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HPV+ Oropharyngeal Squamous Cell Carcinomas from patients with two tumors display synchrony of viral genomes yet discordant mutational profiles and signatures.

Abstract：

:Human Papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV+OPSCC) is increasing in prevalence in the United States, as are cases of patients with multiple HPV+OPSCCs (mHPV+OPSCC). mHPV+OPSCCs present a unique opportunity to examine HPV+OPSCC mutation acquisition and evolution. We performed sequencing of the viral genome, somatic exome and somatic transcriptome from eight patients each with two spatially distinct HPV+OPSCCs, and 37 "traditional" HPV+OPSCCs to first address if paired tumors are caused by the same viral isolate and next, if acquired alterations, and the underlying processes driving mutagenesis, are shared within pairs. All tumor pairs contained viral genomes from the same HPV16 sublineage and differed by 0-2 clonal SNPs, suggesting infection with the same viral isolate. Despite this, there was significant discordance in expression profiles, mutational burden and mutational profiles between tumors in a pair, with only two pairs sharing any overlapping mutations (3/3,343 variants). Within tumor pairs there was a striking discrepancy of mutational signatures, exemplified by no paired tumors sharing high APOBEC mutational burden. Here, leveraging mHPV+OPSCCs as a model system to study mutation acquisition in virally mediated tumors, in which the germline, environmental exposures, immune surveillance and tissue/organ type were internally controlled, we demonstrate that despite infection by the same viral isolate, paired mHPV+OPSCCs develop drastically different somatic alterations and even more strikingly, appear to be driven by disparate underlying mutational processes. Thus, despite a common starting point, HPV+OPSCCs evolve through variable mutational processes with resultant stochastic mutational profiles.

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

Faden DL,Langenbucher A,Kuhs K,Lewis JS,Mirabello L,Yeager M,Boland JF,Bass S,Steinberg M,Cullen M,Lawrence MS,Ferris RL

doi

10.1093/carcin/bgaa111

subject

Has Abstract

pub_date

2020-10-19 00:00:00

eissn

0143-3334

issn

1460-2180

pii

5930843

pub_type

杂志文章

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HPV+ Oropharyngeal Squamous Cell Carcinomas from patients with two tumors display synchrony of viral genomes yet discordant mutational profiles and signatures.