TY - JOUR
T1 - Variations in HPV function are associated with survival in squamous cell carcinoma
AU - Gleber-Netto, Frederico O.
AU - Rao, Xiayu
AU - Guo, Theresa
AU - Xi, Yuanxin
AU - Gao, Meng
AU - Shen, Li
AU - Erikson, Kelly
AU - Kalu, Nene N.
AU - Ren, Shuling
AU - Xu, Guorong
AU - Fisch, Kathleen M.
AU - Akagi, Keiko
AU - Seiwert, Tanguy
AU - Gillison, Maura
AU - Frederick, Mitchell J.
AU - Johnson, Faye M.
AU - Wang, Jing
AU - Myers, Jeffrey N.
AU - Califano, Joseph
AU - Skinner, Heath D.
AU - Pickering, Curtis R.
N1 - Publisher Copyright:
© Copyright 2019, American Society for Clinical Investigation.
PY - 2019/1/10
Y1 - 2019/1/10
N2 - 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 deescalation 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.
AB - 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 deescalation 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.
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U2 - 10.1172/jci.insight.124762
DO - 10.1172/jci.insight.124762
M3 - Article
C2 - 30626753
AN - SCOPUS:85063758185
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 1
M1 - e124762
ER -