Identification of Las2, a major modifier gene affecting the Pas1 mouse lung tumor susceptibility locus.
Lung cancer is the leading cause of cancer death worldwide. Here, we describe a genome-wide association study of chemically induced lung tumorigenesis on 593 mice from 21 inbred strains using 115,904 genotyped and 1,952,918 imputed single nucleotide polymorphisms (SNPs). Using a genetic background-controlled genome search, we identified a novel lung tumor susceptibility gene Las2 (Lung adenoma susceptibility 2) on distal chromosome 18. Las2 showed strong association with resistance to tumor induction (rs30245983; P = 1.87 x 10(-9)) as well as epistatic interactions (P = 1.71 x 10(-3)) with the pulmonary adenoma susceptibility 1 locus, a major locus affecting mouse lung tumor development (rs13459098, P = 5.64 x 10(-27)). Sequencing analysis revealed four nonsynonymous SNPs and two insertions/deletions in the susceptible allele of Las2, resulting in the loss of tumor suppressor activities in both cell colony formation and nude mouse tumorigenicity assays. Deletion of LAS2 was observed in approximately 40% of human lung adenocarcinomas, implying that loss of function of LAS2 may be a key step for lung tumorigenesis.
Liu
Peng-Yuan
PY
Department of Surgery and the Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Vikis
Haris
H
James
Michael
M
Lu
Yan
Y
Wang
Dao-Long
DL
Liu
Hong-Bo
HB
Wen
Wei-Dong
WD
Wang
Yian
Y
You
Ming
M
D000818:Animals; D020022:Genetic Predisposition to Disease; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009857:Oncogenes; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci