Tumor Loci and Their Interactions on Mouse Chromosome 19 That Contribute to Testicular Germ Cell Tumors

Overview

Journal BMC Genet

Publisher Biomed Central

Specialties Biotechnology
Molecular Biology

Date 2014 Jun 3

PMID 24886204

Citations 3

Authors

Rui Zhu

Angabin Matin

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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References

Poynter J, Hooten A, Frazier A, Ross J . Associations between variants in KITLG, SPRY4, BAK1, and DMRT1 and pediatric germ cell tumors. Genes Chromosomes Cancer. 2011; 51(3):266-71. DOI: 10.1002/gcc.20951. View

RAYMOND C, Murphy M, OSullivan M, Bardwell V, Zarkower D . Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes Dev. 2000; 14(20):2587-95. PMC: 316999. DOI: 10.1101/gad.834100. View

Matsuda M, Nagahama Y, Shinomiya A, Sato T, Matsuda C, Kobayashi T . DMY is a Y-specific DM-domain gene required for male development in the medaka fish. Nature. 2002; 417(6888):559-63. DOI: 10.1038/nature751. View

Stevens L, Hummel K . A description of spontaneous congenital testicular teratomas in strain 129 mice. J Natl Cancer Inst. 1957; 18(5):719-47. View

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(4):331-4. PMC: 1050923. DOI: 10.1136/jmg.34.4.331. View

Hussain S, Ma Y, Palmer D, Hutton P, Cullen M . Biology of testicular germ cell tumors. Expert Rev Anticancer Ther. 2008; 8(10):1659-73. DOI: 10.1586/14737140.8.10.1659. View

Comish P, Drumond A, Kinnell H, Anderson R, Matin A, Meistrich M . Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice. PLoS One. 2014; 9(4):e93311. PMC: 3972108. DOI: 10.1371/journal.pone.0093311. View

Kimura T, Suzuki A, Fujita Y, Yomogida K, Lomeli H, Asada N . Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production. Development. 2003; 130(8):1691-700. DOI: 10.1242/dev.00392. View

Looijenga L, Hersmus R, Gillis A, Pfundt R, Stoop H, van Gurp R . Genomic and expression profiling of human spermatocytic seminomas: primary spermatocyte as tumorigenic precursor and DMRT1 as candidate chromosome 9 gene. Cancer Res. 2006; 66(1):290-302. DOI: 10.1158/0008-5472.CAN-05-2936. View

10.

Dieckmann K, Skakkebaek N . Carcinoma in situ of the testis: review of biological and clinical features. Int J Cancer. 1999; 83(6):815-22. DOI: 10.1002/(sici)1097-0215(19991210)83:6<815::aid-ijc21>3.0.co;2-z. View

11.

. Aetiology of testicular cancer: association with congenital abnormalities, age at puberty, infertility, and exercise. United Kingdom Testicular Cancer Study Group. BMJ. 1994; 308(6941):1393-9. PMC: 2540340. View

12.

Stevens L . Embryology of testicular teratomas in strain 129 mice. J Natl Cancer Inst. 1959; 23:1249-95. View

13.

Krentz A, Murphy M, Kim S, Cook M, Capel B, Zhu R . 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(52):22323-8. PMC: 2799724. DOI: 10.1073/pnas.0905431106. View

14.

Oosterhuis J, Looijenga L . Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer. 2005; 5(3):210-22. DOI: 10.1038/nrc1568. View

15.

Collin G, Asada Y, Varnum D, Nadeau J . 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. DOI: 10.1007/s003359900017. View

16.

Frankel W, Schork N . Who's afraid of epistasis?. Nat Genet. 1996; 14(4):371-3. DOI: 10.1038/ng1296-371. View

17.

Linger R, Dudakia D, Huddart R, Easton D, Bishop D, Stratton M . 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(2):357-61. PMC: 2360005. DOI: 10.1038/sj.bjc.6603557. View

18.

Veitia R, Nunes M, Brauner R, Doco-Fenzy M, Jaubert F, Lortat-Jacob S . 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(2):271-4. DOI: 10.1006/geno.1997.4648. View

19.

Youngren K, Nadeau J, Matin A . Testicular cancer susceptibility in the 129.MOLF-Chr19 mouse strain: additive effects, gene interactions and epigenetic modifications. Hum Mol Genet. 2003; 12(4):389-98. DOI: 10.1093/hmg/ddg036. View

20.

Rescorla F . Pediatric germ cell tumors. Semin Surg Oncol. 1999; 16(2):144-58. DOI: 10.1002/(sici)1098-2388(199903)16:2<144::aid-ssu6>3.0.co;2-m. View