Rong Tang1,2,3,4, Xiaomeng Liu1,2,3,4, Wei Wang1,2,3,4, Jie Hua1,2,3,4, Jin Xu1,2,3,4, Chen Liang1,2,3,4, Qingcai Meng1,2,3,4, Jiang Liu1,2,3,4, Bo Zhang1,2,3,4, Xianjun Yu5,6,7,8, Si Shi9,10,11,12. 1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China. 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. 3. Shanghai Pancreatic Cancer Institute, Shanghai, China. 4. Pancreatic Cancer Institute, Fudan University, Shanghai, China. 5. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China. yuxianjun@fudanpci.org. 6. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. yuxianjun@fudanpci.org. 7. Shanghai Pancreatic Cancer Institute, Shanghai, China. yuxianjun@fudanpci.org. 8. Pancreatic Cancer Institute, Fudan University, Shanghai, China. yuxianjun@fudanpci.org. 9. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China. shisi@fudanpci.org. 10. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. shisi@fudanpci.org. 11. Shanghai Pancreatic Cancer Institute, Shanghai, China. shisi@fudanpci.org. 12. Pancreatic Cancer Institute, Fudan University, Shanghai, China. shisi@fudanpci.org.
Abstract
BACKGROUND: High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. However, whether high TMB predicts the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC) remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC. METHODS: The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study. RESULTS: The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBlowMicrosatellite instabilityhigh (MSIhigh) was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits. CONCLUSION: This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.
BACKGROUND:High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. However, whether high TMB predicts the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC) remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC. METHODS: The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study. RESULTS: The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBlowMicrosatellite instabilityhigh (MSIhigh) was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits. CONCLUSION: This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.
Authors: Mikhail Binnewies; Edward W Roberts; Kelly Kersten; Vincent Chan; Douglas F Fearon; Miriam Merad; Lisa M Coussens; Dmitry I Gabrilovich; Suzanne Ostrand-Rosenberg; Catherine C Hedrick; Robert H Vonderheide; Mikael J Pittet; Rakesh K Jain; Weiping Zou; T Kevin Howcroft; Elisa C Woodhouse; Robert A Weinberg; Matthew F Krummel Journal: Nat Med Date: 2018-04-23 Impact factor: 53.440
Authors: Stephan Kruger; Matthias Ilmer; Sebastian Kobold; Bruno L Cadilha; Stefan Endres; Steffen Ormanns; Gesa Schuebbe; Bernhard W Renz; Jan G D'Haese; Hans Schloesser; Volker Heinemann; Marion Subklewe; Stefan Boeck; Jens Werner; Michael von Bergwelt-Baildon Journal: J Exp Clin Cancer Res Date: 2019-06-19