Abstract
The immunotherapy agent pembrolizumab has been approved for gastric cancer (GC) patients with recurrent or advanced disease who are PD-L1 positive. Mutations in the primary lesion may drive the expression of immune targets thereby priming the tumor to therapeutic sensitivity. In this study, we aimed to uncover mutations associated with elevated PD-L1 expression in GC patients. Data from 410 GC patients were available, including the mutational spectrum of 39,916 genes and expression values of 20,500 genes. PD-L1 gene expression was compared to the mutational status of each gene separately by using a Mann-Whitney U-test and a Receiver Operating Characteristic test. Only mutations with a prevalence over 5% were considered. Significance was accepted in cases of p < 1E-05 and a fold change over 1.44. Mutations in 209 genes were associated with increased PD-L1 expression. These mutations were enriched in genes related to microtubule-based movement (p = 3.4E-4), cell adhesion (p = 4.9E-4), response to DNA-damage (p = 6.9E-4), and double-strand break-repair (p = 1.6E-3). Mutations in TTK (p = 8.8E-10, AUC = 0.77), COL7A1 (p = 2.0E-9, AUC = 0.74), KIF15 (p = 2.5E-9, AUC = 0.75), and BDP1 (p = 3.3E-9, AUC = 0.74) had the strongest link to elevated PD-L1 expression. Finally, we established a decision tree based on mutations in PIK3CA, MEF2C, SLC11A1, and KIF15 capable to separate patient sub-cohorts with elevated PD-L1 expression. In summary, we identified mutations associated with elevated PD-L1 expression that facilitate the development of better prognostic biomarkers for GC, and might offer insight into the underlying tumor biology.
Highlights
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related mortality in both sexes worldwide with the highest mortality being observed in Eastern Asia, Central and Eastern Europe (Ferlay et al, 2015)
Over 8% of the patients were identified with residual disease, while pathological complete response following adjuvant therapy occurred in 32.4% of the patients
We identified mutations of 209 genes associated with PD-L1 upregulation in GC that are involved in functions, such as microtubule-based movement, cell adhesion, gene expression regulation, response to DNA damage and double-strand break repair
Summary
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related mortality in both sexes worldwide with the highest mortality being observed in Eastern Asia, Central and Eastern Europe (Ferlay et al, 2015). Despite a steady decline in gastric cancer related mortality in the Western hemisphere (Malvezzi et al, 2010), population aging, a distinctive feature of developed countries, contributes once again to increasing trends (Menyhart et al, 2018). Diagnosis is difficult due to lack of symptoms, in countries without active screening programs, while detection in an advanced stage limits survival prospects (Seeruttun et al, 2017). Standard treatment options based on combined chemotherapy regimens provide limited benefits, and the median overall survival is
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