Genetic mapping of a pulmonary adenoma resistance locus (Par1) in mouse

Manenti, Giacomo; Gariboldi, Manuela; Elango, Ramu; Fiorino, Antonio; Gregorio, Laura De; Falvella, Felicia Stefania; Hunter, Kent W.; Housman, David E.; Pierotti, Marco A.; Dragani, Tommaso A.

doi:10.1038/ng0496-455

Cited by 64 publications

(45 citation statements)

References 16 publications

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“…Alternatively, in addition to skin-specific cancer modifier alleles, one or a few cancer modifier alleles might inhibit both types of tumorigenesis. An example of a mouse strain carrying independent loci that inhibit different types of tumorigenesis is provided by M. spretus, which carries the Par1 locus on chromosome 11 to inhibit lung tumorigenesis 9 and independent loci on chromosomes 1, 4, 5, 7, 9, 12 and 16 to inhibit skin papilloma multiplicity. 18 The BALB/c strain also carries cancer resistance loci to two types of tumorigenesis, i.e., lung and liver.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of both skin and lung tumorigenesis by Car‐R mouse‐derived cancer modifier loci

Saran

Zaffaroni

Pazzaglia

et al. 2001

Intl Journal of Cancer

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The Car-R outbred mouse line was phenotypically selected for high resistance to two-stage skin tumorigenesis. In the present study we tested the hypothesis that a subset of genetic loci responsible for resistance to skin tumorigenesis of Car-R mice might also inhibit lung tumorigenesis. Skin and lung tumorigenesis were induced in groups of Car-R, SWR/J, (SWR/JxCar-R)F1 and SWR/Jx(SWR/JxCar-R) backcross mice by i.p. urethane initiation and skin TPA promotion. Car-R mice showed a much lower susceptibility to both skin and lung tumorigenesis as compared to SWR/J mice, which are susceptible to both lung and skin tumorigenesis. The Car-R-inherited genome significantly inhibited both skin and lung cancer development in the F1 progeny of Car-R with SWR/J mice. In the backcross population, skin and lung tumor phenotypes showed a statistically significant correlation, indicating that a subset of the cancer resistance alleles, which segregated in the Car-R line during selection for resistance to skin carcinogenesis, provides resistance to both skin and lung tumorigenesis. © 2002 Wiley-Liss, Inc. Key words: cancer modifiers; genetic susceptibility; inherited predisposition; Kras2 linkage disequilibrium; lung neoplasm; Pthlh Non-inbred carcinogenesis-resistant (Car-R) and carcinogensusceptible (Car-S) mouse lines were generated by phenotypic selection for resistance and susceptibility, respectively, to 2-stage skin carcinogenesis, starting from a cross of 8 inbred strains (A, BALB/c, C57BL/6, CBA, DBA/2, P, SJL and SWR). 1,2 The Car mice interline difference in susceptibility is Ͼ100-fold. 3 Tumor susceptibility and resistance in the Car lines were initially considered skin tissue-specific, because there was no interline difference in sarcoma induction by subcutaneous injection of chemical carcinogens. 4 In our present study, we tested the hypothesis that Car-R mice carry cancer resistance loci that inhibit susceptibility to both skin and lung tumorigenesis. Tumors were initiated in SWR/J mice, which are highly susceptible to both lung and skin cancer 3 and in Car-R and (SWR/JxCar-R)F1 mice using urethane, a multi-organ carcinogen that can initiate both lung and skin tumorigenesis. 5,6 Analysis of urethane-initiated and TPA-promoted Car-R, SWR/J and (SWR/JxCar-R)F1 mice revealed resistance to both skin and lung carcinogenesis in the Car-R line and F1 hybrids, showing that the genetic resistance of Car-R mice to both tumor types is dominant over the susceptibility of the SWR/J strain. Linkage disequilibrium (LD) and haplotype analyses showed that Car-R mice carry the Pulmonary adenoma susceptibility 1 (Pas1 s ) allele despite their resistance to lung tumorigenesis. The Pas1 s allele is carried by A/J and SWR/J mice and is dominant in crosses between A/J and C3H/He or C57BL/6 mice. 7,8 Resistance alleles, however, carried by some mouse strains (e.g., M. spretus, BALB/c, SM/J) at pulmonary adenoma resistance (Par) loci inhibit Pas1-mediated susceptibility to lung tumorigenesis in a dominant or co-dominant way. 9 -11 Skin an...

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Section: Resultsmentioning

confidence: 99%

Inhibition of both skin and lung tumorigenesis by Car‐R mouse‐derived cancer modifier loci

Saran

Zaffaroni

Pazzaglia

et al. 2001

Intl Journal of Cancer

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“…Only one of these QTLs maps in the same region as lung cancer modifier loci: the Aliq1 locus (acute lung injury QTL 1), affecting acute lung injury, maps in the Par1 region on chromosome 11 (Manenti et al, 1996;Prows et al, 1999). However, both the A/J and C57BL/6J strains of the cross used to map the Aliq1 locus carry a null allele at the Par1 locus (Manenti et al, 1996), suggesting that the Aliq1 locus is distinct from the Par1 locus.…”

Section: Discussionmentioning

confidence: 97%

“…Lung tumorigenesis in mice is under complex genetic control in which the pulmonary adenoma susceptibility 1 (Pas1) locus plays a major role in predisposition to this tumor (Gariboldi et al, 1993), whereas several pulmonary adenoma resistance (Par) loci inhibit the phenotypic effects of the Pas1 susceptibility (Pas1 s ) allele (Manenti et al, 1996;Obata et al, 1996;Pataer et al, 1997). Linkage disequilibrium (LD), haplotype, and phenetic analyses indicate that the Pas1 s allele most likely originated from a single mutation in an ancestral mouse and that it is carried by all laboratory inbred strains characterized by high or intermediate susceptibility to lung tumorigenesis (Manenti et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Pulmonary adenoma susceptibility 1 (Pas1) locus affects inflammatory response

et al. 2003

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Two outbred mouse lines, phenotypically selected for differential subcutaneous (s.c.) acute inflammatory response (AIR), were analysed for urethane-induced lung inflammatory response and susceptibility to lung tumorigenesis. AIR min mice, which show a low response to s.c. acute inflammation, developed a persistent subacute lung inflammatory response and a 40-fold higher lung tumor multiplicity than did AIR max mice, which are selected for high response to s.c. acute inflammation and showed a transient lung inflammatory response. 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. AIR min and AIR max mice segregated by descent the Pas1 s and Pas1 r alleles, respectively, providing evidence for the involvement of the Pas1 locus in the inflammatory response. The 452-kb region contains Kras2 and four additional genes, including the lymphoidrestricted membrane protein (Lrmp) gene, whose ProLeu nonconservative variation was linked with inflammatory response and Pas1 allelotype. These results provide a model to explore the mechanism underlying inherited predisposition to lung cancer in the context of a link to inflammation.

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“…In BALB mice, the sensitive Pas1 phenotype is modulated by a single major gene, Par2, so that they provide a useful model for analysing the interactions between tumor susceptibility and resistance genes. Another lung tumor resistance gene of Mus spretus mice, Par1 (Pulmonary adenoma resistance 1), which modulates the Pas1 phenotype was also identi®ed by Manenti et al (1996). Molecular identi®cation of these murine genes and their functional analysis should aid fundamental understanding of tumor pathogenesis and its prevention in man.…”

Section: Discussionmentioning

confidence: 99%