse recurrence-free survival (RFS) compared to HPV 16-related types. The HPV 16 Asian American lineage D3 and Asian lineage A4 associated more frequently with ICC than with in situ disease and women with an intratypic HPV 16 lineage B exhibited a trend toward worse RFS than those with A, C, or D lineages. Participants with intratypic E6 variants predicted to stabilize the E6-E6AP-p53 complex had worse RFS. Variants within the highly immunogenic HPV 16 E6 region (E14-I34) were enriched in ICC compared to in-situ lesions but were not associated with survival. Collectively, our results suggest that cervical cancer outcome is associated with HPV variants that affect virus-host interactions.

Adult

Base Sequence

DNA, Viral - genetics

DNA-Binding Proteins - genetics

DNA-Binding Proteins - metabolism

Female

Genetic Variation - genetics

Human papillomavirus 16 - genetics

Human papillomavirus 18 - genetics

Humans

Oncogene Proteins, Viral - genetics

Oncogene Proteins, Viral - metabolism

Papillomavirus Infections - virology

Protein Binding - genetics

Repressor Proteins - genetics

Repressor Proteins - metabolism

Sequence Analysis, DNA

Uterine Cervical Neoplasms - virology

Details

Title: Subtitle: Genetic variations in human papillomavirus and cervical cancer outcomes
Creators: Janet S Rader - Medical College of Wisconsin
Shirng-Wern Tsaih - Medical College of Wisconsin
Daniel Fullin - Medical College of Wisconsin
Miriam W Murray - Medical College of Wisconsin
Marissa Iden - Medical College of Wisconsin
Michael T Zimmermann - Medical College of Wisconsin
Michael J Flister - Medical College of Wisconsin
Resource Type: Journal article
Publication Details: International journal of cancer, Vol.144(9), pp.2206-2214
DOI: 10.1002/ijc.32038
PMID: 30515767
PMCID: PMC6450540
NLM abbreviation: Int J Cancer
ISSN: 0020-7136
eISSN: 1097-0215
Grant note: R01 CA193343 / NCI NIH HHS R01 CA095713 / NCI NIH HHS
Language: English
Date published: 05/01/2019
Academic Unit: Obstetrics and Gynecology
Record Identifier: 9984318226502771

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