Tumor loci and their interactions on mouse chromosome 19 that contribute to testicular germ cell tumors

BMC Genetics

Angabin Matin²  Rui Zhu¹ 

[1] Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, Texas 77030, USA;Department of Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA

关键词: Epistasis;    Modifiers;    Testicular germ cell tumor;    M19;    Chromosome substitution strain;    Congenic strain;   

Others  :  866482
DOI  :  10.1186/1471-2156-15-65

 received in 2014-02-04, accepted in 2014-05-23,  发布年份 2014

【 摘 要 】

Background

Complex genetic factors underlie testicular germ cell tumor (TGCT) development. One experimental approach to dissect the genetics of TGCT predisposition is to use chromosome substitution strains, such as the 129.MOLF-Chr 19 (M19). M19 carries chromosome (Chr) 19 from the MOLF whereas all other chromosomes are from the 129 strain. 71% of M19 males develop TGCTs in contrast to 5% in 129 strain. To identify and map tumor loci from M19 we generated congenic strains harboring MOLF chromosome 19 segments on 129 strain background and monitored their TGCT incidence.

Results

We found 3 congenic strains that each harbored tumor promoting loci that had high (14%-32%) whereas 2 other congenics had low (4%) TGCT incidences. To determine how multiple loci influence TGCT development, we created double and triple congenic strains. We found additive interactions were predominant when 2 loci were combined in double congenic strains. Surprisingly, we found an example where 2 loci, both which do not contribute significantly to TGCT, when combined in a double congenic strain resulted in greater than expected TGCT incidence (positive interaction). In an opposite example, when 2 loci with high TGCT incidences were combined, males of the double congenic showed lower than expected TGCT incidence (negative interaction). For the triple congenic strain, depending on the analysis, the overall TGCT incidence could be additive or could also be due to a positive interaction of one region with others. Additionally, we identified loci that promote bilateral tumors or testicular abnormalities.

Conclusions

The congenic strains each with their characteristic TGCT incidences, laterality of tumors and incidence of testicular abnormalities, are useful for identification of TGCT susceptibility modifier genes that map to Chr 19 and also for studies on the genetic and environmental causes of TGCT development. TGCTs are a consequence of aberrant germ cell and testis development. By defining predisposing loci and some of the locus interactions from M19, this study further advances our understanding of the complex genetics of TGCTs, which is the most common cancer in young human males.

【 授权许可】

   
2014 Zhu and Matin; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Dieckmann K-P, Skakkebaek NE: Carcinoma in situ of the testis: review of biological and clinical features. Int J Cancer 1999, 83:815-822.
• [2]Lutke Holzik MF, Sijmons RH, Sleijfer DT, Sonneveld DJ, Hoekstra-Weebers JE, van Echten-Arends J, Hoekstra HJ: Syndromic aspects of testicular carcinoma. Cancer 2003, 97(4):984-992.
• [3]Hussain SA, Ma YT, Palmer DH, Hutton P, Cullen MH: Biology of testicular germ cell tumors. Expert Rev Anticancer Ther 2008, 8:1659-1673.
• [4]Nathanson KL, Kanetsky PA, Hawes R, Vaughn DV, Letrero R, Tucker K, Friedlander M, Phillips K-A, Hogg D, Jewett MA, Lohynska R, Daugaard G, Richard S, Chompret A, Bonaïti-Pellié C, Heidenreich A, Olah E, Geczi L, Bodrogi I, Ormiston WJ, Daly PA, Oosterhuis JW, Gillis AJ, Looijenga LH, Guilford P, Fosså SD, Heimdal K, Tjulandin SA, Liubchenko L, Stoll H: The Y deletion gr/gr and susceptibility to testicular germ cell tumor. Am J Hum Genet 2005, 77:1034-1043.
• [5]Crockford GP, Linger R, Hockley S, Dudakia D, Johnson L, Huddart R, Tucker K, Friedlander M, Phillips KA, Hogg D, Jewett MA, Lohynska R, Daugaard G, Richard S, Chompret A, Bonaïti-Pellié C, Heidenreich A, Albers P, Olah E, Geczi L, Bodrogi I, Ormiston WJ, Daly PA, Guilford P, Fosså SD, Heimdal K, Tjulandin SA, Liubchenko L, Stoll H, Weber W: Genome-wide linkage screen for testicular germ cell tumour susceptibility loci. Hum Mol Genet 2006, 15:443-451.
• [6]Linger R, Dudakia D, Huddart R, Easton D, Bishop DT, Stratton MR, Rapley EA: A physical analysis of the Y chromosome shows no additional deletions, other than Gr/Gr, associated with testicular germ cell tumour. Br J Cancer 2007, 96:357-361.
• [7]Kanetsky PA, Mitra N, Vardhanabhuti S, Li M, Vaughn DJ, Letrero R, Ciosek SL, Doody DR, Smith LM, Weaver J, Albano A, Chen C, Starr JR, Rader DJ, Godwin AK, Reilly MP, Hakonarson H, Schwartz SM, Nathanson KL: Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nat Genet 2009, 41:811-815.
• [8]Rapley EA, Turnbull C, Al Olama AA, Dermitzakis ET, Linger R, Huddart RA, Renwick A, Hughes D, Hines S, Seal S, Morrison J, Nsengimana J, Deloukas P, Rahman N, Bishop DT, Easton DF, Stratton MR, UK Testicular Cancer Collaboration: A genome-wide association study of testicular germ cell tumor. Nat Genet 2009, 41:807-810.
• [9]Turnbull C, Rapley EA, Seal S, Pernet D, Renwick A, Hughes D, Ricketts M, Linger R, Nsengimana J, Deloukas P, Huddart RA, Bishop DT, Easton DF, Stratton MR, Rahman N, UK Testicular Cancer Collaboration: Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nat Genet 2010, 42:604-607.
• [10]Skakkebaek NE, Berthelsen JG, Giwercman A, Muller J: Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int J Androl 1987, 10(1):19-28.
• [11]Oosterhuis JW, Looijenga LHJ: Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer 2005, 5:210-222.
• [12]Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 1999, 16:144-158.
• [13]Stevens LC, Hummel KP: A description of spontaneous congenital testicular teratomas in strain 129 mice. J Natl Cancer Inst 1957, 18:719-747.
• [14]Stevens LC: Embryology of testicular teratomas in strain 129 mice. J Natl Cancer Inst 1959, 23:1249-1295.
• [15]Stevens LC: Testicular teratomas in fetal mice. J Natl Cancer Inst 1962, 28:247-267.
• [16]Youngren KK, Nadeau JH, Matin A: Testicular cancer susceptibility in the 129.MOLF-Chr 19 mouse strain: additive effects, gene interactions and epigenetic modifications. Hum Mol Genet 2003, 12:389-398.
• [17]Looijenga LH, Hersmus R, Gillis AJ, Pfundt R, Stoop HJ, van Gurp RJ, Veltman J, Beverloo HB, van Drunen E, van Kessel AG, Pera RR, Schneider DT, Summersgill B, Shipley J, McIntyre A, van der Spek P, Schoenmakers E, Oosterhuis JW: Genomic and expression profiling of human spermatocytic seminomas: primary spermatocyte as tumorigenic precursor and DMRT1 as candidate chromosome 9 gene. Cancer Res 2006, 66:290-302.
• [18]Heaney JD, Lam M-YJ, Michelson MV, Nadeau JH: Loss of the transmembrane but not the soluble Kit ligand isoform increases testicular germ cell tumor susceptibility in mice. Cancer Res 2008, 68:5193-5197.
• [19]Krentz AD, Murphy MW, Kim S, Cook MS, Capel B, Zhu R, Matin A, Sarver AL, Parker KL, Griswold MD, Looijenga LH, Bardwell VJ, Zarkower D: The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proc Natl Acad Sci U S A 2009, 106:22323-22328.
• [20]Kanetsky PA, Mitra N, Vardhanabhuti S, Vaughn DJ, Li M, Ciosek SL, Letrero R, D'Andrea K, Vaddi M, Doody DR, Weaver J, Chen C, Starr JR, Håkonarson H, Rader DJ, Godwin AK, Reilly MP, Schwartz SM, Nathanson KL: A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility. Hum Mol Genet 2011, 20:3109-3117.
• [21]Collin GB, Asada Y, Varnum DS, Nadeau JH: DNA pooling as a quick method for finding candidate linkages in multigenic trait analysis: an example involving susceptibility to germ cell tumors. Mamm Genome 1996, 7(1):68-70.
• [22]Matin A, Collin GB, Asada Y, Varnum D, Nadeau JH: Susceptibility to testicular germ-cell tumours in a 129.MOLF-Chr 19 chromosome substitution strain. Nat Genet 1999, 23(2):237-240.
• [23]Silver LM: Mouse genetics: concepts and applications. New York: Oxford University Press; 1995:32-61.
• [24]Rieseberg LH, Archer MA, Wayne RK: Transgressive segregation, adaptation and speciation. Heredity 1999, 83:363-372.
• [25]Kimura T, Suzuki A, Fujita Y, Yomogida K, Lomeli H, Asada N, Ikeuchi M, Nagy A, Mak TW, Nakano T: Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production. Development 2003, 130:1691-1700.
• [26]Zhu R, Heaney J, Nadeau J, Ali S, Matin A: Deficiency of Splicing Factor 1 (SF1) suppresses occurrence of testicular germ cell tumors. Cancer Res 2010, 70:7264-7272.
• [27]Zhu R, Ji Y, Xiao L, Matin A: Testicular germ cell tumor susceptibility genes from the consomic 129.MOLF-Chr 19 mouse strain. Mamm Genome 2007, 18:584-595.
• [28]Cordell HJ: Epistasis: what it means, what it doesn't mean. and statistical methods to detect it in humans. Hum Mol Genet 2002, 11:2463-2468.
• [29]Frankel WN, Schork NJ: Who's afraid of epistasis? Nat Genet 1996, 14:371-373.
• [30]Tollerud DJ, Blattner WA, Fraser MC, Brown LM, Pottern L, Shapiro E, Kirkemo A, Shawker TH, Javadpour N, O'Connell K, Stutzman RE, Fraumeni JF Jr: Familial testicular cancer and urogenital developmental anomalies. Cancer 1985, 55:1849-1854.
• [31]United Kingdom Testicular Cancer Study Group U: Aetiology of testicular cancer: association with congenital abnormalities, age at puberty, infertility, and excercise. BMJ 1994, 308:1393-1399.
• [32]Poynter JN, Hooten AJ, Frazier AL, Ross JA: Associations between variants in KITLG, SPRY4, BAK1, and DMRT1 and pediatric germ cell tumors. Genes Chromosomes Cancer 2012, 51:266-271.
• [33]Kratz CP, Han SS, Rosenberg PS, Berndt SI, Burdett L, Yeager M, Korde LA, Mai PL, Pfeiffer R, Greene MH: Variants in or near KITLG, BAK1, DMRT1, and TERT-CLPTM1L predispose to familial testicular germ cell tumour. J Med Genet 2011, 48:473-476.
• [34]Matsuda M, Nagahama Y, Shinomiya A, Sato T, Matsuda C, Kobayashi T, Morrey CE, Shibata N, Asakawa S, Shimizu N, Hori H, Hamaguchi S, Sakaizumi M: DMY is a Y-specific DM-domain gene required for male development in the medaka fish. Nature 2002, 417:559-563.
• [35]Raymond CS, Murphy MW, O'Sullivan MG, Bardwell VJ, Zarkower D: Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes Dev 2000, 14:2587-2595.
• [36]McDonald MT, Flejter W, Sheldon S, Putzi MJ, Gorski JL: XY sex reversal and gonadal dysgenesis due to 9p24 monosomy. Am J Med Genet 1997, 73:321-326.
• [37]Veitia R, Nunes M, Brauner R, Doco-Fenzy M, Joanny-Flinois O, Jaubert F, Lortat-Jacob S, Fellous M, McElreavey K: Deletions of distal 9p associated with 46, XY male to female sex reversal: definition of the breakpoints at 9p23.3–p24.1. Genomics 1997, 41:271-274.
• [38]Flejter WL, Fergestad J, Gorski JL, Varvill T, Chandrasekharappa S: A gene involved in XY sex reversal is located on chromosome 9, distal to marker D9S1779. Am J Hum Genet 1998, 63:794-802.
• [39]Ogata T, Muroya K, Matsuo N, Hata J, Fukushima Y, Suzuki Y: Impaired male sex development in an infant with molecularly defined partial 9p monosomy: implication for a testis forming gene(s) on 9p. J Med Genet 1997, 34:331-334.
• [40]Shetty G, Comish PB, Weng CC, Matin A, Meistrich ML: Fetal radiation exposure induces testicular cancer in genetically susceptible mice. PLoS One 2012, 7(2):e32064. doi:32010.31371/journal.pone.0032064
• [41]Comish PB, Drumond AL, Kinnell HL, Anderson RA, Matin A, Meistrich ML, Shetty G: Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice. PLoS One 2014, 9(4):e93311.