title: Oligogenic germline mutations identified in early non-smokers lung adenocarcinoma patients.
abstract: OBJECTIVE
  A polygenic model is commonly assumed for the predisposition to common cancers. With respect to lung cancer, Genome Wide Association Studies (GWAS) have identified three loci at 15q25, 5p15.33, and 6p21. However, the relative risks associated with alleles at these loci are low; in addition, the data are limited to smokers, and have not been quite reproducible.
  
  
  METHODS
  In order to investigate genetic susceptibility we have adopted an entirely novel patient selection strategy. First, we have selected for adenocarcinoma (ADCA) histology only; second, we have selected non-smokers; third we have selected patients who developed ADCA of lung before the age of 60 and who had an older unaffected sib: we have identified 31 such sib-pairs. Among them, we selected two patients with very early age at disease onset (37- and 49-years old), and having a healthy sibling available for genome comparison older than at least 7 years.
  
  
  RESULTS
  On germline DNA samples of four subjects of two such pairs we have carried out whole exome sequencing. Truncating mutations were detected in 8 'cancer genes' in one affected, and in 5 cancer genes in the other affected subject: but none in the two healthy sibs (p=0.0026). Some of these mutant genes (such as BAG6, SPEN and WISP3) are recognized as major cancer players in lung tumors; others have been previously identified in other human cancers (JAK2, TCEB3C, NELFE, TAF1B, EBLN2), in mouse models (GON4L, NOP58, and RBMX) or in genome-wide association studies (KIAA2018, ZNF311).
  
  
  CONCLUSIONS
  This study identifies for the first time in non-smokers with lung adenocarcinoma specific sets of germline mutations that, together, may predispose to this tumor.
authors: Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy; Istituto Toscano Tumori, Florence, Italy. Electronic address: alessandra.renieri@unisi.it.
authors: Alessandra
authors: A
authors: Renieri
authors: Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors: Maria Antonietta
authors: MA
authors: Mencarelli
authors: IRCCS MultiMedica, Milan, Italy.
authors: Francesco
authors: F
authors: Cetta
authors: Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy.
authors: Margherita
authors: M
authors: Baldassarri
authors: Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy.
authors: Francesca
authors: F
authors: Mari
authors: Department of Medical Biotechnology, University of Siena, Siena, Italy.
authors: Simone
authors: S
authors: Furini
authors: Department of Medicine, Surgery & Neuroscience, University of Siena, Siena, Italy.
authors: Pietro
authors: P
authors: Piu
authors: Medical Genetics, University of Siena, Siena, Italy.
authors: Francesca
authors: F
authors: Ariani
authors: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Tommaso A
authors: TA
authors: Dragani
authors: Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. Electronic address: elisa.frullanti@dbm.unisi.it.
authors: Elisa
authors: E
authors: Frullanti
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D017668:Age of Onset; D019295:Computational Biology; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D012907:Smoking
keywords: Germline variants; Lung adenocarcinoma; Lung cancer susceptibility; Next-generation sequencing; Oligogenic model; Whole-exome sequencing