Correlation of genomic alterations and PD-L1 expression in thymoma

Abstract

Thymic epithelial tumors (TETs) include several anterior mediastinal malignant tumours: thymomas, thymic carcinomas and thymic neuroendocrine cancers. There is significant variety in the biologic features and clinical course of TETs and many attempts have been made to identify target genes for successful therapy of TETs. Next generation sequencing (NGS) represents a huge advancement in diagnostics and these new molecular technologies revealed that thymic neoplasms have the lowest tumor mutation burden among all adult malignant tumours with a different pattern of molecular aberrations in thymomas and thymic carcinomas. As for the PD-L1 expression in tumor cells in thymoma and thymic carcinoma, it varies a lot in published studies, with findings of PD-L1 expression from 23% to 92% in thymoma and 36% to 100% in thymic carcinoma. When correlated PD-L1 expression with disease stage some controversial results were obtained, with no association with tumor stage in most studies. This is, at least in part, explained by the fact that several diverse PD-L1 immunohistochemical tests were used in each trial, with four different antibodies (SP142, SP263, 22C3, and 28-8), different definition of PD-L1 positivity and cutoff values throughout the studies as well. There is a huge interest in using genomic features to produce predictive genomic-based immunotherapy biomarkers, particularly since recent data suggest that certain tumor-specific genomic alterations, either individually or in combination, appear to influence immune checkpoint activity and better responses as the outcome, so as such in some cancer types they may complement existing biomarkers to improve the selection criteria for immunotherapy.

Association of differential expression of immunoregulatory molecules and presence of targetable mutations may inform rational design of clinical trials

“… 48 , 49 , 50 , 51 Further, the PI3KA, EGFR, and MAPK pathways and other gene products appear to influence PD-L1 expression, which was demonstrated within this dataset. 52 , 53 , 54 , 55 Within our dataset, KRAS mutations were associated with downregulation of PD - L1/2; however, other groups have found within NSCLC that KRAS mutations caused upregulation of PD-L1 and that RAS mutations stabilize PD-L1; the clinical significance of these findings is unclear. 56 , 57 These data support the notion that trials combining various targeted therapies and IRM inhibitors have biologic rationale and may have positive clinical impact.…”

PD-L1 Expression in Neoplastic and Immune Cells of Thymic Epithelial Tumors: Correlations with Disease Characteristics and HDAC Expression

“…The specificity of factors involved in PD-L1 regulation varies among various types of cells in a context-dependent manner. In the case of thymic neoplasms, higher PD-L1 expression is detected in tumors bearing TP53 and PTEN alterations [49]. A study aiming to provide insight into the molecular pathways regulating PD-L1 expression was conducted on four TET cell lines, and identified the cylindromatosis (CYLD) gene as a crucial regulator [50].…”

Molecular profiling of rare thymoma using next-generation sequencing: meta-analysis

“… 22 , 31 , 32 One of the newest studies by Xu S et al ., included in our meta-analysis, has analyzed the genomic profile of TETs that has indicated TP53 as the most mutated gene especially in both B3 and C thymoma causing worse prognosis. 33 HRAS gene belongs to the Ras signaling pathway, commonly mutated in many tumors harboring pathogenic variants, for instance, G13V in thymoma. One study suggests gain-off function mutations in HRAS , especially in type A and AB thymomas.…”

“…24 , 25 Our meta-analysis of prevalence has reported the HRAS gene to be involved in the pathogenesis of thymoma. 22 , 33 , 35 , 36 Genes that have shown the prevalence in less aggressive forms of thymoma, especially thymomaspecific oncogene GTF2I (transcription factor), TP53, and members of Ras family HRAS have been involved in crucial processes including cell cycle regulation, cell proliferation, cell differentiation, apoptosis, and cell survival. Therefore, pathogenic variants within these genes could be important disease markers and potential therapeutic targets for thymoma.…”