HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis

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HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis Lisa Mirabello, Meredith Yeager, Kai Yu, Gary M. Clifford, Yanzi Xiao, Bin Zhu, Michael Cullen, Joseph F. Boland, Nicolas Wentzensen, Chase W. Nelson, Tina Raine-Bennett, Zigui Chen, Sara Bass, Lei Song, Qi Yang, Mia Steinberg, Laurie Burdett, Michael Dean, David Roberson, Jason Mitchell, Thomas Lorey, Silvia Franceschi, Philip E. Castle, Joan Walker, Rosemary Zuna, Aimée R. Kreimer, Daniel C. Beachler, Allan Hildesheim, Paula Gonzalez, Carolina Porras, Robert D. Burk, Mark Schiffman  Cell  Volume 170, Issue 6, Pages 1164-1174.e6 (September 2017) DOI: 10.1016/j.cell.2017.08.001 Copyright © 2017 Terms and Conditions

Cell 2017 170, 1164-1174.e6DOI: (10.1016/j.cell.2017.08.001) Copyright © 2017 Terms and Conditions

Figure 1 Individual SNP Associations with CIN3+ Compared to the Controls within the A1/A2 Lineages in Women in the PaP Cohort Logistic regression models were used to obtain the odds ratio and 95% confidence intervals for CIN3+ risk for each SNP minor allele using the controls as the referent group. The x axis indicates the viral genome nucleotide position; The y axis indicates the p-value. The vertical arrows indicate the most significant SNPs identified. SNPs are colored by gene region in the legend. URR, upstream regulatory region; E6, early gene 6; E7, early gene 7; E1, early gene 1; E2, early gene 2; E4, early gene 4; E5, early gene 5; L2, late gene 2; L1, late gene 1; NC, non-coding region. See also Table S2. Cell 2017 170, 1164-1174.e6DOI: (10.1016/j.cell.2017.08.001) Copyright © 2017 Terms and Conditions

Figure 2 Rare Non-silent Variant Distributions across the Viral Genomes of A1/A2 Lineages for the CIN3+ Cases and Controls in the PaP Cohort Each viral gene region is represented by a wedge in the plots and the size of the wedge corresponds to the nucleotide size of the region. The nucleotide positions of each viral gene region are shown in the center. The two inner rings illustrate the genome positions of the rare variants within each of the viral gene regions for cases in red and controls in blue. Each vertical line represents a variant and the height of the line corresponds to how many individuals had this variant. The total variant counts for each viral region are given in Table 4. The outermost ring illustrates the cumulative rare variant counts by viral gene region. The density of the variants and the variant increase across each region are represented by the slope of the line for the cases and controls. URR, upstream regulatory region; E6, early gene 6; E7, early gene 7; E1, early gene 1; E2, early gene 2; E4, early gene 4; E5, early gene 5; L2, late gene 2; L1, late gene 1. See also Figure S1 and Tables S3 and S4–S6. Cell 2017 170, 1164-1174.e6DOI: (10.1016/j.cell.2017.08.001) Copyright © 2017 Terms and Conditions

Figure 3 HPV16 Rare Nonsynonymous and Nonsense Nucleotide Variants Observed in the E7 ORF. Women in the PAP Cohort with HPV16 A1/A2 lineage infections were included in this analysis. Rare nonsynomous and nonsensense variants are shown as black and red sticks, respectively. Controls are shown as blue lollipops and CIN3+ cases as either red or grey lollipops corresponding to CIN3 or AIS, respectively. Amino acid changes are indicated with each lollipop, and number of lollipop circles indicates the number of individuals with that variant. The domains of E7 are colored, see legend, and the stars indicate changes consistent with an APOBEC3-induced change. CR1, conserved region 1; CR2, conserved region 2; RB1, retinoblastoma (Rb) protein interacting region. CIN3, cervical intraepithelial neoplasia grade 3; AIS, adenocarcinoma in situ. See also Figure S2. Cell 2017 170, 1164-1174.e6DOI: (10.1016/j.cell.2017.08.001) Copyright © 2017 Terms and Conditions

Figure S1 Rare Nonsynonymous Variation within the E7, E1, and L1 Gene Regions for the CIN3+ Cases and Controls with an A1/A2 HPV16, Related to Figure 2 and Table 4 Cases and controls have a significantly different rare variant distribution in E7, E1, and L1. Cumulative rare variant counts (y axis) are shown for the CIN3+ cases in red and controls in blue by viral genome position for the specified gene (x axis). CIN3+, cervical intraepithelial neoplasia grade 3 and cancer. Cell 2017 170, 1164-1174.e6DOI: (10.1016/j.cell.2017.08.001) Copyright © 2017 Terms and Conditions

Figure S2 HPV16 Rare Nonsynonymous and Nonsense Nucleotide Variants Observed in the E6 ORF. Related to Figure 3 and Table 4 Women in the PAP Cohort with HPV16 A1/A2 lineage infections were included in this analysis. Rare nonsynomous and nonsensense variants are shown as black and red sticks, respectively. Controls are shown as blue lollipops and CIN3+ cases as either red, dark red, grey or black lollipops corresponding to CIN3, SCC, AIS, or Adeno, respectively. Amino acid changes are indicated with each lollipop, and number of circles indicates the number of individuals with that variant. Specific domains of E6 are colored, see legend, and the stars indicate changes consistent with an APOBEC3-induced change. CIN3, cervical intraepithelial neoplasia grade 3; SCC, squamous cell carcinoma; AIS, adenocarcinoma in situ; Adeno, adenocarcinoma. Cell 2017 170, 1164-1174.e6DOI: (10.1016/j.cell.2017.08.001) Copyright © 2017 Terms and Conditions