Genetic Analysis of Congenital Cystic Adenomatoid Malformation Reveals a Novel Pulmonary Gene: Fatty Acid Binding Protein-7 (Brain Type)

Abstract

ABSTRACT:The pathogenesis of congenital cystic adenomatoid malformation (CCAM) is unknown and its natural history is unpredictable. Fatty acid binding protein-7 (FABP-7) has been previously described in brain and breast development, but never before in the lung. We investigate gene expression in CCAM, and hypothesize that CCAM results from an aberration in the signaling pathway during lung development. Under IRB approval, tissue specimens of fetal CCAM, fetal control, postnatal CCAM, and postnatal control were examined and microarray analysis was performed. Candidate differentially expressed genes were selected with log-odds ratio (B) Ͼ0 and false discovery rate Ͻ0.05. Validation of differential expression was achieved at the RNA and protein levels. FABP-7 was underexpressed in fetal CCAM compared with fetal lung in both the microarray and by RT-PCR. Findings were duplicated by Western Blot analysis and immunohistochemistry. This is the first description of FABP-7 in the human lung. Decreased expression of FABP-7 in fetal CCAM compared with normal fetal lung at both the RNA and protein levels suggests FABP-7 may have a role in pulmonary development and in the pathogenesis of CCAM. (Pediatr Res 64: 11-16, 2008) C ongenital cystic adenomatoid malformation (CCAM) is a multicystic pulmonary mass characterized by an abnormal proliferation of tissue resembling terminal respiratory bronchioles. The relatively rare lesions usually occur unilaterally and involve only one lobe of the lung. Diagnosis is often made by prenatal ultrasonography.CCAM has a variable natural history. Some lesions regress in utero with no residual abnormality at birth (1-2), others are associated with fetal polyhydramnios, mediastinal shift, and nonimmune hydrops fetalis resulting in the risk of fetal demise (3). Mediastinal shift and hydrops fetalis are indications for fetal intervention.Stocker et al.'s original classification of CCAM included three subtypes based predominantly on the cyst size. Type I lesions are composed of single or multiple large cysts (Ͼ2 cm in diameter); type II lesions are multiple, smaller cysts (Ͻ1 cm in diameter); and type III are more solid, microcystic lesions. Two variants were later added to the original classification system: type 0, composed of bronchial-like histology and type IV, a more distal acinar lesion (4).The pathogenesis of CCAM is unclear. Its original description was that of a hamartomatous lesion. The five Stocker CCAM types have also been described as each being distinct malformations, with unique etiologies resulting from a localized obstruction or atresia (2). The parenchymal maldevelopment characterizing CCAM has been associated with bronchial atresia (5). The bronchial atresia may result from a localized arrest in the bronchial tree during the branching phase of lung development, the pseudoglandular phase.Lung development during the pseudoglandular phase involves extensive epithelial-mesenchymal interaction of growth factors, transcription factors, and signaling molecules. Previous studies evalu...

Prenatal and Postnatal Management of Congenital Pulmonary Airway Malformation

“…Another candidate gene is the fatty acid-binding protein FABP-7 [34], the expression of which is reduced in foetal CPAM specimens. An overexpression of Clara cell marker 10 was also identified [13].…”

“…2 Genes implicated in CPAM, PPB and BAC [14,30,31,32,33,34,35,127,137,138,139,140,141,142,143]. TTF1 = Thyroid transcription factor 1; PDGF-B = platelet-derived growth factor B; FABP-7 = fatty acid-binding protein 7; GDNF = glial cell-derived neurotrophic factor; Shh = sonic hedgehog; FGFR2b = FGF receptor-2b; FHIT = fragile histidine triad; Rb = retinoblastoma protein; EGFR = epidermal growth factor receptor. …”

Limited overlap in significant hits between genome-wide association studies on two airflow obstruction definitions in the same population

“…FABP7 is an intracellular lipid-binding protein, involved in long-chain fatty acids transport and cell proliferation [43]. It may be involved in abnormal pulmonary development, since lower expression of FABP7 was found in patients with congenital cystic adenomatoid malformation [44]. In addition, higher expression of FABP7 was seen in clear cell renal cell carcinoma and the authors suggested that the gene activates the ERK and STAT3 signalling pathways [45].…”

Analysis of Wnt7B and BMP4 expression patterns in congenital pulmonary airway malformation

“…The disease is characterized by proliferation of pseudoglandular bronchial structures, formation of multiple cysts in the terminal bronchioles, and lack of alveolar development 4 . Stocker classification of CPAM includes five subtypes: type 0, lesions are composed of bronchial‐like tissue; type I, single or multiple large cysts (>2 cm in diameter); type II, multiple small cysts (<1 cm in diameter); type III, solid and microcystic lesions; and type IV, lesions of more distal acinar origin 5 . The condition does not regress after birth, and the development of fetal hydrops is associated with an increased risk of death 6 .…”