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. 2024 Sep 12;15(1):7895.
doi: 10.1038/s41467-024-51713-y.

Somatic mutations in 3929 HPV positive cervical cells associated with infection outcome and HPV type

Maisa Pinheiro  1 , Nicolas Wentzensen  1 , Michael Dean  1   2 , Meredith Yeager  1   2   3 , Zigui Chen  4 , Amulya Shastry  1   2 , Joseph F Boland  1   2 , Sara Bass  1   2 , Laurie Burdett  1   2 , Thomas Lorey  5 , Sambit Mishra  1   2 , Philip E Castle  1   6 , Mark Schiffman  1 , Robert D Burk  7   8 , Bin Zhu #  1 , Lisa Mirabello #  9
Affiliations

Somatic mutations in 3929 HPV positive cervical cells associated with infection outcome and HPV type

Maisa Pinheiro et al. Nat Commun. .

Abstract

Invasive cervical cancers (ICC), caused by HPV infections, have a heterogeneous molecular landscape. We investigate the detection, timing, and HPV type specificity of somatic mutations in 3929 HPV-positive exfoliated cervical cell samples from individuals undergoing cervical screening in the U.S. using deep targeted sequencing in ICC cases, precancers, and HPV-positive controls. We discover a subset of hotspot mutations rare in controls (2.6%) but significantly more prevalent in precancers, particularly glandular precancer lesions (10.2%), and cancers (25.7%), supporting their involvement in ICC carcinogenesis. Hotspot mutations differ by HPV type, and HPV18/45-positive ICC are more likely to have multiple hotspot mutations compared to HPV16-positive ICC. The proportion of cells containing hotspot mutations is higher (i.e., higher variant allele fraction) in ICC and mutations are detectable up to 6 years prior to cancer diagnosis. Our findings demonstrate the feasibility of using exfoliated cervical cells for detection of somatic mutations as potential diagnostic biomarkers.

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Conflict of interest statement

M.P. is currently an employee of GlaxoSmithKline, J.F.B. and S.B. are now employees of AstraZeneca, and Amulya Shastry is now a doctoral student at Boston University, but they all completed the work associated with this project while employed at the National Cancer Institute. P.E.C. has received HPV tests and assays at a reduced or no cost for research from Roche, Becton Dickinson, Cepheid and Arbor Vita Corporation. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Workflow of mutation filters and the TIER classification scheme.
Footnote: Samples from single time-point analyses only. aa = amino acid.
Fig. 2
Fig. 2. Distribution of hotspot mutations by gene and TIER classification.
a Distribution of mutated sites classified in each TIER. b Proportion of mutations in each gene by the total number of mutations in each TIER, by status. c Proportion of mutations in each gene by the total number of mutations in each TIER, by HPV type. Mutations from multiple HPV16/18/45 type co-infections were excluded. Footnote: CIN3 Cervical intraepithelial neoplasia grade 3, AIS adenocarcinoma in situ. P-values were estimated with two-sided Fisher’s Exact tests for count data with simulated p-values (based on 2000 replicates). Source data are provided as a Source Data file.
Fig. 3
Fig. 3. Frequency of individual hotspot mutations in the ICC cases by HPV type and histology.
Footnote: SCC squamous cell carcinoma, ADC adenocarcinoma, Cancer* = unknown histology. Somatic mutation distribution for 141 total cancers, HPV16-positive or HPV18/45-positive, using single time point samples within 2 years of diagnosis. Source data are provided as a Source Data file.
Fig. 4
Fig. 4. Variant allele fraction (AF) of hotspot mutations by status in the single time-point analyses for TIER1 mutations, and by serial time-point analyses in cancer samples.
Footnote: CIN3 cervical intraepithelial neoplasia grade 3, AIS adenocarcinoma in situ. P-values estimated using Wilcoxon rank sum test with continuity correction. Tests were two sided. ns not significant; ***p-value ≤ 0.001; ****p-value ≤ 0.0001. Source data are provided as a Source Data file, and provide the exact p-values.
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References

    1. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin.68, 394–424 (2018). 10.3322/caac.21492 - DOI - PubMed
    1. Schiffman, M. et al. Carcinogenic human papillomavirus infection. Nat. Rev. Dis. Primers2, 16086 (2016). 10.1038/nrdp.2016.86 - DOI - PubMed
    1. Hutter, C. & Zenklusen, J. C. The cCancer genome Atlas: creating lasting value beyond its data. Cell173, 283–285 (2018). 10.1016/j.cell.2018.03.042 - DOI - PubMed
    1. Cancer Genome Atlas Research, N. et al. Integrated genomic and molecular characterization of cervical cancer. Nature543, 378–384 (2017). 10.1038/nature21386 - DOI - PMC - PubMed
    1. Ojesina, A. I. et al. Landscape of genomic alterations in cervical carcinomas. Nature506, 371–375 (2014). 10.1038/nature12881 - DOI - PMC - PubMed

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