Mutations in the LKB1 tumour suppressor are frequently detected in tumours from Caucasian but not Asian lung cancer patients

Abstract

Somatic mutations of LKB1 tumour suppressor gene have been detected in human cancers including non-small cell lung cancer (NSCLC). The relationship between LKB1 mutations and clinicopathological characteristics and other common oncogene mutations in NSCLC is inadequately described. In this study we evaluated tumour specimens from 310 patients with NSCLC including those with adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma histologies. Tumours were obtained from patients of US (n ¼ 143) and Korean (n ¼ 167) origin and screened for LKB1, KRAS, BRAF, and EGFR mutations using RT-PCR-based SURVEYOR-WAVE method followed by Sanger sequencing. We detected mutations in the LKB1 gene in 34 tumours (11%). LKB1 mutation frequency was higher in NSCLC tumours of US origin (17%) compared with 5% in NSCLCs of Korean origin (P ¼ 0.001). They tended to occur more commonly in adenocarcinomas (13%) than in squamous cell carcinomas (5%) (P ¼ 0.066). LKB1 mutations associated with smoking history (P ¼ 0.007) and KRAS mutations (P ¼ 0.042) were almost mutually exclusive with EGFR mutations (P ¼ 0.002). The outcome of stages I and II NSCLC patients treated with surgery alone did not significantly differ based on LKB1 mutation status. Our study provides clinical and molecular characteristics of NSCLC, which harbour LKB1 mutations.

LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling

“…Our data show that high LOX expression or serum activity significantly correlates with lung cancer poor prognosis, and cancer stages and metastasis, respectively. A previous study found no correlation between LKB1 loss-of-function mutations and clinical outcome in stage I and II NSCLC patients (9). Although a largerscale analysis of LKB1 mutation and/or expression is necessary to reach a conclusive point, it is conceivable that signaling components, e.g., mTOR and/or HIF-1α, which regulate LOX gene expression downstream of LKB1, may be commonly hyperactivated at late stages of lung cancer in a LKB1-dependent or -independent manner.…”

“…The roles of LKB1 as a tumor suppressor have emerged from the observation of increased risk of malignancy in gastrointestinal tract in PeutzJeghers syndrome (PJS) patients harboring germ-line LKB1 mutations (2,3). Although rare in most types of human cancers (4,5), LKB1 loss-of-function somatic mutations are frequently observed in human non-small-cell lung cancer (NSCLC) (6)(7)(8)(9)(10). Mice with oncogenic Kras G12D mutant develop lung tumors with long latency and low aggressiveness.…”

LKB1; linking cell structure and tumor suppression

“…Mutational analysis across a range of sporadic tumors has identified loss of function LKB1 mutations most frequently in non-small cell lung carcinomas; between 5 and 17% of cases depending on the population studied (Sanchez-Cespedes et al, 2002;Ji et al, 2007;Koivunen et al, 2008). Somatic inactivating mutations in LKB1 have also been reported in approximately 5% of pancreatic cancers and melanomas, and in single specimens of prostate cancer and cervical cancer (Avizienyte et al, , 1999Bignell et al, 1998;Wang et al, 1998;Guldberg et al, 1999;Rowan et al, 1999;Su et al, 1999;Forster et al, 2000;Ikediobi et al, 2006).…”

Enhanced antitumor effect of cisplatin in human NSCLC cells by tumor suppressor LKB1

“…12,13 It has been reported that the LKB1 inactivating mutation rate ranges from 17 to 54% in lung adenocarcinomas and particularly prevails in multiple subtype of NSCLC. 14,15 LKB1 has been ranked as one of the most frequently mutated genes in lung adenocarcinomas after TRP53 and Kras. 16 Moreover, recent studies have provided strong evidences that the loss of LKB1 promotes lung carcinogenesis process, such as cell apoptosis, cycle regulation, tumor angiogenesis and metastasis.…”