The main interest of the group is the study of the genes in host genome, which control the development of cancer. We aim to map and subsequently clone such genes, understand the way they interact with different molecular pathways during tumor development and progression, and determine what their relationship is to processes of regulation of cellular homeostasis at different developmental stages. The first evidence for the role of genetic factors in cancer has been obtained in familial cancer syndromes, which are caused by germ-line mutations in tumor suppressor or mismatch repair genes like APC, Rb, NF2, MSH2. However, these syndromes account for a small part of all cancers. The largest proportion of cancers is of non-familial, sporadic, type. Nevertheless, also in these apparently non-inherited cancers the host genetic factors play an important role (e.g., Lichtenstein et al., New Eng J Med 343:78, 2000). Moreover, especially in the breast cancer there is extended evidence that many, and probably most, cases of the apparently non-familial breast cancer appear in the genetically predisposed individuals (Peto and Mack, Nat Genet 26:411-414, 2000; Pharoah et al., Nat Genet 31:33-36, 2002). The largest part of this predisposition is caused by presently unknown genes. In contrast to the germ-line mutations of oncogenes or tumor suppressor and mismatch repair genes, the genes affecting development and progression of sporadic cancers are multiple and have smaller effects. Therefore, they are difficult to detect in classical family and population studies, and they have to be analyzed in experimental animals, which offer the advantage of defined genetic constitution, possibility of producing informative crosses, and standardized tumor-induction procedures (Demant, Nat Rev Genet 4:721-734, 2003). We used recombinant congenic strains of mice to map and identify lung and colon cancer susceptibility genes in mice and subsequently to search for their homologues in humans.
Project 1. Genetics of Colon Cancer Susceptibility
The cloning of cancer susceptibility genes becomes a subject of major interest for cancer geneticists. The first reported success in this respect is the Scc1 (Susceptibility to colon cancer 1) gene, identified as the Ptprj (Protein tyrosine phosphatase receptor-type J) (Ruivenkamp et al., 2002). Ptprj has one intracytoplasmatic enzyme domain, a transmembrane part and an extracellular chain consisting of fibronectin III-like domains. The Ptprj products of the susceptible and resistant strains differ at several amino acids in their fibronectin type III domains. Most of these amino-acid substitutions reside in the extracellular portion of the molecule. Similarly, the sequence of the coding regions of the homologous human gene (PTPRJ), which has been established in a large number of human DNAs, revealed several amino-acid replacements in extracellular regions. Sequence alignment, secondary structure prediction and homology modeling predict that the substitutions in the mouse as well as in humans occur in the exposed regions of the molecule that are available for interactions with ligands or other proteins, and thus could affect the signaling process. Presently, a Ptprj knockout mouse has been prepared and is being tested for its pattern of colon tumor susceptibility.
A large proportion of colon, breast and lung cancers exhibits loss of heterozygosity (LOH) at the short PTPRJ-bearing segment of chromosome 11p11 with their minimal shared segment containing PTPRJ In order to investigate the specific pathway and tumor progression stage, at which this gene may operate, we examined the possible correlation of the LOH in colon cancers with other somatic alterations. This analysis revealed a correlation between the LOH at PTPRJ and the deletion of the chromosomal segment 18q12-21 (Ruivenkamp et al., Oncogene 22:3472-3474, 2003) in progressed adenomas, indicating that haplodeficiency of PTPRJ is an early event in colon carcinogenesis and that its loss, in possible synergy with a deficiency of another gene on chromosome 18q, supports the transition of early adenomas into a more progressed stage. A significant definition of the susceptibility genotype requires definition of a large number of susceptibility genes. The search for novel colon cancer susceptibility genes revealed five novel Scc loci, Scc10 – Scc14 (Ruivenkamp et al., Oncogene 22:3472-3474, 2003).
Project 2. Lung Cancer Susceptibility
Lung cancer is the leading cause of cancer deaths worldwide. It exhibits familial clustering both in smokers and non-smokers, indicating the involvement of presently unknown genes. However, no such genes have been identified yet in humans. Using the mice as a model for study of genetics of lung cancer, the comparison of a number of mouse inbred strains revealed large differences in susceptibility to both spontaneous and chemically induced lung tumors and resulted in the mapping of several susceptibility loci. We have shown that the total number of Sluc genes (Susceptibility to lung cancer) probably exceeds 60 (Tripodis et al., 2001). Thirty of them have been mapped in the crosses of OcB/Dem RC strains, in which the genomes of the strain O20 and B10.O20 are segregated. OcB/Dem RCS have each only a random ~12.5% subset of genes derived from the resistant strain B10.O20, and the rest from the strain O20. In the past period, we used these strains to study the genetic control of lung cancer phenotype, because their respective parents, O20 and B10.O20, produce lung tumors with different biological properties. The microscopic appearance of cancer has been the major predictor of its clinical behavior. In order to be able to study the genes affecting lung tumor progression and correlate them with gene expression patterns, we used a new method for qualitative assessment of mouse lung tumors that provides a numerical description of the 3-D shape of a tumor. Eight new lung tumor shape determining (Ltsd) loci have been detected that influence the overall three dimensional (3D) shape of a tumor. We established the specific effects of these loci on presence of focal or regional regions of tumor progression. These studies lay the basis for a more detailed study of the mechanisms of genetic control of tumor progression (Tripodis and Demant, Cancer Res 63:125-131, 2003). These findings open way for expression profiling studies to establish the correlation between the host genotype, tumor phenotype, and tumor gene expression pattern.
Genetics of Colon Cancer Susceptibility
Lung Cancer Susceptibility
Cancer Susceptibility Genes in Mice and Their Human Homologues
Lipoldova M, Havelkova H, Badalova J, Vojtiskova J, Quan L, Krulova M, Sohrabi Y, Stassen AP, Demant P. Loci controlling lymphocyte production of interferon gamma after alloantigen stimulation in vitro and their co-localization with genes controlling lymphocyte infiltration of tumors and tumor susceptibility.Cancer immunology, immunotherapy : CII 2010; 59(2):203-213
Quan L, Hutson A, Demant P. A locus on chromosome 8 controlling tumor regionality-a new type of tumor diversity in the mouse lung. International journal of cancer 2010; 126(11):2603-2613
Saless N, Lopez Franco GE, Litscher S, Kattappuram RS, Houlihan MJ, Vanderby R, Demant P, Blank RD. Linkage mapping of femoral material properties in a reciprocal intercross of HcB-8 and HcB-23 recombinant mouse strains. Bone 2010; 46(5):1251-1259
Kurey I, Demant P, Hutson A, Stassen AP, Svobodova M, Grekov I, Trtkova K, Quan L, Slapnickova M, Havelkova H, Kobets T, Lipoldova M. Distinct genetic control of parasite elimination, dissemination, and disease after Leishmania major infection. Immunogenetics 2009; 61(9):619-633
Saless N, Demant P, Vanderby R, O'Neil TK, Raheem KA, Sudhakaran S, Houlihan MJ, Lopez Franco GE, Litscher SJ, Blank RD. Quantitative trait loci for biomechanical performance and femoral geometry in an intercross of recombinant congenic mice: restriction of the Bmd7 candidate interval. FASEB journal 2009; 23(7):2142-2154
Telerman A, Amson R, Demant P, Marrack P. Jean Dausset (1916-2009) Obituary. Immunity 2009; 31(2):171-173
Quan L, Stassen APM, Ruivenkamp CAL, van Wezel T, Fijneman RJA, Hutson A, Kakarlapudi N, Hart AAM, Demant P. Most lung and colon cancer susceptibility genes are pair-wise linked in mice, humans and rats. PloS one2011; 6(2):e14727
Saless N, Litscher SJ, Vanderby R, Demant P, Blank RD. Linkage mapping of principal components for femoral biomechanical performance in a reciprocal HCB-8 x HCB-23 intercross. Bone 2011; 48(3):647-653
Piskorowska J, Pienkowska-Grela B, Czarnomska A, Skurzak HM, Grygalewicz B, Quan L, Krysiak E, Szymanska H, Gajewska M, Demant P. Susceptibility loci and chromosomal abnormalities in radiation induced hematopoietic neoplasms in mice. Journal of radiation research 2011; 52(2):147-158
Kakarlapudi N, Vernooy JH, Quan L, Fijneman RJ, Demant P. Control of lymphocyte infiltration of lung tumors in mice by host's genes: mapping of four Lynf (lymphocyte infiltration) loci. Cancer immunology, immunotherapy : CII2008; 57(2):217-225
Banus S, Hoebee B, Mooi FR, Demant P, Breit TM, van Kranen HJ, Wester PW, Gremmer ER, Pennings JL, Vandebriel RJ, Kimman TG. Comparative gene expression profiling in two congenic mouse strains following Bordetella pertussis infection. BMC microbiology 2007; 7:88
Gouya L, Beaumont C, Demant P, Fleming R, Puy H, Deybach JC, Lyoumi S, Couchi E, Letteron P, Robreau AM, Muzeau F, Grandchamp B. Genetic study of variation in normal mouse iron homeostasis reveals ceruloplasmin as an HFE-hemochromatosis modifier gene. Gastroenterology 2007; 132(2):679-686
Piavaux B, Jeurink PV, Groot PC, Hofman GA, Demant P, Van Oosterhout AJ.Mouse genetic model for antigen-induced airway manifestations of asthma.Genes and immunity 2007; 8(1):28-34
Sevignani C, Calin GA, Nnadi SC, Shimizu M, Davuluri RV, Hyslop T, Demant P, Croce CM, Siracusa LD. MicroRNA genes are frequently located near mouse cancer susceptibility loci. Proceedings of the National Academy of Sciences of the United States of America 2007; 104(19):8017-8022
Saless N, Litscher SJ, Houlihan MJ, Han IK, Wilson D, Demant P, Blank RD.Comprehensive skeletal phenotyping and linkage mapping in an intercross of recombinant congenic mouse strains HcB-8 and HcB-23. Cells, tissues, organs2011; 194(2-4):244-248
Sima M, Havelkova H, Quan L, Svobodova M, Jarosikova T, Vojtiskova J, Stassen APM, Demant P, Lipoldova M. Genetic control of resistance to Trypanosoma brucei brucei infection in mice. PLoS neglected tropical diseases2011; 5(6):e1173
Quan L, Demant P. Genetics of location of tumors in an organ: A mouse lung cancer susceptibility gene affecting predominantly or only peribronchial tumors.Proceedings of the American Association for Cancer Research Annual Meeting2009; 50:806-807
Saless N, Litscher S, Houlihan MJ, O'Neil TK, Kattappuram RS, Sudhakaran S, Raheem KGA, Olson S, Franco GL, Demant P, Blank RD. Geometric Property QTLs in HcB/8 x HcB/23 F2 cross. Journal of bone and mineral research 2008;23(Suppl.):S106-S107
Saless N, Litscher SJ, Houlihan MJ, Kattappuram RS, Fraco GEL, Vanderby R,Demant P, Blank RD. Biomechanical performance principal component linkage mapping in recombinant congenic mice: Ostf is a candidate gene. Bone 2009;44(Suppl. 1):306
Saless N, Litscher SJ, Kattapuram RS, Houlihan MJ, O'Neil TK, Sudhakaran S, Raheem KGA, Olson S, Demant P, Blank RD. Strong and Extensive Epistatic Interactions Affect Bone Traits in a Mouse Reciprocal Intercross of HcB/8 and HcB/23. Journal of bone and mineral research 2008; 23(Suppl.):S158
Demant P. Donald wayne bailey 1926-2010. Immunogenetics 2012; 64(1):1-2
Lipoldova M, Havelkova H, Badalova J, Vojtiskova J, Quan L, Krulova M, Sohrabi Y, Stassen AP, Demant P. Genetic link between genes that control lymphocyte activation and susceptibility to cancer. International journal of molecular medicine 2011; 28(Suppl. 1):S12
Quan L, Dittmar A, Zhou Y, Hutson A, Stassen APM, Demant P. Susceptibility loci affecting ERBB2/neu-induced mammary tumorigenesis in mice. Genes, chromosomes and cancer 2012; 51(7):631-643
Kobets T, Havelkova H, Grekov I, Volkova V, Vojtiskova J, Slapnickova M, Kurey I, Sohrabi Y, Svobodova M, Demant P, Lipoldova M. Genetics of host response to Leishmania tropica in mice - different control of skin pathology, chemokine reaction, and invasion into spleen and liver. PLoS neglected tropical diseases 2012; 6(6):e1667