The mutational landscape of recurrent versus nonrecurrent human papillomavirus–related oropharyngeal cancer
R. Alex Harbison, Mark Kubik, Eric Q. Konnick, Qing Zhang, Seok-Geun Lee, Heuijoon Park, Jianan Zhang, Christopher S. Carlson, Chu Chen, Stephen M. Schwartz, Cristina P. Rodriguez, Umamaheswar Duvvuri, Eduardo Méndez
R. Alex Harbison, Mark Kubik, Eric Q. Konnick, Qing Zhang, Seok-Geun Lee, Heuijoon Park, Jianan Zhang, Christopher S. Carlson, Chu Chen, Stephen M. Schwartz, Cristina P. Rodriguez, Umamaheswar Duvvuri, Eduardo Méndez
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Clinical Research and Public Health Oncology

The mutational landscape of recurrent versus nonrecurrent human papillomavirus–related oropharyngeal cancer

Abstract

BACKGROUND. Human papillomavirus–related (HPV-related) oropharyngeal squamous cell carcinomas (OPSCCs) have an excellent response rate to platinum-based chemoradiotherapy. Genomic differences between primary HPV-related OPSCCs that do or do not recur are unknown. Furthermore, it is unclear if HPV-related OPSCCs that recur share a genomic landscape with HPV-negative head and neck cancers (HNCs). METHODS. We utilized whole exome sequencing to analyze somatic nucleotide (SNVs) and copy number variants (CNVs) among a unique set of 51 primary HPV-related OPSCCs, including 35 that did not recur and 16 that recurred. We evaluated 12 metachronous recurrent OPSCCs (7 with paired primary OPSCCs) and 33 primary HPV-unrelated oral cavity and OPSCCs. RESULTS.KMT2D was the most frequently mutated gene among primary HPV-related OPSCCs (n = 51; 14%) and among metachronous recurrent OPSCCs (n = 12; 42%). Primary HPV-related OPSCCs that recurred shared a genomic landscape with primary HPV-related OPSCCs that did not recur. However, TSC2, BRIP1, NBN, and NFE2L2 mutations occurred in primary OPSCCs that recurred but not in those that did not recur. Moreover, primary HPV-related OPSCCs that recur harbor features of HPV-unrelated HNCs, notably including MAPK, JAK/STAT, and differentiation signaling pathway aberrations. Metachronous recurrent OPSCCs shared a genomic landscape with HPV-unrelated HNCs, including a high frequency of TP53, CASP8, FAT1, HLA-A, AJUBA, and NSD1 genomic alterations. CONCLUSION. Overall, primary HPV-related OPSCCs that recur share a genomic landscape with nonrecurrent OPSCCs. Metachronous recurrent OPSCCs share genomic features with HPV-negative HNCs. These data aim to guide future deescalation endeavors and functional experiments. FUNDING. This study is supported by the American Cancer Society (RSG TBG-123653), funding support for RAH (T32DC00018, Research Training in Otolaryngology, University of Washington), funds to EM from Seattle Translational Tumor Research (Fred Hutchinson Cancer Research Center), and center funds from the Fred Hutchinson Cancer Research Center to EM. UD is supported by the Department of Veterans Affairs, Biomedical Laboratory Research and Development (BLR&D), grant IO1-oo23456, and funds from the Pittsburgh Foundation and PNC Foundation.

Authors

R. Alex Harbison, Mark Kubik, Eric Q. Konnick, Qing Zhang, Seok-Geun Lee, Heuijoon Park, Jianan Zhang, Christopher S. Carlson, Chu Chen, Stephen M. Schwartz, Cristina P. Rodriguez, Umamaheswar Duvvuri, Eduardo Méndez

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Figure 4

Integrated analysis of genomic aberrations.

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Integrated analysis of genomic aberrations. (A) Multiple correspondence ...
(A) Multiple correspondence analysis (MCA) was performed to compare patterns of genomic alterations (i.e., somatic mutation and copy number variants) between primary HPV-related OPSCCs that did (n = 16) or did not recur (n = 35), metachronous recurrent OPSCCs (n = 12), and primary HPV-unrelated OCSCCs and OPSCCs (n = 33). Associations between genomic features are represented graphically in the MCA plot illustrating the statistical relationships among distinct features. The analysis considers 41 HPV-negative–like genes. A sample that has a mutation and/or copy number aberration is defined as having a genomic aberration for a given gene. Small colored dots represent individual tumors. Large dots represent the average position on the first 2 principal dimensions of variance among all tumors within a group. There is one large point for each of the 4 groups. Diamonds represent the contribution of the selected genes to each of the first 2 principal dimensions. Groups that plot close to each other on the ordinate and/or abscissa are related statistically. MCA coordinates are encompassed by 95% confidence ellipses. Samples clustering on the positive pole of the x axis harbor more HPV-negative–like genomic features, while those on the negative pole of the x axis harbor fewer HPN-negative–like features. (B) Dot plot illustrating the percent of tumors in each of the 4 groups with a somatic mutation and/or copy number variant in a set of 10 genes that are frequently altered in HPV-negative head and neck cancer.