Experiment
Loci involved in lung tumor susceptibility were mapped using a panel of 123,073 SNPs at a resolution of 1 SNP per 20 kb. Animals from 21 inbred strains were injected with urethane and assessed for lung adenoma incidence and multiplicity 14-16 weeks later.
A QTL on the distal region of Chr 6 colocalized with a previously identified QTL, Pas1 (pulmonary adenoma susceptibility 1). The authors refer to this colocalizing QTL as Pas1.
02.02.2016 Curator Note: However, because Pas1 was originally mapped in J:17778 using AXB and BXA RI mice and confirmed in an (C57BL/6J x A/J)F2 cross, a mapping population that differs from the mapping population used here, we condsider the current study a separate mapping experiment and have named this QTL Clas1, carcinogen-induced lung adenoma susceptibility 1.
Clas1 was mapped to a distal region on mouse Chromosome 6 and localized to a region of less than 0.5 Mb. The interval spanned approximatley 26 cM between D6Mit54 and D6Mit373 with a highly significant LOD score of 6.4, p=0.0014.
Seven candidate genes reside in the Clas1 interval: Bcat1 (73.9 cM), Lrmp (71 cM), Casc1 (71.1 cM), 4930469P12Rik (71.12 cM), Kras (71.2 cM), 1700073E17Rik, and 4933403M22Rik (71.3 cM). One of the strongest linkage signals corresponded to the N60S polymorphism in Casc1. Treatment of Casc1 knockout animals with urethane resulted in 6-fold more tumors compared to wild type.
A novel locus named Clas2 (carcinogen-induced lung adenoma susceptibility 2) mapped to approximately 6 cM on mouse Chromosome 4. Linkage disequilibrium analysis identified a single candidate gene at approximately 30.7 Mb near RIKEN sequence 4931422A14 (authors tentatively name this gene Lasc1). The D102E polymorphism is strongly correlated to lung tumor incidence. Resistant inbred strains carry the AKR-derived T allele (Asp102) whereas susceptible inbred strains carry the SWR-derived G allele (Glu102). Furthermore, the SWR allele of 4931422A14 appears to promote rapid cell growth in vitro and in vivo. Sluc18 (12 cM) is a previously identified lung cancer QTL mapping near Clas2.
Clas3 (carcinogen-induced lung adenoma susceptibility 3) mapped to mouse Chromosome 13. Potential candidate genes in this region include Dapk1 (40 cM), Ctla2a (36 cM), Tpbpa (36 cN), Ctsj (35.5 cM), Ctsq (35 cM), and Ctsr (35 cM). Pas10 (36 cM) and Sluc23 (32 cM) are previously identified lung tumor susceptibility QTL mapping near Clas3.
Clas4 (carcinogen-induced lung adenoma susceptibility 4) mapped to approximately 60 cM on mouse Chromosome 15. Acvrl1 and Ankrd33 are potential candidate genes with significant SNPs closest to Clas4. Sluc26 (48.9 cM) is a previously identified lung cancer QTL mapping near Clas4.
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