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Transcripts originating from the transcriptional read through of two adjacent, similarly oriented genes have been identified in normal and neoplastic tissues, but their functional role and the mechanisms that regulate their expression are mostly unknown. Here, we investigated whether the expression of read-through transcripts previously identified in the non-involved lung tissue of lung adenocarcinoma patients was genetically regulated. Data on genome-wide single nucleotide variant genotypes and expression levels of 10 read-through transcripts in 201 samples of lung tissue were combined to identify expression quantitative trait loci (eQTLs). Then, to identify genes whose expression levels correlated with the 10 read-through transcripts, we used whole transcriptome profiles available for 154 patients. For 8 read-though transcripts, we identified 60 eQTLs (false discovery rate <0.05), including 17 cis-eQTLs and 43 trans-eQTLs. These eQTLs did not maintain their behavior on the 'parental' genes involved in the read-through transcriptional event. The expression levels of 7 read-through transcripts were found to correlate with the expression of other genes: CHIA-PIFO and CTSC-RAB38 correlated with CHIA and RAB38, respectively, while 5 other read-through transcripts correlated with 43 unique non-parental transcripts; thus offering indications about the molecular processes in which these chimeric transcripts may be involved. We confirmed 9 eQTLs (for 4 transcripts) in the non-involved lung tissue from an independent series of 188 lung adenocarcinoma patients. Therefore, this study indicates that the expression of four read-through transcripts in normal lung tissue is under germline genetic regulation, and that this regulation is independent of that of the genes involved in the read-through event., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: In an intercross between the SWR/J and BALB/c mouse strains, the pulmonary adenoma progression 1 (Papg1) locus on chromosome 4 modulates lung tumor size, one of several measures of lung tumor progression. This locus has not been fully characterized and defined in its extent and genetic content. Fine mapping of this and other loci affecting lung tumor phenotype is possible using recombinant inbred strains., Results: A population of 376 mice, obtained by crossing mice of the SWR/J strain with CXBN recombinant inbred mice, was treated with a single dose of urethane and assayed for multiplicity of large lung tumors (N2lung). A genome-wide analysis comparing N2lung with 6364 autosomal SNPs revealed multiple peaks of association. The Papg1 locus had two peaks, at rs3654162 (70.574 Mb, -logP=2.8) and rs6209043 (86.606 Mb, -logP=2.7), joined by an interval of weaker statistical association; these data confirm the presence of Papg1 on chromosome 4 and reduce the mapping region to two stretches of ~6.8 and ~4.2 Mb, in the proximal and distal peaks, respectively. The distal peak included Cdkn2a, a gene already proposed as being involved in Papg1 function. Other loci possibly modulating N2lung were detected on chromosomes 5, 8, 9, 11, 15, and 19, but analysis for linkage disequilibrium of these putative loci with Papg1 locus suggested that only those on chromosomes 11 and 15 were true positives., Conclusions: These findings suggest that Papg1 consists, most likely, of two distinct, nearby loci, and point to putative additional loci on chromosomes 11 and 15 modulating lung tumor size. Within Papg1, Cdkn2a appears to be a strong candidate gene while additional Papg1 genes await to be identified. Greater knowledge of the genetic and biochemical mechanisms underlying the germ-line modulation of lung tumor size in mice is relevant to other species, including humans, in that it may help identify new therapeutic targets in the fight against tumor progression.

Genome-wide screening for genetic loci associated with risk of lung adenocarcinoma (ADCA) was carried out in pooled DNA using the Illumina 300K single-nucleotide polymorphism (SNP) array, in a joint analysis of 2 Italian case-control series matched by age, gender and smoking habit. The rare allele carrier status of 8 SNPs was associated with a decreased lung ADCA risk [odds ratios (OR): 0.6-0.8]. In a polygenic model characterized by additive and interchangeable effects, individuals carrying 2 to 6 rare alleles at these 8 SNPs showed a significant trend toward a decreased risk of lung ADCA (up to OR of 0.3). These results suggest the relevance of a polygenic model in the modulation of individual risk of lung ADCA in the general population., ((c) 2008 Wiley-Liss, Inc.)

CD-1 is the outbred mouse line most often used in toxicology and carcinogenicity bioassays. A literature survey revealed a relatively high (21.8%) incidence of spontaneous lung tumors in these mice, and a susceptibility to lung tumorigenesis induced by vinyl chloride, styrene or benzene inhalation that is not seen in B6C3F1 or C57BL/6 mice, or in rats and hamsters. As the pulmonary adenoma susceptibility 1 (Pas1) locus is the major determinant of genetic susceptibility to lung tumorigenesis in mice, we analyzed CD-1 mice for genetic polymorphisms of the Kras2 and Pthlh genes, which are tightly linked with the Pas1 locus. From 95 to 98% of CD-1 mice carried the susceptibility allele at the Pas1 locus either at homozygosity or heterozygosity, providing a molecular genetic explanation for the high susceptibility of CD-1 mice to spontaneous and chemically induced lung tumorigenesis. These results may have implications for the risk assessment of chemicals in humans using experimental animals that display strain-specific lung tumorigenicity.