Multiomics data reveals the influences of myasthenia gravis on thymoma and its precision treatment

Abstract

Thymoma is a rare characterized by a unique association with autoimmune diseases, especially myasthenia gravis (MG). However, little is known about the molecular characteristics of MG-associated thymoma individuals. We aim to examine the influences of MG on thymoma by analyzing multiomics data. A total of 105 samples with thymoma was analyzed from TCGA and these samples were divided into subgroups with MG (MGT) or without MG (MGF) according to clinical information. We then characterized the differential gene expression, pathway activity, somatic mutation frequency, and likelihood of responding to chemotherapies and immunotherapies of the two identified subgroups. MGT subgroup was characterized by elevated inflammatory responses and metabolically related pathways, whereas the MGF subgroup was predicted to be more sensitive to chemotherapy and presented with mesenchymal characteristics. More copy number amplifications and deletions were observed in MGT, whereas GTF2I mutations occur at significantly higher frequencies in MGF. Two molecular subtypes were further identified within MGF samples by unsupervised clustering where one subtype was enriched in TGF-β and WNT pathways with higher sensitivity to relevant targeted drugs but hardly respond to immunotherapy. For another subtype, a higher recurrence rate of thymoma and more likelihood of responding to immunotherapy were observed. Our findings presented a comprehensive molecular characterization of thymoma patients given the status of MG, and provided potential strategies to help individualized management and treatment.

Dermatan Sulfate Is a Potential Regulator of IgH via Interactions With Pre-BCR, GTF2I, and BiP ER Complex in Pre-B Lymphoblasts

“…The GTF2I gene is well known for its association with Williams-Beuren syndrome and supravalvular aortic stenosis ( 28 ). Amazingly, recent large-scale genome-wide association studies have identified close association of the GTF2I gene with various autoimmune diseases, including primary Sjögren syndrome ( 29 ), systemic lupus erythematosus ( 30 ), rheumatoid arthritis ( 31 ), myasthenia gravis ( 32 ), ANCA-associated vasculitis ( 33 ), and neuromyelitis optica spectrum disorder ( 34 ).…”

Narrative review of immunotherapy in thymic malignancies

“…A Chinese study with a cohort of 105 patients reporting and not MG found that patients suffering MG showed elevated inflammatory responses and metabolic related pathways, whereas those patients with no autoimmune event were presented with mesenchymal characteristics (56). Of note, GTF2I mutations were assessed at significantly higher frequency in patients with no autoimmunity (56).…”

“…A Chinese study with a cohort of 105 patients reporting and not MG found that patients suffering MG showed elevated inflammatory responses and metabolic related pathways, whereas those patients with no autoimmune event were presented with mesenchymal characteristics (56). Of note, GTF2I mutations were assessed at significantly higher frequency in patients with no autoimmunity (56). Indeed, GTF2I mutation have been correlated with better survival outcomes (57); thus, we could hypothesize that patients with GTF2I alterations would be good candidates for immunotherapy; however, GTF2I mutations have been detected in type A (82%) and type AB (74%) and rarely in the aggressive subtypes (22,57), such as TC, where recurrent mutations of known cancer genes have been identified including TP53, CYLD, CDKN2A, BAP1 and PBRM1 (22,57).…”

“…Some other molecular features have been further described for patients not reporting TRMG, such as upregulated TGF-β and WNT pathways (56), nonetheless those routes hardly respond to immunotherapy. Finally, several other biomarkers have been evaluated to differentiate thymomas from TCs (55,59) and to understand the pathogenesis of MG such as IGFBP1, KLF15, PDK4 and, HIF3A (60).…”

Dermatan Sulfate Is a Potential Master Regulator of IgH via Interactions with Pre-BCR, GTF2I, and BiP ER Complex in Pre-B Lymphoblasts

“…GTF2I gene mutations occur at significantly higher frequencies in thymoma patients with myasthenia gravis than those without(29).GTF2I proteins are unusual transcriptional regulators that function as both basal and signalinduced transcription factors. Among its related pathways are the BCR signaling pathway and RNA polymerase II transcription initiation and promoter clearance.…”