title: LKB1 mutations frequently detected in mucinous bronchioloalveolar carcinoma.
abstract: OBJECTIVE
  LKB1 mutations are common in patients with Peutz-Jeghers syndrome, which is characterized by mucocutaneous pigmentation, intestinal polyps and a high incidence of cancers at variable sites. This study investigated the status of the LKB1 gene in mucinous bronchioloalveolar carcinoma with or without Peutz-Jeghers syndrome.
  
  
  METHODS
  Three mucinous bronchioloalveolar carcinoma tumors from two Peutz-Jeghers syndrome patients and seven tumors from sporadic mucinous bronchioloalveolar carcinoma patients were collected by surgery between 2002 and 2008, and high molecular weight genomic DNA was extracted from them. The nucleotide sequences in exons 1-9 of LKB1 were determined by genomic polymerase chain reaction-direct sequencing. The loss of heterozygosity was analyzed by high-resolution fluorescent microsatellite analysis using two microsatellite markers that encompass the LKB1 locus, D19S886 and D19S565. The mutations of KRAS, EGFR and p53 were also evaluated.
  
  
  RESULTS
  The germline mutation of LKB1 in the Peutz-Jeghers syndrome patients was identified as G215D by analyzing genomic DNA from normal lung tissue specimens. Furthermore, two of the three mucinous bronchioloalveolar carcinomas from these Peutz-Jeghers syndrome patients exhibited additional somatic mutations. On the other hand, four of seven sporadic 'non-Peutz-Jeghers syndrome' mucinous bronchioloalveolar carcinomas had LKB1 mutations. Loss of heterozygosity analyses revealed allelic loss in two tumors with LKB1 mutations. As a result, 70% of the mucinous bronchioloalveolar carcinomas exhibited LKB1 mutations. KRAS, EGFR and p53 mutations were mutually exclusive and observed in four, two and one tumors, respectively. Among them, five mutations occurred concomitantly with LKB1 mutations.
  
  
  CONCLUSIONS
  The relatively high frequency of LKB1 mutations in mucinous bronchioloalveolar carcinoma patients may therefore suggest its involvement in lung carcinogenesis, at least in mucinous bronchioloalveolar carcinoma.
authors.affiliation: Department of Thoracic Oncology, National Kyushu Cancer Center, Notame 3-1-1, Minami-ku, Fukuoka 811-1395, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Osoegawa
authors.forename: Takuro
authors.initials: T
authors.lastname: Kometani
authors.forename: Kaname
authors.initials: K
authors.lastname: Nosaki
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ondo
authors.forename: Motoharu
authors.initials: M
authors.lastname: Hamatake
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hirai
authors.forename: Takashi
authors.initials: T
authors.lastname: Seto
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugio
authors.forename: Yukito
authors.initials: Y
authors.lastname: Ichinose
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics*; D002288:Adenocarcinoma, Mucinous / Q000235:genetics*; D000328:Adult; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010580:Peutz-Jeghers Syndrome / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins