A Multi-omics Study Of Tracheobronchial Adenoid Cystic Carcinoma

Adenoid cystic carcinoma(ACC)originates mainly from secretory gland of head and neck,and much less in trachea.Tracheobronchial adenoid cystic carcinoma(TACC)originating from the tracheal submucosal glands,which is even more rare,has an insidious onset,and it is easy to be misdiagnosed.At present,as for advanced TACC,there is currently no effective targeted therapy.And the research on pathogenic mechanism is not sufficient due to the rareness of this disease.This study took ACC as the object and was done in two steps.The first step aimed to define the signatures of the gene expressions of the head and neck ACC,and to explore the differences of gene expressions with mucoepidermoid carcinoma(MEC).The latter one is another major type of salivary gland tumor.This part we used bioinformatics tools and public data from the GEO database.Therefore,different gene expressions of ACC and MEC were obtained,and then we found that the expression levels of MYB,VCAN,HAPLN1 in ACC were significantly increased.As a transcription factor,overexpression of MYB could be easily observed in ACC.This is owing to the fusion of MYB and another significant upstream enhancer.Overexpression of MYB protein will activate TP63 in myoepithelial cells or Notch program in luminal epithelial cells,which continues to cause other changes of downstream.The proteins encoded by VCAN and HAPLN1 are mainly located in the extracellular matrix.Both proteins were reported to be involved in cell adhesion and migration,and especially to be engaged in the process of tumor metastasis.Consistent with the high rate of metastasis/recurrence,all the signaling pathways would impact extracellular matrix and tumorigenesis.The second step aimed to analyze the multi-omics data of tracheobronchial adenoid cystic carcinoma,focused on its unique mutational characteristics.We collected 62 pairs of samples diagnosed in our hospital from 2007 to 2017 retrospectively and obtained tumor genome and transcriptome data through WES and RNA-seq.Multi-omics data suggested that the mutation burden was very low,and oncogenes commonly involved in other malignant tumors were also lacking,which were consistent with the clinical low-grade malignancy characteristics.We also found the obvious heterogeneity among samples.The mutation signatures were mainly involved in signature 1,signature 6 and signature 5,which revealed some of the pathogenic mechanisms including age,mismatch repair defects and so on.Finally,transcriptome data have confirmed the MYB fusions in TACC,which laid the foundation for potential therapeutic strategies.