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. 2018 Jul 26;3(14):e99327.
doi: 10.1172/jci.insight.99327.

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

R Alex Harbison  1   2   3 , Mark Kubik  4 , Eric Q Konnick  5 , Qing Zhang  6 , Seok-Geun Lee  3   7 , Heuijoon Park  3 , Jianan Zhang  8 , Christopher S Carlson  9 , Chu Chen  1   2   9 , Stephen M Schwartz  2   9 , Cristina P Rodriguez  3   10 , Umamaheswar Duvvuri  4 , Eduardo Méndez  1   3
Affiliations

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

R Alex Harbison et al. JCI Insight. .

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.

Keywords: Cancer; Head & neck cancer; Molecular diagnosis; Oncology.

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Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists. This work does not represent the views of the US Government nor the Department of Veterans Affairs.

Figures

Figure 1
Figure 1. Mutational landscape of primary HPV-related OPSCCs (n = 51).
(A) Conceptual diagram illustrating study aims and sample sizes. (B) Genes mutated in at least 5% of primary OPSCC tumors are shown in order of descending frequency. Each column represents a patient. Rows represent genes. q values from the MutSigCV and VEST algorithms are listed in the right 2 columns. Colored bars represent mutations as described in the legend. Gray bars represent a nonmutated gene of a given tumor. (C) Amino acid changes associated with respective KMT2D mutations in this study population are illustrated. Colored bars represent functional domains of the amino acid sequence. Gray areas between colored bars represent nonfunctional domains of the amino acid sequence.
Figure 2
Figure 2. Mutational differences between primary HPV-related OPSCC tumors that did not (n = 35) or did recur (n = 16) and mutational characteristics of metachronous recurrences.
(A) Genes mutated in at least 2 samples across primary HPV-related OPSSC that did or did not recur were analyzed. Columns represent individual patients. Genes (rows) are sorted by descending mutation frequency across all samples. While there were no statistically different gene mutation frequencies between groups, between-group comparisons with a Fisher exact q < 1.0 are denoted by an asterisk. Colored bars represent mutations as annotated in the legend, and gray bars represent nonmutated genes for a respective tumor. (B) Mutation patterns in 7 paired index primary and subsequent metachronous recurrent HPV-related OPSCCs. Gene mutations (rows) affecting at least 2 patients are illustrated. Genes mutated both in the index primary and paired metachronous recurrence are annotated in dark blue. Genes mutated only in the index primary tumor are annotated in light blue (i.e., lost at recurrence). Genes mutated only in a metachronous recurrence but not the index primary are annotated in red (i.e., gained at recurrence).
Figure 3
Figure 3. DNA copy number alterations.
(A) Log2 copy number alteration data for primary HPV-related OPSCC tumors that did not (n = 35, blue box) or did recur (n = 16, red box). Metachronous recurrent HPV-related OPSCCs (n = 12, green box) and primary HPV-unrelated OCSCCs and OPSCCs (n = 33, black box) are also illustrated. Rows represent cytobands. Columns represent samples. Copy number gains are represented in shades of red. Log2 copy number ratio equal to 1 is represented in darker red, with smaller gains in lighter shades of red. Copy number losses are represented by shades of blue. Log2 copy number ratio equal to –1 is represented by dark shades of blue, with smaller losses in lighter shades of blue. (B) Percent of samples with a copy gain or loss greater than log2 of 0.2 or less than log2 of –0.2. Rows represent cytobands. Fraction of tumors with copy loss or gain greater is on the x axis. Left panel: primary HPV-related OPSCCs that did vs. did not recur. Right panel: primary HPV-related OPSCCs that recurred vs. metachronous recurrent HPV-related OPSCCs. (C) GISTIC2.0 significant amplifications and deletions across primary HPV-related OPSCCs that did not recur (left panels) or recurred (middle panels) and metachronous recurrent HPV-related OPSCCs (right panels). Selected genes are annotated on respective cytobands. Green line, significance threshold (FDR q = 0.25).
Figure 4
Figure 4. Integrated analysis of genomic aberrations.
(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.
Figure 5
Figure 5. Analysis of key gene alterations grouped by biological function.
Somatic mutation and/or copy number alterations per tumor. Pathway constituents are described in the text. Dark blue boxes and points represent primary HPV-related OPSCCs that did not recur, and red boxes and points represent primary HPV-related OPSCCs that did recur. Metachronous recurrent OPSCCs are illustrated in light blue. TCGA HPV-unrelated OCSCCs and OPSCCs are represented in black. Boxes represent median and quartiles. Whiskers represent minimum and maximum. RTK, receptor tyrosine kinase; DDR, DNA damage repair; *, statistically significant differences in genomic aberration between the HPV-related OPSCCs vs. the HPV-unrelated control group (FDR q < 0.1, Dunn’s test). #, non–statistically significant differences between HPV-related OPSCCs that did vs. did not recur (FDR q < 0.15, Dunn’s test).
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