LKB1 tumor suppressor gene alterations in sporadic lung adenocarcinomas
Germ-line mutations at LKB1, also called STK11, cause the Peutz-Jeghers syndrome (PJS), characterized by an increased risk of cancer. We recently demonstrated that LKB1 is somatically inactivated in lung adenocarcinomas of sporadic origin. LKB1 encodes a serine-threonine kinase implicated in several cell functions such as cell polarity and signal transduction. In the present work we study the mutational profile of LKB1 gene inactivation in lung adenocarcinomas. Among the 100 lung adenocarcinomas screened for LKB1 gene inactivation, including both primary tumors and cell lines, about 20% harbored alterations. Most were nucleotide substitutions or frameshift mutations leading to truncated proteins. In addition to point mutations we detected large intragenic deletions, spanning several exons, that completely abrogated the expression of wild type protein. Most mutations were located in the first half of the LKB1 genome and no mutation was found in the last coding exon. The profile of LKB1 mutations in lung adenocarcinomas was similar to that found in the germ-line of PJS patients. We have also evaluated the co-existence of LKB1 mutations with alterations at other common oncogenes/tumor suppressor genes. Inactivation of LKB1 frequently coexisted with alterations at the p53, KRAS or p16 genes. However, our analysis in 30 lung cancer cell lines revealed that none of the cell harbored simultaneous LKB1 and PTEN gene alterations, suggesting that the inactivation of these genes may be mutually exclusive. In conclusion, our present data further highlights the relevance of LKB1 inactivation in lung adenocarcinomas.