Differential expression of CRKL and AXL genes in lung adenocarcinoma subtypes according to the epidermal growth factor receptor and anaplastic lymphoma kinase gene status.

Abstract

Non-small-cell lung cancer (NSCLC) is the most common cause of cancer-related mortality. Adenocarcinoma (AC) is the predominant histological type of NSCLC; however, AC consists of several subtypes. It has not yet been determined whether there is a correlation of CRKL and AXL expression with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene status in lung AC. We assayed exons 18 through 21 of the EGFR gene by direct sequencing; ALK rearrangement and the expression of CRKL and AXL were detected by immunostaining. A total of 212 cases of AC were included in this study, diagnosed using the novel classification system established by the International Association for the Study of Lung Cancer, the American Thoracic Society and the European Respiratory Society in 2011, including 69 acinar ACs, 17 lepidic predominant ACs (LPAs), 63 papillary, 14 mucinous, 17 micropapillary and 32 solid ACs. Of the 212 cases, 101 harbored EGFR mutations. The most common subtypes carrying delK745-S753 were papillary and acinar ACs. ALK rearrangement was found in 23 cases (11%) of lung ACs. Acinar and solid ACs were the most frequent subtypes with ALK aberrance, particularly in acinar ACs with cribriform structure (4/5 cases, 80%). The expression of CRKL was significantly different among the AC subtypes (P=0.01), with the highest and lowest expression levels of CRKL protein in papillary ACs and LPAs, respectively (P<0.05). AXL expression was also significantly different among the AC subtypes (P=0.002) and was correlated with lymph node infiltration in acinar ACs. ACs with EGFR mutations exhibited high levels of AXL protein expression compared to those without mutations (P<0.001). Acinar AC with cribriform structure is a distinct subtype that frequently harbors ALK rearrangement. The activation of AXL may be one of the factors contributing to the invasion of acinar and micropapillary ACs.