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Pulmonary Neoplasms in Patients with Birt-Hogg-Dubé Syndrome: Histopathological Features and Genetic and Somatic Events
- Source :
- PLoS ONE, PLoS ONE, Vol 11, Iss 3, p e0151476 (2016)
- Publication Year :
- 2016
- Publisher :
- Public Library of Science, 2016.
-
Abstract
- Birt-Hogg-Dube syndrome (BHD) is an inherited disorder caused by genetic mutations in the folliculin (FLCN) gene. Individuals with BHD have multiple pulmonary cysts and are at a high risk for developing renal cell carcinomas (RCCs). Currently, little information is available about whether pulmonary cysts are absolutely benign or if the lungs are at an increased risk for developing neoplasms. Herein, we describe 14 pulmonary neoplastic lesions in 7 patients with BHD. All patients were confirmed to have germline FLCN mutations. Neoplasm histologies included adenocarcinoma in situ (n = 2), minimally invasive adenocarcinoma (n = 1), papillary adenocarcinoma (n = 1), micropapillary adenocarcinoma (n = 1), atypical adenomatous hyperplasia (n = 8), and micronodular pneumocyte hyperplasia (MPH)-like lesion (n = 1). Five of the six adenocarcinoma/MPH-like lesions (83.3%) demonstrated a loss of heterozygosity (LOH) of FLCN. All of these lesions lacked mutant alleles and preserved wild-type alleles. Three invasive adenocarcinomas possessed additional somatic events: 2 had a somatic mutation in the epidermal growth factor receptor gene (EGFR) and another had a somatic mutation in KRAS. Immunohistochemical analysis revealed that most of the lesions were immunostained for phospho-mammalian target of rapamycin (p-mTOR) and phospho-S6. Collective data indicated that pulmonary neoplasms of peripheral adenocarcinomatous lineage in BHD patients frequently exhibit LOH of FLCN with mTOR pathway signaling. Additional driver gene mutations were detected only in invasive cases, suggesting that FLCN LOH may be an underlying abnormality that cooperates with major driver gene mutations in the progression of pulmonary adenocarcinomas in BHD patients.
- Subjects :
- 0301 basic medicine
Male
Pathology
Lung Neoplasms
DNA Mutational Analysis
lcsh:Medicine
Immunostaining
Gene mutation
medicine.disease_cause
Pathology and Laboratory Medicine
Birt–Hogg–Dubé syndrome
Lung and Intrathoracic Tumors
Birt-Hogg-Dube Syndrome
0302 clinical medicine
Papillary adenocarcinoma
Neoplasms
Adenocarcinomas
Medicine and Health Sciences
Phosphorylation
lcsh:Science
Staining
Multidisciplinary
Adenocarcinoma of the Lung
TOR Serine-Threonine Kinases
Middle Aged
Oncology
030220 oncology & carcinogenesis
Adenocarcinoma
Female
KRAS
Anatomy
Research Article
Signal Transduction
medicine.medical_specialty
Histology
Molecular Sequence Data
Adenocarcinoma of Lung
Biology
Research and Analysis Methods
Carcinomas
03 medical and health sciences
Germline mutation
Signs and Symptoms
medicine
Genetics
Humans
Atypical adenomatous hyperplasia
Folliculin
Germ-Line Mutation
Aged
Base Sequence
lcsh:R
Cancers and Neoplasms
Biology and Life Sciences
medicine.disease
030104 developmental biology
Specimen Preparation and Treatment
Alveolar Epithelial Cells
Mutation
Lesions
Somatic Mutation
lcsh:Q
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 11
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....24f79168dcaa94297380da02e3132550