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

Maisa Pinheiro, Nicolas Wentzensen, Michael Dean, Meredith Yeager, Zigui Chen, Amulya Shastry, Joseph F. Boland, Sara Bass, Laurie Burdett, Thomas Lorey, Sambit Mishra, Philip E. Castle, Mark Schiffman, Robert D. Burk, Bin Zhu and Lisa Mirabello ()
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Maisa Pinheiro: National Cancer Institute, National Institutes of Health
Nicolas Wentzensen: National Cancer Institute, National Institutes of Health
Michael Dean: National Cancer Institute, National Institutes of Health
Meredith Yeager: National Cancer Institute, National Institutes of Health
Zigui Chen: The Chinese University of Hong Kong
Amulya Shastry: National Cancer Institute, National Institutes of Health
Joseph F. Boland: National Cancer Institute, National Institutes of Health
Sara Bass: National Cancer Institute, National Institutes of Health
Laurie Burdett: National Cancer Institute, National Institutes of Health
Thomas Lorey: Kaiser Permanente Northern California
Sambit Mishra: National Cancer Institute, National Institutes of Health
Philip E. Castle: National Cancer Institute, National Institutes of Health
Mark Schiffman: National Cancer Institute, National Institutes of Health
Robert D. Burk: Albert Einstein College of Medicine
Bin Zhu: National Cancer Institute, National Institutes of Health
Lisa Mirabello: National Cancer Institute, National Institutes of Health

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51713-y

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