| Title | Mutational analysis of microsatellite-stable gastrointestinal cancer with high tumour mutational burden: a retrospective cohort study |
| Authors | Wang, Jingyuan Xiu, Joanne Farrell, Alex Baca, Yasmine Arai, Hiroyuki Battaglin, Francesca Kawanishi, Natsuko Soni, Shivani Zhang, Wu Millstein, Joshua Shields, Anthony F. Grothey, Axel Weinberg, Benjamin A. Marshall, John L. Lou, Emil Khushman, Moh'd Sohal, Davendra P. S. Hall, Michael J. Liu, Tianshu Oberley, Matthew Spetzler, David Korn, W. Michael Shen, Lin Lenz, Heinz-Josef |
| Affiliation | Peking Univ, Canc Hosp & Inst, Dept Gastrointestinal Oncol, Key Lab Carcinogenesis & Translat Res, Beijing, Peoples R China Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Div Med Oncol, Los Angeles, CA 90007 USA Univ Southern Calif, Keck Sch Med, Dept Populat & Publ Hlth Sci, Los Angeles, CA USA Fudan Univ, Zhongshan Hosp, Canc Ctr, Dept Med Oncol, Shanghai, Peoples R China Caris Life Sci, Phoenix, AZ USA Wayne State Univ, Karmanos Canc Inst, Dept Oncol, Detroit, MI USA West Canc Ctr & Res Inst, Germantown, TN USA Georgetown Univ, Ruesch Ctr Cure Gastrointestinal Canc, Lombardi Comprehens Canc Ctr, Med Ctr, Washington, DC USA Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN USA Univ S Alabama, Mitchell Canc Inst, Dept Interdisciplinary Clin Oncol, Mobile, AL USA Univ Cincinnati, Div Hematol Oncol, Cincinnati, OH USA Fox Chase Canc Ctr, Dept Clin Genet, Philadelphia, PA USA Univ Southern Calif, Los Angeles, CA 90033 USA |
| Keywords | SURVIVAL EFFICACY |
| Issue Date | Feb-2023 |
| Publisher | LANCET ONCOLOGY |
| Abstract | Background Genomic signatures contributing to high tumour mutational burden (TMB-H) independent from mismatch-repair deficiency (dMMR) or microsatellite instability-high (MSI-H) status are not well studied. We aimed to characterise molecular features of microsatellite stable (MSS) TMB-H gastrointestinal tumours.Methods Molecular alterations of 48 606 gastrointestinal tumours from Caris Life Sciences (CARIS) identified with next-generation sequencing were compared among MSS-TMB-H, dMMR/MSI-H, and MSS-TMB-low (L) tumours, using chi 2 or Fisher's exact tests. Antitumour immune response within the tumour environment was predicted by analysing the infiltration of immune cells and immune signatures using The Cancer Genome Atlas database. The Kaplan-Meier method and the log-rank test were used to evaluate the impact of gene alterations on the efficacy of immune checkpoint inhibitors in MSS gastrointestinal cancers from the CARIS database, a Memorial Sloan Kettering Cancer Center cohort, and a Peking University Cancer Hospital cohort.Findings MSS-TMB-H was observed in 1600 (3middot29%) of 48 606 tumours, dMMR/MSI-H in 2272 (4middot67%), and MSS-TMB-L in 44 734 (92middot03%). Gene mutations in SMAD2, MTOR, NFE2L2, RB1, KEAP1, TERT, and RASA1 might impair antitumour immune response despite TMB-H, while mutations in 16 other genes (CDC73, CTNNA1, ERBB4, EZH2, JAK2, MAP2K1, MAP2K4, PIK3R1, POLE, PPP2R1A, PPP2R2A, PTPN11, RAF1, RUNX1, STAG2, and XPO1) were related to TMB-H with enhanced antitumour immune response independent of dMMR/MSI-H, constructing a predictive model (modified TMB [mTMB]) for immune checkpoint inhibitor efficacy. Patients with any mutation in the mTMB gene signature, in comparison with patients with mTMB wildtype tumours, showed a superior survival benefit from immune checkpoint inhibitors in MSS gastrointestinal cancers in the CARIS cohort (n=95, median overall survival 18middot77 months [95% CI 17middot30-20middot23] vs 7middot03 months [5middot73-8middot34]; hazard ratio 0middot55 [95% CI 0middot31-0middot99], p=0middot044). In addition, copy number amplification in chromosome 11q13 (eg, CCND1, FGF genes) was more prevalent in MSS-TMB-H tumours than in the dMMR/MSI-H or MSS-TMB-L subgroups.Interpretation Not all mutations related to TMB-H can enhance antitumour immune response. More composite biomarkers should be investigated (eg, mTMB signature) to tailor treatment with immune checkpoint inhibitors. Our data also provide novel insights for the combination of immune checkpoint inhibitors and drugs targeting cyclin D1 or FGFs.Funding US National Cancer Institute, Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Gene Gregg Pancreas Research Fund, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Victoria and Philip Wilson Research Fund, Fong Research Project, Ming Hsieh Research Fund, Shanghai Sailing Program, China National Postdoctoral Program for Innovative Talents, China Postdoctoral Science Foundation, National Natural Science Foundation of China.Copyright (c) 2023 Elsevier Ltd. All rights reserved. |
| URI | http://hdl.handle.net/20.500.11897/671168 |
| ISSN | 1470-2045 |
| DOI | 10.1016/S1470-2045(22)00783-5 |
| Indexed | SCI(E) |
| Appears in Collections: | 北京肿瘤医院 |
