Deciphering the Network Architecture of APOBEC3-Driven Mutagenesis in HPV-Positive Head and Neck Cancers
- 1Texas Biomedical Research Institute
Abstract
APOBEC3A (A3A) and APOBEC3B (A3B) are cytosine deaminases that restrict viral infection and can also mutate the host genome. In human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC), expression of both enzymes is elevated, but bulk sequencing averages their effects across mixed cell populations. Here we profile single cells from HPV16-positive HNSCC tumors and matched normal tissue. We find that the APOBEC3 (A3) single base substitution mutational signature, SBS2, is enriched in cells expressing more A3A than A3B, whereas copy number alteration (CNA) burden is enriched in cells expressing more A3B than A3A. Tumor versus normal co-expression networks identify the A3 interactors RALY and HNRNPA2B1 as candidate A3 activators. We find that SBS2 and CNA mark the maintenance and virus assembly stages of the HPV16 life cycle, and their ratio may offer a molecular estimate of tumor age. The neoantigens from immune-visible SBS2-HIGH and immune-evasive CNA-HIGH cells identify candidates for mRNA vaccines matched to a tumor's viral state.
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BibTeX
@misc{lehle2026deciphering,
title = {{Deciphering the Network Architecture of APOBEC3-Driven Mutagenesis in HPV-Positive Head and Neck Cancers}},
author = {J. D. Lehle and M. Soleimanpour and N. Haghjoo and C. Rorex and F. Li and A. D. Mendez and R. Springman-Rodriguez and E. Sommer and C.-M. Chiang and D. Ebrahimi},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752415},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752415v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Deciphering the Network Architecture of APOBEC3-Driven Mutagenesis in HPV-Positive Head and Neck Cancers
AU - J. D. Lehle
AU - M. Soleimanpour
AU - N. Haghjoo
AU - C. Rorex
AU - F. Li
AU - A. D. Mendez
AU - R. Springman-Rodriguez
AU - E. Sommer
AU - C.-M. Chiang
AU - D. Ebrahimi
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752415
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752415v1
AB - APOBEC3A (A3A) and APOBEC3B (A3B) are cytosine deaminases that restrict viral infection and can also mutate the host genome. In human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC), expression of both enzymes is elevated, but bulk sequencing averages their effects across mixed cell populations. Here we profile single cells from HPV16-positive HNSCC tumors and matched normal tissue. We find that the APOBEC3 (A3) single base substitution mutational signature, SBS2, is enriched in cells expressing more A3A than A3B, whereas copy number alteration (CNA) burden is enriched in cells expressing more A3B than A3A. Tumor versus normal co-expression networks identify the A3 interactors RALY and HNRNPA2B1 as candidate A3 activators. We find that SBS2 and CNA mark the maintenance and virus assembly stages of the HPV16 life cycle, and their ratio may offer a molecular estimate of tumor age. The neoantigens from immune-visible SBS2-HIGH and immune-evasive CNA-HIGH cells identify candidates for mRNA vaccines matched to a tumor's viral state.
ER -