High-risk human papillomavirus (hrHPV) causes squamous cell carcinoma (SCC) at a variety of sites, including cervix, head and neck, anus, vulva, vagina, and penis. The 9-valent HPV vaccine is highly effective at preventing carcinomas at these sites related to the specific HPV types it covers. Among women with hrHPV detected in routine cervical swabs, however, the distribution of hrHPV types is known to differ by racial/ethnic group, with East and West Africans1 and North Americans of African ancestry2,3 showing overrepresentation of hrHPV types that are not covered by the current 9-valent HPV vaccine. Corresponding studies of HPV type distribution by ethnicity in advanced-stage hrHPV-related cancers are limited. In this investigation, we performed a retrospective analysis of a large multiethnic study of advanced-stage carcinoma samples to test the hypothesis that patients of African vs non-African ancestry may show dissimilar distributions of nonvaccine hrHPV types.
Our archive of 290 311 tumor samples, each from a different patient, underwent comprehensive genomic profiling using a hybrid-capture–based DNA sequencing platform.4 The samples were sent from medical care facilities across North America from January 2014 to June 2020 for detection of targetable genetic alterations during routine clinical care. Western Institutional Review Board approved this study, including issuing an informed consent waiver and a HIPAA waiver of authorization. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies. We detected hrHPV genomic sequences in 3793 cervical, anogenital, and head and neck SCCs by de novo assembly of nonhuman reads, followed by alignment to the RefSeq database, which distinguishes hrHPV types.5 Patient ancestry was determined by classifying specific single-nucleotide variations by genomic profiling based on their known variation among populations in the 1000 Genomes Project.6 The comparator groups were individuals of African vs non-African ancestry. Categorical data were analyzed by Fisher exact test using Prism version 8.3.1 (GraphPad Software). Data were analyzed in July 2020. A 2-tailed P value of <.05 was considered statistically significant; the Bonferroni correction was applied for multiple simultaneous comparisons. Statistical analysis was performed for hrHPV types with 10 or more cancer cases total in individuals of African ancestry.
We identified 5 hrHPV types each with 10 or more SCC cases in individuals of African ancestry: HPV-16 (193 cases), HPV-18 (56 cases), HPV-35 (17 cases), HPV-45 (27 cases), and HPV-59 (16 cases). Compared with non-African groups, individuals of African ancestry showed significant, several-fold enrichments for HPV types 35 (5.3% vs 1.6%; P < .001), 45 (8.4% vs 3.4%; P < .001), and 59 (5.0% vs 0.5%; P < .001) (Figure), with significant enrichments in cervical (HPV-35, 5.2% vs 1.3%; P = .003; HPV-59, 9.0% vs 0.9%; P < .001) and anal (HPV-45, 7.0% vs 1.0%; P = .003) carcinomas after stratification by primary site (Figure).
The 2 nonvaccine hrHPV types (HPV-35 and HPV-59) accounted for 10.3% (33/321 cases) of all hrHPV-related SCCs in persons of African ancestry, but only 2.1% (72/3472 cases) of hrHPV-related SCCs in individuals of other ancestries, a difference of nearly 5-fold (P < .00001). Prevalences were comparatively low across all 4 non-African ancestral groups (eTable in the Supplement). Demographic data by primary site and African vs non-African ancestry are provided in the Table. Tumor mutational burden and genomic alterations showed essentially no significant differences based on patient ancestry, suggesting similar tumorigenic mechanisms (Table).
In our pan-hrHPV analysis of SCCs, hrHPV types not covered by the current 9-valent vaccine were increased in individuals of African ancestry. It has been hypothesized that HPV-35 might be better adapted to individuals of African ancestry,3 or the increased prevalence may be a consequence of ancient geographic isolation.3 The current study was limited by its retrospective nature, lack of knowledge of vaccination status, and the nature of our underlying sample set, which favored advanced disease. While our study indicated that the large majority of hrHPV types identified in advanced SCCs are included in the current 9-valent vaccine irrespective of patient ancestry, our data argue for the addition of HPV types 35 and 59. Future studies and vaccine decisions should involve consideration of ancestrally diverse populations.
Accepted for Publication: February 27, 2021.
Published: May 10, 2021. doi:10.1001/jamanetworkopen.2021.6481
Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2021 Williams EA et al. JAMA Network Open.
Corresponding Author: Erik A. Williams, MD, University of California, San Francisco, 1701 Divisadero St, San Francisco, CA 94115 (erik.williams@ucsf.edu).
Author Contributions: Drs E. Williams and Montesion had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Lin and Elvin contributed equally to this work.
Concept and design: E. Williams, K. Williams, Elvin.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: E. Williams, Lin.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: E. Williams, Newberg, K. Williams.
Administrative, technical, or material support: Montesion, Alexander.
Supervision: Elvin.
Conflict of Interest Disclosures: Drs E. Williams, Newberg, Montesion, Alexander, Lin, and Elvin are employees or consultants of Foundation Medicine Inc, a wholly owned subsidiary of Roche Holdings Inc and Roche Finance Ltd, and these employees have equity interest in an affiliate of these Roche entities. No other disclosures were reported.
Meeting Presentation: This work was presented at the Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-21, 2021.
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