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Mutational analysis of microsatellite-stable gastrointestinal cancer with high tumour mutational burden: a retrospective cohort study - 31/01/23

Doi : 10.1016/S1470-2045(22)00783-5 
Jingyuan Wang, PhD a, b, d, Joanne Xiu, PhD e, Alex Farrell, PhD e, Yasmine Baca, PhD e, Hiroyuki Arai, PhD b, Francesca Battaglin, MD b, Natsuko Kawanishi, PhD b, Shivani Soni, PhD b, Wu Zhang, MD b, Joshua Millstein, PhD c, Anthony F Shields, ProfMD f, Axel Grothey, ProfMD g, Benjamin A Weinberg, MD h, John L Marshall, ProfMD h, Emil Lou, MD i, Moh’d Khushman, MD j, Davendra P S Sohal, MD k, Michael J Hall, MD l, Tianshu Liu, ProfMD d, Matthew Oberley, PhD e, David Spetzler, PhD e, W Michael Korn, MD e, Lin Shen, ProfMD a, Heinz-Josef Lenz, ProfMD b, ⁎
a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China 
b Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 
c Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 
d Department of Medical Oncology, Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China 
e Caris Life Sciences, Phoenix, AZ, USA 
f Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA 
g West Cancer Center and Research Institute, Germantown, TN, USA 
h Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA 
i Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA 
j Departments of Interdisciplinary Clinical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA 
k Division of Hematology/Oncology, University of Cincinnati, Cincinnati, OH, USA 
l Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA 

* Correspondence to: Prof Heinz-Josef Lenz, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA Division of Medical Oncology Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles CA 90033 USA

Summary

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 χ2 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 (3·29%) of 48 606 tumours, dMMR/MSI-H in 2272 (4·67%), and MSS–TMB-L in 44 734 (92·03%). 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 18·77 months [95% CI 17·30–20·23] vs 7·03 months [5·73–8·34]; hazard ratio 0·55 [95% CI 0·31–0·99], p=0·044). 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.

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Vol 24 - N° 2

P. 151-161 - février 2023 Retour au numéro
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