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Genetic Control of Testicular Germ Cell Tumor Susceptibility in Mice

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Genetic Control of Testicular Germ Cell Tumor Susceptibility in Mice GENETIC CONTROL OF TESTICULAR GERM CELL TUMOR SUSCEPTIBILITY IN MICE By PHILIP DAVID ANDERSON Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation advisor: Dr. Joseph H. Nadeau Department of Genetics CASE WESTERN RESERVE UNIVERSITY August 2009 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of _____________________________________________________ candidate for the ______________________degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. TABLE OF CONTENTS ABSTRACT ............................................................................................................................... 8 1 CHAPTER 1: BACKGROUND AND SIGNIFICANCE .............................................................. 10 1.1 TESTICULAR CANCER IN HUMANS ............................................................................................... 11 1.1.1 Effect of age on testicular cancer risk ..................................................................... 11 1.1.2 Histopathological subtypes are associated with particular age groups .................. 14 1.1.3 Accelerating rates of TGCT diagnoses throughout the First World ......................... 15 1.1.4 Risk factors for TGCTs .............................................................................................. 16 1.1.5 Genetic contributors to TGCTs in humans ............................................................... 17 1.1.6 Genetics of cancer ................................................................................................... 19 1.2 TESTICULAR CANCER IN MICE .................................................................................................... 19 1.2.1 TGCTs in strain 129 mice ......................................................................................... 20 1.2.2 PGC migration and colonization of the genital ridges ............................................. 21 1.2.3 The Y chromosome and its role in sex determination.............................................. 22 1.2.4 Biology of TGCT tumorigenesis ................................................................................ 23 1.2.5 Defects in key developmental pathways may promote TGCTs ................................ 24 1.2.6 TGCT susceptibility genes and modifier genes ........................................................ 26 1.2.7 Mapping TGCT loci .................................................................................................. 29 1.3 RESEARCH AIMS ..................................................................................................................... 38 2 CHAPTER 2: TGCT SURVEY IN A RECIPROCAL B6.129 CSS PANEL AND A PARTIAL 129‐ CHRMOLF CSS PANEL .............................................................................................................................. 39 2.1 ABSTRACT ............................................................................................................................ 40 2.2 INTRODUCTION ..................................................................................................................... 40 2.3 MATERIALS AND METHODS ..................................................................................................... 43 1 2.3.1 Backcrosses ............................................................................................................. 43 2.3.2 Genotyping .............................................................................................................. 44 2.3.3 SNP selection and primer design ............................................................................. 45 2.3.4 TGCT survey ............................................................................................................. 45 2.4 RESULTS ............................................................................................................................... 46 2.4.1 TGCT occurrence in 129‐ChrMOLF backcross mice ..................................................... 46 2.4.2 Evidence for MOLF modifiers in 129‐Chr 2MOLF and 129‐Chr 18MOLF ........................ 46 2.4.3 TGCT occurrence in 129‐ChrB6 and B6‐Chr129 backcross mice .................................. 51 2.4.4 The model accurately predicted a modifier(s) on MOLF‐18 .................................... 52 2.4.5 High bilateral TGCT prevalence in 129‐Chr XMOLF .................................................... 52 2.5 DISCUSSION .......................................................................................................................... 56 3 CHAPTER 3: THREE TGCT QTLS MAPPED TO CHROMOSOME 18 ...................................... 61 3.1 ABSTRACT ............................................................................................................................ 62 3.2 INTRODUCTION ..................................................................................................................... 62 3.3 MATERIALS AND METHODS ..................................................................................................... 66 3.3.1 Construction of 129‐Chr 18MOLF ............................................................................... 66 3.3.2 Genotyping .............................................................................................................. 67 3.3.3 Construction of congenic strains from 129‐Chr 18MOLF ............................................ 67 3.3.4 Identification of novel SSR markers ......................................................................... 68 3.3.5 Breakpoint mapping ................................................................................................ 69 3.3.6 TGCT survey ............................................................................................................. 69 3.3.7 Histology.................................................................................................................. 69 3.4 RESULTS ............................................................................................................................... 70 3.4.1 Evidence for at least three TGCT QTLs on chromosome 18. .................................... 72 3.4.2 Testes of 129‐Chr18MOLF and congenic mice were affected by calcification ............ 73 3.4.3 Does length of the congenic segments influence TGCT prevalence? ....................... 75 2 3.5 DISCUSSION .......................................................................................................................... 77 4 CHAPTER 4: THE ROLE OF THE MOUSE Y CHROMOSOME ON TGCT SUSCEPTIBILITY ........ 82 4.1 ABSTRACT ............................................................................................................................ 83 4.2 INTRODUCTION ..................................................................................................................... 83 4.3 MATERIALS AND METHODS ..................................................................................................... 86 4.3.1 CSSs ......................................................................................................................... 86 4.3.2 Sox9Ods crosses......................................................................................................... 87 4.3.3 Genotyping .............................................................................................................. 87 4.3.4 TGCT survey ............................................................................................................. 87 4.3.5 Histology and immunohistochemistry ..................................................................... 87 4.4 RESULTS ............................................................................................................................... 88 4.4.1 The 129/Sv Y chromosome is not necessary for TGCTs ........................................... 88 4.4.2 The 129/Sv Y chromosome is not sufficient for TGCTs ............................................ 89 4.4.3 Adult XX sex‐reversed males do not have TGCTs ..................................................... 91 4.4.4 Neonate XY males, but not XX sex‐reversed males, have germ cells at birth .......... 93 4.4.5 Neonate XY males, but not XX sex‐reversed males, have TGCTs at birth ................ 95 4.5 DISCUSSION .......................................................................................................................... 95 5 CHAPTER 5: SUMMARY AND FUTURE DIRECTIONS ....................................................... 100 5.1 SUMMARY .......................................................................................................................... 101 5.1.1 Three new CSSs with TGCT QTLs ............................................................................ 101 5.1.2 Chromosome 18 has multiple factors influencing TGCT susceptibility .................. 103 5.1.3 At least one factor on the Y chromosome is necessary for TGCTs. ........................ 103 5.2 FUTURE DIRECTIONS ...........................................................................................................
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