A Genomics Study Of Tracheobronchial Adenoid Cystic Carcinoma

Background:Tracheobronchial Adenoid Cystic Carcinoma(TACC)is a rare tumor that always occurs in the head,neck,mammary gland,skin,cervix,trachea,bronchia and so on.It is a low-grade malignant tumor.At present,the main clinical treatment means is radical surgical resection,which is often combined with postoperative radiotherapy.The clinical benefit of chemotherapy has not been concluded,and targeted therapy is still in the research stage.Previous genomic studies on adenoid cystic carcinoma(ACC)suggest that the tumor mutational burden of ACC is low,which is characterized by the MYB-NFIB fusion gene.Important signal pathways related to ACC include epigenetic modification pathway,DNA damage pathway,MYB/MYC signaling pathway,FGF/IGF/PI3K signaling pathway,Notch signaling pathway,etc.This study attempts to analyze Single nucleotide variants(SNV)and copy number variations(CNVs)through whole-exon sequencing(WES),to study the genomic characteristics of TACC.We want to find genes or pathways that play an important role in the development of tumors,so as to provide evidence for potential therapeutic targets.Methods:We performed WES and bioinformatics analysis of tumor tissues and normal control tissues from 14 surgically resected primary TACC.An integrated analysis of genomic data at the exon level was performed,including analysis of tumor mutational burden,SNV,mutation signature,CNV and tumor heterogeneity were analyzed respectively.Results:There is a mean of 201 non-silent mutations per tumor,which is a high level among all types of cancer.Genes involved in cellular adhesion and metastasis were mutated relatively frequently by somatic alterations of CELSR2(36%),ADGRL2(29%),FAT1(29%),and FAT3(29%).POLE(29%)associated with DNA mismatch repair and NOTCH1 involved in Notch signaling pathways were also mutated frequently.Analysis of mutation signature suggested that mutation signature 1 and mutation signature 5 accounted for a high proportion in patients,suggesting that some environmental factors such as aging and smoking may also affect the development of TACC.CNV analysis revealed that mitosis spindle assembly,Rho GTPase family,Wnt signaling pathway,SMAD2 signaling pathway,and FoxO signaling pathway all had high frequency deletions,while high frequency amplification was found in estrogen receptor-related pathways.Analysis of TACC heterogeneity suggested that intratumoral heterogeneity of TACC was high,which may be one reason for TACC drug resistance.Conclusions:Our study described the mutational profile of TACC and identified some genes and pathways associated with the tumorigenesis and development of TACC,providing a basis for the search of potential therapeutic targets.