Identification of driver genes and somatic mutations in cell‐free DNA of patients with pulmonary lymphangioleiomyomatosis

• Published in: International journal of cancer Vol. 146; no. 1; pp. 103 - 114
• Main Authors: Zhang, Li, Wang, Ming‐Jie, Wang, Wei, Zhao, Jing‐Ya, Wu, Jia‐Liang, Liu, Yan‐Pu, Zhu, Hong, Qu, Jie‐Ming, Zhou, Min
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.01.2020; Wiley Subscription Services, Inc
• Subjects: Adenomatous polyposis coli; Adult; BRCA1 protein; BRCA2 protein; BRCA2 Protein - genetics; Cancer; Cell-Free Nucleic Acids - genetics; cell‐free DNA; Circulating Tumor DNA - genetics; Deoxyribonucleic acid; DNA; DNA sequencing; DNA, Neoplasm - genetics; DNA-Binding Proteins - genetics; driver genes; Female; Gene frequency; Gene Frequency - genetics; Genome - genetics; Genomics - methods; Humans; Lung Neoplasms - genetics; lymphangioleiomyomatosis; Lymphangioleiomyomatosis - genetics; Male; Medical research; Middle Aged; Mutation; Mutation - genetics; Myogenesis; next‐generation sequencing; Patients; Phenotypes; somatic mutations; Tumor cells; somatic mutations; cell-free DNA; next-generation sequencing; lymphangioleiomyomatosis; driver genes
• DOI: 10.1002/ijc.32511
• ISSN: 0020-7136; 1097-0215

Next‐generation sequencing of cell‐free circulating DNA (cfDNA) has emerged as promising technique for identifying minimally invasive genomic profiling of tumor cells recently. However, it remains relatively unknown in LAM disease. In our study, paired cfDNA and genomic DNA (gDNA) in blood samples were obtained from 23 LAM patients and seven healthy controls to explore mutations profiles of targeted 70 cancer‐related genes. As results, log2‐based allele frequencies of mutations in cfDNA were significantly different from those of gDNA. By comparing the mutual mutations identified both in cfDNA and gDNA, a significant correlation was also observed. After removing mutations in gDNA, distinct somatic mutation profiles of cfDNA were observed in LAM patients. Forty of 70 targeted genes had recurrent mutations, of which ATM, BRCA2 and APC showed the highest frequency. Based on the mutation, correlation network constructed of 40 mutated genes, 11 hub genes bearing intensive interactions were highlighted, including BRCA1, BRCA2, RAD50, RB1, NF1, APC, MLH3, ATM, PDGFRA, PALB2 and BLM. Expression of the hub genes showed significant clusters between LAM patients and controls and that RAD50 and BRCA2 had the strongest associations with subject phenotypes. Myogenesis and estrogen response were confirmed to be positively regulated in LAM patients. Collectively, our study provided a landscape of genomic alterations in LAM and discovered several potential driver genes, that is, BRCA2 and RAD50, which shed a substantial light on the clinical application of key molecular markers and potential therapy targets for precision diagnosis and treatment in the future. What's new? A rare disease exclusively affecting women, pulmonary lymphangioleiomyomatosis (LAM) typically emerges spontaneously and appears to be infrequently associated with genetic alterations. Little is known, however, about genetic variants in LAM, owing to a lack of biopsy specimens. Here, cell‐free DNA analysis on LAM patient blood samples, carried out using next‐generation sequencing technology, uncovered recurring somatic mutations in 40 cancer‐related genes in LAM. A subset of these genes was found to form a gene–gene interaction network. Moreover, several potential driver genes, among them BRCA2 and RAD50, were identified and characterized as possible markers for novel LAM interventions.