20 was fitted and the result was similar to the result in Table 3 (not shown). A linear predictor based on LKB1 CN,

KRAS mutation, N stage and diagnosis age was constructed from the previously described multivariate model by using the model estimates. ROC curve was used to evaluate the prediction of this multivariate model ( Fig. 3). Area under the curve (AUC) was estimated to be 0.832 and significantly different from 0.5 (p < 0.001, CI: 76.6–93.5%). The ROC curve suggests the test performance over a range of potential cut points on this linear predictor. The optimal cut points cannot be clearly defined because this will depend on user preference for defining false positives and false negatives. For example, with a false positive rate of approximately 30%, the model successfully captured APO866 cell line 80% of the true brain metastasis patients. The poor outcomes of patients with lung

cancer have been widely reported, including the frequent occurrence of brain metastases in patients who have otherwise controlled their disease through primary therapy. In small cell lung cancer http://www.selleckchem.com/products/AZD0530.html progress has been made toward preventing brain metastases through prophylactic cranial radiation which has a proven survival benefit [21]. Attempts to extend this benefit to patients with NSCLC have similarly documented a small benefit in terms of prevention of brain metastasis but without impact on survival [22] and [23]. Such data suggest that biomarkers to enrich for patients at highest risk for brain metastasis may be necessary to make progress in NSCLC. LKB1 is one of the most important tumor suppressor genes and is observed to be inactivated in approximately 30% of all NSCLCs [8]. LKB1 encodes a widely expressed serine/threonine protein kinase whose primary action is through 5′-AMP-activated protein kinase (AMPK) to regulate metabolism and ensure efficient energy production in times of stress [24]. Decreased expression of AMPK

pathway genes have also been shown to be related to metastasis in NSCLC [25]. AMPK controls cell proliferation through the mammalian target of rapamycin (mTOR) kinase, which regulates numerous downstream targets [26]. LKB1 loss impairs downstream AMPK signaling, leading to unsuppressed cell proliferation. LKB1 deficiency can be associated Pyruvate dehydrogenase with increased expression of genes believed to control angiogenesis and metastatic potential [9]. LKB1 can be inactivated through a variety of mechanisms, including gene mutation, deletion and epigenetic events, like promoter methylation. Somatic mutations, mainly nonsense or frameshift mutation, can result in truncated and dysfunctional proteins [27]. As has been shown in this study as well as previous research [5] and [28], somatic mutation can account for only a small fraction of tumors and cannot be the sole reason of LKB1 inactivation.