Variations in HPV function are associated with survival in squamous cell carcinoma
Frederico O. Gleber-Netto, … , Heath D. Skinner, Curtis R. Pickering
Frederico O. Gleber-Netto, … , Heath D. Skinner, Curtis R. Pickering
Published January 10, 2019
Citation Information: JCI Insight. 2019;4(1):e124762. https://doi.org/10.1172/jci.insight.124762.
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Research Article Oncology Virology

Variations in HPV function are associated with survival in squamous cell carcinoma

Abstract

Incidence of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has been increasing dramatically. Although long-term survival rates for these patients are high, they often suffer from permanent radiotherapy-related morbidity. This has prompted the development of de-escalation clinical protocols to reduce morbidity. However, a subset of patients do not respond even to standard therapy and have poor outcomes. It is unclear how to properly identify and treat the high- and low-risk HPV+ OPSCC patients. Since HPV positivity drives radiotherapy sensitivity, we hypothesized that variations in HPV biology may cause differences in treatment response and outcome. By analyzing gene expression data, we identified variations in HPV-related molecules among HPV+ OPSCC. A subset of tumors presented a molecular profile distinct from that of typical HPV+ tumors and exhibited poor treatment response, indicating molecular and clinical similarities with HPV– tumors. These molecular changes were also observed in vitro and correlated with radiation sensitivity. Finally, we developed a prognostic biomarker signature for identification of this subgroup of HPV+ OPSCC and validated it in independent cohorts of oropharyngeal and cervical carcinomas. These findings could translate to improved patient stratification for treatment deintensification and new therapeutic approaches for treatment-resistant HPV-related cancer.

Authors

Frederico O. Gleber-Netto, Xiayu Rao, Theresa Guo, Yuanxin Xi, Meng Gao, Li Shen, Kelly Erikson, Nene N. Kalu, Shuling Ren, Guorong Xu, Kathleen M. Fisch, Keiko Akagi, Tanguy Seiwert, Maura Gillison, Mitchell J. Frederick, Faye M. Johnson, Jing Wang, Jeffrey N. Myers, Joseph Califano, Heath D. Skinner, Curtis R. Pickering

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Figure 1

Expression of HPV-correlated human tumor genes among OPSCC samples.

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Expression of HPV-correlated human tumor genes among OPSCC samples. (A) ...
(A) Expression of 582 HPV-correlated genes (vertical axis) among 80 OPSCC patients (horizontal axis) from TCGA. Three groups with distinct gene expression were identified: OPSCC C1 (n = 20, 2 HPV– and 18 HPV+), C2 (n = 34, all HPV+), and C3 (n = 26, all HPV–). (B) Expression of 582 HPV-correlated genes in OPSCC C1 (n = 20) group relative to OPSCC C2 (n = 34) and to OPSCC C3 (n = 26) groups. Vertical axis represents the product of fold change (log2) between OPSCC C1 and OPSCC C3 and between OPSCC C2 and C3. Values close to 0 (–0.2 to 0.2, blue) indicate OPSCC C1 gene expression similar to OPSCC C3 mean. Values close to 1 (0.8 to 1.2, orange) indicate OPSCC C1 gene expression similar to OPSCC C2 mean. Gene expression in OPSCC C1 group was similar to OPSCC C2 in 50% of cases (n = 291) and was intermediate between OPSCC C2 and C3 in 44% (n = 256) of cases. (C) PCA confirmed the different expression profiles among the groups of OPSCC (n = 80). (D) Survival curves indicate that the OPSCC C1 (7 deaths) and OPSCC C3 (13 deaths) groups had significantly lower survival rates in the 5-year follow-up period compared with OPSCC C2 group (2 deaths). (E) Expression of 38 HPV-correlated genes (differentially expressed between OPSCC C1 and OPSCC C2) (vertical axis) among TCGA patients with HPV+ OPSCC (n = 52) shows 2 groups of patients, HPV+ C1 (n = 19) and HPV+ C2 (n = 33). (F) Survival curves show that the HPV+ C1 group had a significantly lower 5-year survival rate than the HPV+ C2 group (log-rank test). (G) PCA based on expression levels of 38 HPV-correlated genes indicates HPV+ C1 (n = 19) samples have an intermediate expression profile between HPV– (n = 28) and HPV+ C2 (n = 33) samples. (H) Expression of 38 HPV-correlated genes in HPV+ C1 (n = 19) group relative to HPV+ C2 (n = 33) and HPV– (n = 19) groups. Vertical axis represents the product of fold change (log2) between HPV+ C1 and HPV– and between HPV+ C2 and HPV–. Values close to 0 (–0.2 to 0.2, blue), indicate HPV+ C1 gene expression similar to HPV– cases. Values close to 1 (0.8 to 1.2, orange), indicate HPV+ C1 gene expression similar to HPV+ C2 mean. Expression levels of 97% (n = 37) of these genes in HPV+ C1 group were intermediate between HPV+ C2 and HPV– groups.