Identification of Las2, a major modifier gene affecting the Pas1 mouse lung tumor susceptibility locus. Cancer Res 2009 Aug 01;69(15):6290-8
Date
07/23/2009Pubmed ID
19622765DOI
10.1158/0008-5472.CAN-09-0782Scopus ID
2-s2.0-68049120471 6 CitationsAbstract
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.
Author List
Liu PY, Vikis H, James M, Lu Y, Wang DL, Liu HB, Wen WD, Wang Y, You MAuthors
Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of WisconsinYian Wang MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsGenetic Predisposition to Disease
Humans
Loss of Heterozygosity
Lung Neoplasms
Mice
Mice, Inbred A
Mice, Inbred BALB C
Mice, Inbred C3H
Mice, Inbred C57BL
Oncogenes
Polymorphism, Single Nucleotide
Quantitative Trait Loci
