YAP1 transcription factor expression to define subsets of cancers with T-cell inflamed phenotype in a pan-tumor analysis across 33 tumor types.
Authors: Dwivedi Bhakti , Ivanov Andrey , Zhang Guojing , Khuri Fadlo Raja , Ramalingam Suresh S. , Fu Haian , Sica Gabriel , Owonikoko Taofeek K. 
Published: June 2021

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Background: Immune checkpoint blockade (ICB) has become an established treatment option for the majority of solid tumors. PD-L1 expression, tumor mutation burden (TMB) and mismatch repair (MMR) deficiency are established but suboptimal predictive markers to select patients for ICB therapy. The identification of better predictive biomarkers to complement existing biomarkers is an area of need. We previously identified Yes Associated Protein 1 (YAP1) gene expression as a marker of inflamed tumor phenotype in small cell lung cancer. We sought to elucidate the role of YAP1 as a tumor agnostic biomarker of inflamed tumor phenotype. Methods: We obtained the publicly available TCGA normalized RSEM expression data (version dated September 29, 2019) from the GDC legacy archive (https://portal.gdc.cancer.gov/legacy-archive) for this analysis. We used the shinySISPA method ( https://bbisr.shinyapps.winship.emory.edu/shinySISPA/ ) to classify the primary tumor samples into YAP1 high or low on the basis of the normalized expression profile for YAP1 gene. The T-cell–inflamed gene expression profile score for each sample was calculated as weighted sum of the normalized expression values of the 18 genes ( PSMB10, HLA-DQA1, HLA-DRB1, CMKLR1, HLA-E, NKG7, CD8A, CCL5, CXCL9, CD27, CXCR6, IDO1, STAT1, TIGIT, LAG3, CD274, PDCD1LG2, CD276) as originally published in the Patent filed under “WO201609437” and validated as a predictor of clinical efficacy in patients treated with anti PD1 immunotherapy drug, pembrolizumab. Results: A total of 11283 samples from 33 different histologic tumor types contained in the TCGA database were included in this analysis. A small but meaningful subset of cases 271 (2%) were classified as YAP1 high with a wide range in proportion of YAP1 high tumors of 0.67% to 12.09% across the 33 histologic tumor types. Adrenocortical, cholangiocarcinoma, chromophobe RCC, DLBCL, and mesothelioma had a high rate of YAP1 high tumors (> 10% of cases). Overall trend showed a higher median interferon gamma GEP score in YAP1 high versus YAP1 low tumors with a GEP score of 11.2 vs. 10.7 respectively. A minority of histologic tumor subtypes (HNSCC, clear cell RCC, sarcoma, uterine carcinosarcoma, testicular GCT, melanoma, mesothelioma and ovarian cancer) showed a reverse trend of lower GEP score in association with YAP1 high status. Ongoing validation of these findings in an independent cohort of clinical samples and correlation of YAP1 status with other predictive biomarkers (TMB, PD-L1 and MSS status) will be presented at the meeting. Conclusions: YAP1 is highly expressed in a small but meaningful subsets of cancers and is associated with the inflamed phenotype in the majority of cancers. YAP1 expression is most common in rarer tumor types and in histologic types where currently available biomarkers have not been shown to predict the benefit of ICB.