Expression Profiling of LKB1 Pathway in Young and Old Lung Adenocarcinoma Patients

BACKGROUND: The youthful lung cancer may constitute an entity with distinct clinicopathologic characteristics. The serine/threonine kinase LKB1, also known as Serine/Threonine Kinase 11-STK11, is a known tumor suppressor gene involved in cellular responses such as energy metabolism, cell polarity and cell growth, but the role of LKB1 pathway in in lung adenocarcinoma (ADC) is barely studied, especially in young patients. MATERIALS AND METHODS: Fifty lung ADC patients were retrospectively analysed. After RNA purification from formalin fixed and paraffin embedded tumor tissues, we analysed the mRNA expression levels of LKB1 and of genes involved in its pathway, such as cyclin D1 (CCND1), beta catenin (CCNNB1), lysyl oxidase (LOX), yes-associated protein-1 (YAP-1), and survivin, with NanoString technology, a new tool for a more accurate expression profiling. KRAS mutations were investigated by pyrosequencing analysis. Clinicopathologic characteristics and survival analysis were available for all patients. RESULTS: Patients under 50 years old (including 50) were defined as the younger group and patients above 50 years old were defined as the older group. Among all the clinicopathologic characteristics, in the younger group there were more women, less solid and more acinar adenocarcinoma prevalent pattern in comparison to the older group. Younger and older groups showed similar survival rates, as well as KRAS mutations frequencies. Also, in the comparison between the gene expression level of the analyzed genes and the two different age subgroups, no statistical difference was found. We then focused on the LKB1 pathway in all series, independently from the age stratification, founding LKB1 low expression associated with low cyclin D1 (CCND1) (p<0.0001), beta catenin (CCNNB1) (p<0.0001), and YAP1 (p=0.0024) levels, suggesting a target regulation by LKB1. We next tested the expression level of LOX, one of its downstream target, and we found that lung ADC with a high LOX mRNA expression showed a significantly worst prognosis, either in terms of disease-free interval or overall post-operative survival. CONCLUSIONS: Based on our preliminary results young patients seem to show similar clinicopathological characteristics, survival rates and LKB1 pathway expression levels in comparison to older group, even if further investigations will be necessary. Moreover, our data suggest LKB1 as a key pathway in lung ADC not age-stratified, with a relevant sfavorable role of LOX. A robust assessment of LKB1 and of its downstream gene, LOX in particular, may elucidate the role of this pathway deregulation in lung adenocarcinoma in order to identify potential target for lung cancer therapy.