Yipeng Song1, Jian Huang2, Dandan Liang3, Ying Hu4, Beibei Mao3, Qiujing Li5, Huaibo Sun3, Ying Yang3, Jiao Zhang3, Henghui Zhang6, Huan Chen3, Hao Liu7, Shukun Zhang5. 1. Department of Radiation Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China. 2. Institute of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, China. 3. Medical Department, Genecast Biotechnology Co., Ltd, Wuxi, China. 4. Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China. 5. Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, China. 6. Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China. 7. Department of Oncology, Sichuan Provincial People's Hospital, Chengdu, China.
Abstract
BACKGROUND: DNA damage repair (DDR) genes were recently implicated in the anti-tumor immune response. Therefore, it is worthwhile to unravel the implications of DDR pathways in the shaping of immune responsiveness in colorectal cancer (CRC) patients receiving immune checkpoint inhibitors (ICI). METHODS: We analyzed publicly available genomic data from a cohort treated with ICI from Memorial Sloan Kettering Cancer Center (MSK ICI cohort). To characterize the impact of the DDR mutation, the genomic data of The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma (COADREAD) dataset was explored. We also analyzed the incidence of DDR mutation and microsatellite instability-high (MSI-H) in a Chinese CRC cohort using panel sequencing. RESULTS: The DDR pathway was commonly mutated (21.8%) in the multicancer MSK ICI cohort, with the highest frequency of 36.4% in CRCs. Survival analysis showed that DDR mutation correlated with an improved overall survival (OS) in CRCs and pan-cancer in the MSK ICI cohort. However, no significant associations were identified in the TCGA COADREAD and MSK non-ICI CRCs. DDR mutation was associated with higher tumor mutational burden (TMB) levels and increased immune cell infiltration and immune checkpoint molecule expression in the TCGA COADREAD dataset. Last, we investigated the DDR mutational pattern and its associations with MSI-H and other genomic features in a Chinese CRC cohort. Notably, MSI-H and DDR mutation was present in 5.7% and 13.4% of cases, respectively, which suggests that DDR identifies a higher proportion of potential responders than MSI-H. CONCLUSION: Our data suggest that DDR mutation as an indication of enhanced cancer immunity, and it may function as a biomarker for patients with CRCs receiving ICI treatment. The high incidence of DDR mutation in the Chinese CRC cohort emphasizes the future utility of panel-based DDR evaluation in guiding ICI treatment.
BACKGROUND: DNA damage repair (DDR) genes were recently implicated in the anti-tumor immune response. Therefore, it is worthwhile to unravel the implications of DDR pathways in the shaping of immune responsiveness in colorectal cancer (CRC) patients receiving immune checkpoint inhibitors (ICI). METHODS: We analyzed publicly available genomic data from a cohort treated with ICI from Memorial Sloan Kettering Cancer Center (MSK ICI cohort). To characterize the impact of the DDR mutation, the genomic data of The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma (COADREAD) dataset was explored. We also analyzed the incidence of DDR mutation and microsatellite instability-high (MSI-H) in a Chinese CRC cohort using panel sequencing. RESULTS: The DDR pathway was commonly mutated (21.8%) in the multicancer MSK ICI cohort, with the highest frequency of 36.4% in CRCs. Survival analysis showed that DDR mutation correlated with an improved overall survival (OS) in CRCs and pan-cancer in the MSK ICI cohort. However, no significant associations were identified in the TCGA COADREAD and MSK non-ICI CRCs. DDR mutation was associated with higher tumor mutational burden (TMB) levels and increased immune cell infiltration and immune checkpoint molecule expression in the TCGA COADREAD dataset. Last, we investigated the DDR mutational pattern and its associations with MSI-H and other genomic features in a Chinese CRC cohort. Notably, MSI-H and DDR mutation was present in 5.7% and 13.4% of cases, respectively, which suggests that DDR identifies a higher proportion of potential responders than MSI-H. CONCLUSION: Our data suggest that DDR mutation as an indication of enhanced cancer immunity, and it may function as a biomarker for patients with CRCs receiving ICI treatment. The high incidence of DDR mutation in the Chinese CRC cohort emphasizes the future utility of panel-based DDR evaluation in guiding ICI treatment.
Authors: Jessica N McAlpine; Henry Porter; Martin Köbel; Brad H Nelson; Leah M Prentice; Steve E Kalloger; Janine Senz; Katy Milne; Jiarui Ding; Sohrab P Shah; David G Huntsman; C Blake Gilks Journal: Mod Pathol Date: 2012-01-27 Impact factor: 7.842
Authors: Kent W Mouw; Michael S Goldberg; Panagiotis A Konstantinopoulos; Alan D D'Andrea Journal: Cancer Discov Date: 2017-06-19 Impact factor: 39.397
Authors: Wenjuan Dong; Xiaojin Wu; Shoubao Ma; Yufeng Wang; Ansel P Nalin; Zheng Zhu; Jianying Zhang; Don M Benson; Kai He; Michael A Caligiuri; Jianhua Yu Journal: Cancer Discov Date: 2019-07-24 Impact factor: 39.397
Authors: Mark Ayers; Jared Lunceford; Michael Nebozhyn; Erin Murphy; Andrey Loboda; David R Kaufman; Andrew Albright; Jonathan D Cheng; S Peter Kang; Veena Shankaran; Sarina A Piha-Paul; Jennifer Yearley; Tanguy Y Seiwert; Antoni Ribas; Terrill K McClanahan Journal: J Clin Invest Date: 2017-06-26 Impact factor: 14.808
Authors: Dung T Le; Jennifer N Uram; Hao Wang; Bjarne R Bartlett; Holly Kemberling; Aleksandra D Eyring; Andrew D Skora; Brandon S Luber; Nilofer S Azad; Dan Laheru; Barbara Biedrzycki; Ross C Donehower; Atif Zaheer; George A Fisher; Todd S Crocenzi; James J Lee; Steven M Duffy; Richard M Goldberg; Albert de la Chapelle; Minori Koshiji; Feriyl Bhaijee; Thomas Huebner; Ralph H Hruban; Laura D Wood; Nathan Cuka; Drew M Pardoll; Nickolas Papadopoulos; Kenneth W Kinzler; Shibin Zhou; Toby C Cornish; Janis M Taube; Robert A Anders; James R Eshleman; Bert Vogelstein; Luis A Diaz Journal: N Engl J Med Date: 2015-05-30 Impact factor: 91.245
Authors: Willy Hugo; Jesse M Zaretsky; Lu Sun; Chunying Song; Blanca Homet Moreno; Siwen Hu-Lieskovan; Beata Berent-Maoz; Jia Pang; Bartosz Chmielowski; Grace Cherry; Elizabeth Seja; Shirley Lomeli; Xiangju Kong; Mark C Kelley; Jeffrey A Sosman; Douglas B Johnson; Antoni Ribas; Roger S Lo Journal: Cell Date: 2016-03-17 Impact factor: 41.582
Authors: Valerie Chew; Jinmiao Chen; Deming Lee; Evelyn Loh; Joyce Lee; Kiat Hon Lim; Achim Weber; Ksenija Slankamenac; Ronnie T P Poon; Henry Yang; London Lucien P J Ooi; Han Chong Toh; Mathias Heikenwalder; Irene O L Ng; Alessandra Nardin; Jean-Pierre Abastado Journal: Gut Date: 2011-09-19 Impact factor: 23.059
Authors: Michael S Lawrence; Petar Stojanov; Craig H Mermel; James T Robinson; Levi A Garraway; Todd R Golub; Matthew Meyerson; Stacey B Gabriel; Eric S Lander; Gad Getz Journal: Nature Date: 2014-01-05 Impact factor: 49.962