Disease relevance of Pas1

• Appropriate crosses that include susceptible mice (Pas1(s)) provide a model system for identifying loci that can modify the lung cancer predisposition phenotype caused by Pas1 [1].
• The mapping of Pas1 in mice stimulated us to test the possible association of genetic markers located in the homologous human region (12p12) with risk and prognosis of lung adenocarcinomas in man [1].

High impact information on Pas1

• A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice [2].
• M. spretus mice (SPRET/Ei) carry a Pas1 resistance haplotype for chemically induced lung tumors [2].
• 3. In Pas1/+ mice Par1 accounts for 23% of the phenotypic variance and 10 fold reduction in total tumour volume [3].
• Pulmonary adenoma susceptibility 1 (Pas1), located on chromosome 6, is the major locus affecting inherited predisposition to lung tumor development in mice [4].
• The Lrmp gene bears amino acid polymorphisms among various mouse strains that are highly correlated with the Pas1 allele status [5].

Biological context of Pas1

• Haplotype sharing suggests that a genomic segment containing six genes accounts for the pulmonary adenoma susceptibility 1 (Pas1) locus activity in mice [6].
• A highly significant linkage disequilibrium pattern was observed in AIR(max) and AIR(min) mice at marker alleles located within a 452-kb pulmonary adenoma susceptibility 1 (Pas1) locus region, thus defining the location of gene candidacy for inflammatory response and for the biological effects of Pas1 in this region [7].
• A correlation of lung tumor multiplicity phenotypes with genotypes of microsatellite markers on distal Chromosome (Chr) 6 in the Kras region (Pas1) was confirmed, and a new region on Chr 19 (designated Pas3) was identified that also contributes to susceptibility [8].
• We have previously mapped a major locus (Pulmonary adenoma susceptibility 1, Pas1) affecting inherited predisposition to lung cancer in mice on chromosome 6, near Kras2 [1].
• Since the activating point mutations were observed exclusively in the BALB allele as already reported with lung tumors in (C57BL/6J x BALB/cJ)F1 mice, BALB Pas1 or possibly Kras2 itself may confer selective growth advantage on the affected urethane-initiated lung lesions [9].

Anatomical context of Pas1

• The Pas1c1 gene (RIKEN Ak016641), encoding an intermediate filament tail domain-containing protein, produces alternatively spliced transcripts across inbred strains of mice, and its splicing pattern cosegregates with the Pas1 allele [5].
• Allelic effects of mouse Pas1 candidate genes in human lung cancer cell lines [10].

Associations of Pas1 with chemical compounds

• In the present study, using (C3H x BALB)F1 x C3H backcross mice treated with urethane, we demonstrated that BALB mice possess the disease allele of the Pas1 gene despite their 15-fold more resistance relative to A/J mice (LOD = 22.6) [9].
• A set of genes other than the pas genes governs the response to tumor modulation by butylated hydroxytoluene (BHT) [11].

Other interactions of Pas1

• In addition, an interaction between the Pas1 and Pas2 QTLs was revealed [5].
• Using this approach we have mapped the Pulmonary adenoma resistance 1 (Par1) locus that behaves like a modifier locus of Pas1 [1].
• While the BALB Pas1 allele increased both the mean multiplicity and size of lung tumors, the BALB Par2 allele affected only the mean tumor multiplicity, implying that they are involved in different stages of multi-step lung carcinogenesis [9].
• Pas1 candidate 1 (Pas1c1) gene (also named Lmna-rs1) was found to encode two alternatively spliced mRNA transcripts (i.e. Pas1c1-Va and Pas1c1-Vb) [12].
• Mice with activated Ha-ras transgenes override the resistant pas alleles and are born with lung cancer [11].

Analytical, diagnostic and therapeutic context of Pas1

• The phenotypic difference between C3H and A/J is largely determined by the Pas1 (Pulmonary adenoma susceptibility 1) gene on chromosome 6, the A/J allele of which dominantly increases the tumor burden [9].
• Pas1 haplotype-dependent genetic predisposition to lung tumorigenesis in rodents: a meta-analysis [13].

References