Ryuma Tokunaga1, Joanne Xiu2, Richard M Goldberg3, Philip A Philip4, Andreas Seeber5, Francesca Battaglin6, Hiroyuki Arai6, Jae Ho Lo6, Madiha Naseem6, Alberto Puccini6, Martin D Berger6, Shivani Soni6, Wu Zhang6, Sting Chen2, Jimmy J Hwang7, Anthony F Shields4, John L Marshall8, Hideo Baba9, W Michael Korn10, Heinz-Josef Lenz6. 1. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA; Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: mappymap@hotmail.co.jp. 2. Caris Life Sciences, Phoenix, USA. 3. West Virginia University Cancer Institute, Morgantown, USA. 4. Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, USA. 5. Department of Haematology and Oncology, Innsbruck Medical University, Innsbruck, Austria. 6. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA. 7. Levine Cancer Institute, Carolinas HealthCare System, Charlotte, USA. 8. Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, USA. 9. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. 10. Caris Life Sciences, Phoenix, USA; Division of Hematology, Oncology, University of California San Francisco, San Francisco, USA.
Abstract
BACKGROUND: ARID1A is a key subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the role of ARID1A mutation in colorectal cancer (CRC). The aim of the present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC. METHODS: We used integrated data sets of 7978 CRC cases (one data set from a clinical laboratory improvement amendments [CLIA]-certified laboratory and three independent published data sets). The associations of ARID1A mutation with molecular characteristics including immune profile (the status of microsatellite instability [MSI], tumour mutational burden [TMB], programmed death ligand 1 [PD-L1] and estimated infiltrating immune cells), clinicopathological features and related pathways were analysed using next-generation sequencing, RNA sequencing and immunohistochemistry. RESULTS: ARID1A mutant samples had more genomically unstable tumour features (MSI-high and TMB-high) and exhibited more characteristics of a T-cell-inflamed microenvironment (PD-L1 expression and high estimated infiltrating cytotoxic T lymphocytes [CTLs]) than ARID1A wild-type samples in the discovery and validation cohorts. Even ARID1A mutant samples without MSI-high status were TMB-high, had high levels of PD-L1 expression and high estimated infiltrating CTLs. ARID1A mutations were more common with right-sided primary and earlier stage tumours. ARID1A mutant tumours mainly had co-occurring gene mutations related to chromatin modifying, DNA repair, WNT signalling and epidermal growth factor receptor inhibitor resistance pathways, and ARID1A mutations strongly regulated DNA repair pathways. Key genes for chemotherapy/radiotherapy sensitivity were suppressed in ARID1A mutant samples. CONCLUSIONS: Our findings may provide novel insights to develop individualised approaches for treatment of CRC based on ARID1A mutation status.
BACKGROUND:ARID1A is a key subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the role of ARID1A mutation in colorectal cancer (CRC). The aim of the present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC. METHODS: We used integrated data sets of 7978 CRC cases (one data set from a clinical laboratory improvement amendments [CLIA]-certified laboratory and three independent published data sets). The associations of ARID1A mutation with molecular characteristics including immune profile (the status of microsatellite instability [MSI], tumour mutational burden [TMB], programmed death ligand 1 [PD-L1] and estimated infiltrating immune cells), clinicopathological features and related pathways were analysed using next-generation sequencing, RNA sequencing and immunohistochemistry. RESULTS:ARID1A mutant samples had more genomically unstable tumour features (MSI-high and TMB-high) and exhibited more characteristics of a T-cell-inflamed microenvironment (PD-L1 expression and high estimated infiltrating cytotoxic T lymphocytes [CTLs]) than ARID1A wild-type samples in the discovery and validation cohorts. Even ARID1A mutant samples without MSI-high status were TMB-high, had high levels of PD-L1 expression and high estimated infiltrating CTLs. ARID1A mutations were more common with right-sided primary and earlier stage tumours. ARID1A mutant tumours mainly had co-occurring gene mutations related to chromatin modifying, DNA repair, WNT signalling and epidermal growth factor receptor inhibitor resistance pathways, and ARID1A mutations strongly regulated DNA repair pathways. Key genes for chemotherapy/radiotherapy sensitivity were suppressed in ARID1A mutant samples. CONCLUSIONS: Our findings may provide novel insights to develop individualised approaches for treatment of CRC based on ARID1A mutation status.
Authors: Rona Yaeger; Walid K Chatila; Marla D Lipsyc; Jaclyn F Hechtman; Andrea Cercek; Francisco Sanchez-Vega; Gowtham Jayakumaran; Sumit Middha; Ahmet Zehir; Mark T A Donoghue; Daoqi You; Agnes Viale; Nancy Kemeny; Neil H Segal; Zsofia K Stadler; Anna M Varghese; Ritika Kundra; Jianjiong Gao; Aijazuddin Syed; David M Hyman; Efsevia Vakiani; Neal Rosen; Barry S Taylor; Marc Ladanyi; Michael F Berger; David B Solit; Jinru Shia; Leonard Saltz; Nikolaus Schultz Journal: Cancer Cell Date: 2018-01-08 Impact factor: 31.743
Authors: Yi Ping Zhu; Li Li Sheng; Jing Wu; Mo Yang; Xian Feng Cheng; Ning Ni Wu; Xiao Bing Ye; Juan Cai; Lu Wang; Qian Shen; Jian Qiu Wu Journal: Hum Pathol Date: 2018-04-22 Impact factor: 3.466
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: Soo Young Kim; Yoon Young Choi; Ji Yeong An; Hyun Beak Shin; Ara Jo; Hyeji Choi; Sang Hyuk Seo; Hui-Jae Bang; Jae-Ho Cheong; Woo Jin Hyung; Sung Hoon Noh Journal: Int J Cancer Date: 2015-02-26 Impact factor: 7.396
Authors: Sam C Wang; Ibrahim Nassour; Shu Xiao; Shuyuan Zhang; Xin Luo; Jeon Lee; Lin Li; Xuxu Sun; Liem H Nguyen; Jen-Chieh Chuang; Lan Peng; Scott Daigle; Jeanne Shen; Hao Zhu Journal: Gut Date: 2018-10-12 Impact factor: 23.059
Authors: Katrien Berns; Joseph J Caumanns; E Marielle Hijmans; Annemiek M C Gennissen; Tesa M Severson; Bastiaan Evers; G Bea A Wisman; Gert Jan Meersma; Cor Lieftink; Roderick L Beijersbergen; Hiroaki Itamochi; Ate G J van der Zee; Steven de Jong; René Bernards Journal: Oncogene Date: 2018-05-15 Impact factor: 9.867
Authors: Amira Salah El-Din Youssef; Mohamed A Abdel-Fattah; Mai M Lotfy; Auhood Nassar; Mohamed Abouelhoda; Ahmed O Touny; Zeinab K Hassan; Mohammed Mohey Eldin; Abeer A Bahnassy; Hussein Khaled; Abdel Rahman N Zekri Journal: Curr Issues Mol Biol Date: 2022-03-18 Impact factor: 2.976
Authors: Emil Lou; Joanne Xiu; Yasmine Baca; Andrew C Nelson; Benjamin A Weinberg; Muhammad Shaalan Beg; Mohamed E Salem; Heinz-Josef Lenz; Philip Philip; Wafik S El-Deiry; W Michael Korn Journal: Cells Date: 2021-05-21 Impact factor: 6.600