Somatic mutations in 3929 HPV positive cervical cells associated with infection outcome and HPV type
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.
Authors
- Thomas Lorey (ORCID: https://orcid.org/0000-0002-9075-1515)
- Robert David Burk (ORCID: https://orcid.org/0000-0002-8376-8458)
- Lisa Mirabello (ORCID: https://orcid.org/0000-0001-8485-0106)
- Maísa Pinheiro (ORCID: https://orcid.org/0000-0002-9112-1179)
- Sambit Kumar Mishra (ORCID: https://orcid.org/0000-0001-8319-0599)
- Sara Bass
- Michael Dean (ORCID: https://orcid.org/0000-0003-2234-0631)
- Philip E. Castle (ORCID: https://orcid.org/0000-0002-6408-5985)
- Mark Schiffman (ORCID: https://orcid.org/0000-0002-4625-2508)
- Nicolas Wentzensen (ORCID: https://orcid.org/0000-0003-1251-0836)
- Zigui Chen (ORCID: https://orcid.org/0000-0002-8577-1298)
- Laurie Burdett
- Bin Zhu (ORCID: https://orcid.org/0000-0003-0172-5516)
- Amulya Shastry (ORCID: https://orcid.org/0009-0007-8866-2357)
- Meredith Yeager (ORCID: https://orcid.org/0000-0003-3871-2225)
- Joseph F. Boland (ORCID: https://orcid.org/0000-0003-2762-190X)
Institutions
- Leidos (United States) (US)
- National Institutes of Health (US)
- Albert Einstein College of Medicine (US)
- Kaiser Permanente (US)
- Chinese University of Hong Kong (HK)
- National Cancer Institute (US)
- Department of Health and Human Services (US)
- Leidos Biomedical Research Inc. (United States)
- Hood College (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-12
- DOI
- https://doi.org/10.1038/s41467-024-51713-y
- Citations
- 7
- Primary Topic
- Cervical Cancer and HPV Research
- Type
- article
- Field-Weighted Citation Impact
- 2.71
Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- National Cancer Institute
- Division of Cancer Epidemiology and Genetics, National Cancer Institute