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Genetic variations in human papillomavirus and cervical cancer outcomes.

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.

SUBMITTER: Rader JS

PROVIDER: S-EPMC6450540 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Genetic variations in human papillomavirus and cervical cancer outcomes.

Rader Janet S JS Tsaih Shirng-Wern SW Fullin Daniel D Murray Miriam W MW Iden Marissa M Zimmermann Michael T MT Flister Michael J MJ

International journal of cancer 20190104 9

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 canc ...[more]

PMID: 30515767

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Project description:To investigate the relationship between single nucleotide polymorphisms (SNPs) in human papillomavirus (HPV) receptor associated genes and HPV susceptibility and clinical outcomes in Chinese women, from October 2016 to March 2020, a total of 3,066 women were recruited for a 3-year prospective population-based cervical cancer screening clinical trial. The primary endpoint was histological cervical intraepithelial neoplasia 2 and worse (CIN2+). Twenty-nine SNPs of HPV receptor associated genes on women with available cytology residual samples at baseline were detected using MALDI-TOF MS. Eligible data were available for 2,938 women. Rs16894821 (GG versus AA, OR =1.71 [1.08 to 2.69]) and rs724236 (TT versus AA, OR = 1.73 [1.14 to 2.62]) in SDC2 were significantly related to the HPV susceptibility. And rs2575712 (TT versus GG, OR = 2.78 [1.22 to 6.36]) in SDC2 was associated with increased HPV 16/18 susceptibility. Four SNPs (rs1047057 and rs10510097 in FGFR2 gene, rs2575735 in SDC2 gene, and rs878949 in HSPG2 gene) were significantly associated with persistent HPV infection. Importantly, the genotypes of rs16894821 under recessive model (GG versus AA/AG, OR = 2.40 [1.12 to 5.15]) in SDC2 and rs11199993 under dominant model (GC/CC versus GG, OR = 1.64 [1.01 to 2.68]) in FGFR2 were significantly associated with the disease progression. Finally, SNPs showed comparable efficacy in detecting CIN2+ for the women infected with non-HPV16/18 compared with cervical cytology (sensitivity: 0.51 [0.36 to 0.66] versus 0.44 [0.30 to 0.60], specificity: 0.96 [0.96 to 0.97] versus 0.98 [0.97 to 0.99], positive predictive value: 0.23 [0.15 to 0.33] versus 0.33 [0.22 to 0.47], and negative predictive value: 0.99 [0.98 to 0.99] versus 0.99 [0.98 to 0.99]). SNPs in HPV receptor related genes may influence HPV susceptibilities and clinical outcomes in Chinese women. IMPORTANCE Virus receptors are known to mediate virus attachment and further lead to virus infection of the host cells. In the current study, we investigated the relationship between single nucleotide polymorphisms (SNPs) in human papillomavirus (HPV) receptor associated genes and HPV susceptibility and clinical outcomes in Chinese women, and to explore the new triaging strategy for non-16/18 high-risk HPV infection.

Dataset Information

Genetic variations in human papillomavirus and cervical cancer outcomes.

Publications

Genetic variations in human papillomavirus and cervical cancer outcomes.

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