image: (A) Kaplan–Meier survival analysis stratified by MET mutation status in 2539 cancer patients with 7 tumor types treated with ICIs in the discovery cohort. (B) The association between MET mutation and OS in 1610 patients with 10 tumor types in the validation cohort. (C–E) The comparison of OS (C), PFS (D), and ORR (E) between patients with MET mutation and patients with MET non-mutation in 4149 subjects with 12 tumors treated with ICIs. (F, G) Univariate (F) and multivariate (G) Cox analyses of the association between MET mutation and OS in 4149 patients with 12 tumors treated with ICIs. (H) The nomogram for predicting the 12- and 24-month survival. It can calculate overall survival from the date of immunotherapy start. To use, users should locate the “age” axis and draw a line up to the “point” axis to get a score associated with age and repeat for the other features to get their scores. Afterward, the users sum all scores, locate it on the “total point” axis, and draw a line to the “12-month survival” axis to get the 12-month OS probability. (I) Calibration plots for validation of the 12- and 24-month survival from the nomogram in the discovery cohort. The average predicted probability (X-axis) was plotted against the observed Kaplan-Meier estimate in the subgroup (Y-axis, 95% CIs of the estimates are presented as vertical lines). The continuous line is the reference line, indicating what an optimal nomogram would be. (J, K) Based on the optimal cutoff value (total points = 60) derived from the nomogram, a low score was associated with favorable OS in both the discovery cohort (J) and validation cohort (K). CI, confidence interval; CUP, cancer of unknown primary; CR, complete response; EC, esophagogastric cancer; HNC, head and neck carcinoma; HR, hazard ratio; ICI, immune checkpoint inhibitor; LC, lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PD, progressive disease; PR, partial response; SD, stable disease.
Credit: Genes & Diseases
Immunotherapy is a revolutionary cancer treatment strategy that leverages the body’s immune system to fight cancer. While immune checkpoint inhibitors significantly improve the therapeutic outcomes in many tumors, most cancer patients cannot benefit from these.
The mesenchymal-epithelial transition factor (MET), a proto-oncogene that encodes the tyrosine kinase receptor of the hepatocyte growth factor (HGF), elicits various intracellular signaling cascades, including cell motility, growth & survival, and inflammatory pathways. Aberrant or deregulated MET signaling promotes cancer cell proliferation, survival, and immunosuppression, leading to speculation that MET mutation may impact immunotherapy outcomes and serve as a potential predictive biomarker.
In a recent study published in the Genes & Diseases journal, researchers from Fujian Medical University and the Cancer Center of The Fifth Affiliated Hospital of Sun Yat-Sen University “conducted a comprehensive bioinformatics and clinical analysis to explore the characteristics of MET mutation and its association with the outcomes in pan-cancer immunotherapy.”
To investigate the impact of MET mutation on immunotherapy outcomes, the authors employed a discovery cohort comprising 2539 patients with seven tumor types from 14 datasets and a validation cohort comprising 1610 patients with 10 tumor types. MET mutation was associated with a decreased mortality risk, better progression-free survival, and a higher overall response rate. Furthermore, certain single base substitutions (SBS) such as SBS7a, SBS10b, SBS30, SBS42, and SBS86 were identified “as robust predictive biomarkers for survival in pan-cancer immunotherapy.”
The expression of three key immune checkpoints (CTLA-4, PD-1, and PD-L1) was significantly increased in MET-mutant tumors, with a concomitant increase in the expression of many MHC-related antigen-presenting molecules and co-stimulators. MET mutations were also associated with enhanced immune cell infiltration, especially CD8+ T cells, along with increased levels of most chemokines & their receptors and immune stimulators, suggesting that MET-mutant tumors are immunologically “hot” tumors.
The authors acknowledged several limitations of the study, including i) potential biases or errors in data collected from different centers due to variability among original investigators, ii) a limited sample size of only 12 tumor types, and iii) the absence of molecular experiments to validate the bioinformatics findings.
In conclusion, using multiple bioinformatics and clinical analyses, the authors of this study showed that MET mutation is associated with enhanced tumor immunogenicity, enriched infiltration of immune cells, and improved immune responses, marking it as a versatile positive predictive biomarker in pan-cancer immunotherapy.
Reference
Title of the original paper: Pan-cancer analysis of MET mutation and its association with the efficacy of immune checkpoint blockade
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2024.101450
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