A subset of skin tumor modifier loci determines survival time of tumor-bearing mice.

Studies of mouse models of human cancer have established the existence of multiple tumor modifiers that influence parameters of cancer susceptibility such as tumor multiplicity, tumor size, or the probability of malignant progression. We have carried out an analysis of skin tumor susceptibility in interspecific Mus musculus/Mus spretus hybrid mice and have identified another seven loci showing either significant (six loci) or suggestive (one locus) linkage to tumor susceptibility or resistance. A specific search was carried out for skin tumor modifier loci associated with time of survival after development of a malignant tumor. A combination of resistance alleles at three markers [D6Mit15 (Skts12), D7Mit12 (Skts2), and D17Mit7 (Skts10)], all of which are close to or the same as loci associated with carcinoma incidence and/or papilloma multiplicity, is significantly associated with increased survival of mice with carcinomas, whereas the reverse combination of susceptibility alleles is significantly linked to early mortality caused by rapid carcinoma growth (chi(2) = 25.22; P = 5.1 x 10(-8)). These data indicate that host genetic factors may be used to predict carcinoma growth rate and/or survival of individual backcross mice exposed to the same carcinogenic stimulus and suggest that mouse models may provide an approach to the identification of genetic modifiers of cancer survival in humans.

[1]  K. Hagino-Yamagishi,et al.  [Oncogene]. , 2019, Gan to kagaku ryoho. Cancer & chemotherapy.

[2]  F. Shepherd,et al.  Reduced expression of the cell cycle inhibitor p27Kip1 in non-small cell lung carcinoma: a prognostic factor independent of Ras. , 1999, Cancer research.

[3]  James M. Roberts,et al.  The murine gene p27Kip1 is haplo-insufficient for tumour suppression , 1998, Nature.

[4]  R. Jansen,et al.  High frequency of interactions between lung cancer susceptibility genes in the mouse: mapping of Sluc5 to Sluc14. , 1998, Cancer research.

[5]  S. Yuspa,et al.  Multigenic control of skin tumor susceptibility in SENCARA/Pt mice. , 1998, Carcinogenesis.

[6]  A. Balmain,et al.  Cancer resistance genes in mice: models for the study of tumour modifiers. , 1998, Trends in genetics : TIG.

[7]  T. Dragani,et al.  Association of chromosome 12p genetic polymorphisms with lung adenocarcinoma risk and prognosis. , 1997, Carcinogenesis.

[8]  K. Minda,et al.  Association of a murine chromosome 9 locus (Psl1) with susceptibility to mouse skin tumor promotion by 12‐O‐tetradecanoylphorbol‐13‐acetate , 1997, Molecular carcinogenesis.

[9]  M. Becich,et al.  Association between human cancer and two polymorphisms occurring together in the p21Waf1/Cip1 cyclin‐dependent kinase inhibitor gene , 1997, Cancer.

[10]  Ritsert C. Jansen,et al.  Complex interactions of new quantitative trait loci, Sluc1, Sluc2, Sluc3, and Sluc4, that influence the susceptibility to lung cancer in the mouse , 1996, Nature Genetics.

[11]  A. Hart,et al.  Gene interaction and single gene effects in colon tumour susceptibility in mice , 1996, Nature Genetics.

[12]  F. Canzian,et al.  A polygenic model of inherited predisposition to cancer , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[13]  T. Mukai,et al.  Genomic imprinting of p57KIP2, a cyclin–dependent kinase inhibitor, in mouse , 1995, Nature Genetics.

[14]  A. Balmain,et al.  Distinct genetic loci control development of benign and malignant skin tumours in mice , 1995, Nature Genetics.

[15]  L Kruglyak,et al.  A nonparametric approach for mapping quantitative trait loci. , 1995, Genetics.

[16]  S. Reed,et al.  Molecular cloning, sequencing, chromosomal localization and expression of mouse p21 (Waf1). , 1994, Oncogene.

[17]  J. Witte,et al.  Genetic dissection of complex traits. , 1994, Nature genetics.

[18]  James M. Roberts,et al.  Cloning of p27 Kip1 , a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals , 1994, Cell.

[19]  M. Gariboldi,et al.  A major susceptibility locus to murine lung carcinogenesis maps on chromosome 6 , 1993, Nature Genetics.

[20]  C. Conti,et al.  Characterization of skin tumor promotion and progression by chrysarobin in SENCAR mice. , 1987, Cancer research.

[21]  W. Conover.  Statistical Methods for Rates and Proportions , 1974 .

[22]  J. Fleiss,et al.  Statistical methods for rates and proportions , 1973 .

[23]  P. Lereim.  [Predisposition to cancer]. , 1966, Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke.

[24]  W. Gardner,et al.  Carcinogenesis , 1961, The Yale Journal of Biology and Medicine.

[25]  G. -. Lee,et al.  Identification of hepatocarcinogen-resistance genes in DBA/2 mice. , 1995, Genetics.

[26]  B. Ponder,et al.  Inherited predisposition to cancer. , 1990, Trends in genetics : TIG.

[27]  J. Klotz,et al.  Statistical methods for the analysis of tumor multiplicity data. , 1981, Cancer research.

[28]  B. Bainbridge,et al.  Genetics , 1981, Experientia.