Abstract
By analyzing the genomic data of head and neck squamous cell cancer (HNSCC), we investigated clinical significance of YAP1 activation. Copy number and mRNA expression of YAP1 were analyzed together to assess clinical relevance of YAP1 activation in HNSCC. The clinical significance of YAP1 activation was further validated in four independent test cohorts. We also assessed the correlation of YAP1 activation with genomic alterations such as copy number alteration, somatic mutation, and miRNA expression. The YAP1-activated (YA) subgroup showed worse prognosis for HNSCC as tested and validated in five cohorts. In a multivariate risk analysis, the YAP1 signature was the most significant predictor of overall survival. The YAP1-inactivated (YI) subgroup was associated with HPV-positive status. In multiplatform analysis, YA tumors had gain of EGFR and SNAI2; loss of tumor-suppressor genes such as CSMD1, CDKN2A, NOTCH1, and SMAD4; and high mutation rates of TP53 and CDKN2A. YI tumors were characterized by gain of PIK3CA, SOX2, and TP63; deletion of 11q23.1; and high mutation rates of NFE2L2, PTEN, SYNE1, and NSD1. YA tumors also showed weaker immune activity as reflected in low IFNG composite scores and YAP1 activity is negatively associated with potential response to treatment of pembrolizumab. In conclusion, activation of YAP1 is associated with worse prognosis of patients with HNSCC and potential resistance to immunotherapy.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading type of cancer worldwide, with an annual incidence of approximately 600,000 cases and a mortality rate of 40% to 50% [1, 2]
Activation of Yes-associated protein-1 (YAP1) has been reported in many cancers [5, 16, 18, 21,22,23,24], its relative activity across all cancer types has not been systematically examined
Many tumors without YAP1 amplification showed a high probability of YAP1 activity (Figure 1A), further supporting our notion that YAP1 amplification may not be the only mechanism for YAP1 activation in head and neck squamous cell cancer (HNSCC)
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading type of cancer worldwide, with an annual incidence of approximately 600,000 cases and a mortality rate of 40% to 50% [1, 2]. The kinase module includes mammalian STE20-like protein kinase 1 (MST1) and MST2, large tumor suppressor 1 (LATS1) and LATS2, together with the adaptor proteins Salvador homologue 1 (SAV1), MOB kinase activator 1A (MOB1A), and MOB1B [6,7,8,9,10,11]. These inhibitory kinase modules regulate tissue growth by suppressing the transcription module such as the Yes-associated protein-1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) [12]. In a study of the mutational landscape across 12 major cancer types, significantly mutated genes of hippo signaling were found in several cancers included HNSCC [13]
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