title: Promoter methylation is not associated with FLCN irregulation in lung cyst lesions of primary spontaneous pneumothorax.
abstract: Germline mutations in FLCN are responsible for ~10% of patients with primary spontaneous pneumothorax (PSP), characterized by multiple lung cysts in the middle/lower lobes and recurrent pneumothorax. These clinical features are also observed in a substantial portion of patients with sporadic PSP exhibiting no FLCN coding mutations. To assess the potential underlying mechanisms, 71 patients with PSP were selected, including 69 sporadic and 2 familial cases, who bared FLCN mutation‑like lung cysts, however, harbored no FLCN protein‑altering mutations. Notably, in a significant proportion of the patients, FLCN irregulation was observed at the transcript and protein levels. Genetic analyses of the cis‑regulatory region of FLCN were performed by sequencing and multiplex ligation‑dependent probe amplification assay. No inheritable DNA defect was detected, with the exception of a heterozygous deletion spanning the FLCN promoter, which was identified in a family with PSP. This mutation caused a reduction in the expression of FLCN in the lung cysts. Pedigree analysis demonstrated that haploinsufficiency of FLCN was pathogenic. To determine whether epigenetic mechanisms may be involved in the irregulation of FLCN, the promoter methylation status was measured in the remainder of the patients. No evidence of FLCN promoter methylation was demonstrated. The present study suggested that FLCN irregulation in lung cysts of PSP is not associated with promoter methylation.
authors.affiliation: Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Thoracic Surgery, Nanjing Chest Hospital, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.affiliation: Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China.
authors.forename: Chengchu
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Min
authors.affiliation: Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China.
authors.forename: Dehua
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China.
authors.forename: Baofu
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China.
authors.forename: Minhua
authors.initials: M
authors.lastname: Ye
authors.affiliation: Department of Thoracic Surgery, Nanjing Chest Hospital, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Thoracic Surgery, Nanjing Chest Hospital, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Thoracic Surgery, Nanjing Chest Hospital, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Yueming
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Qiuxiang
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Haizhen
authors.initials: H
authors.lastname: Xia
authors.affiliation: Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Long
authors.initials: L
authors.lastname: Yi
mesh_terms: D018899:CpG Islands; D003560:Cysts / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008168:Lung / Q000473:pathology*; D008297:Male; D009154:Mutation; D011030:Pneumothorax / Q000235:genetics* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins