A Robertsonian translocation suppresses a somatic recombination pathway to loss of heterozygosity

In mammals, loss of APC/Apc gatekeeper function initiates intestinal tumorigenesis. Several different mechanisms have been shown or proposed to mediate functional loss of APC/Apc: mutation in APC/Apc, non-disjunction, homologous somatic recombination and epigenetic silencing. The demonstration that, in the C57BL/6 (B6) ApcMin/+ mouse model of inherited intestinal cancer, loss of Apc function can occur by loss of heterozygosity (LOH) through somatic recombination between homologs presents an opportunity to search for polymorphisms in the homologous somatic recombination pathway. We report that the Robertsonian translocation Rb(7.18)9Lub (Rb9) suppresses the multiplicity of intestinal adenomas in this mouse model. As the copy number of Rb9 increases, the association with the interphase nucleolus of the rDNA repeats centromeric to the Apc locus on Chromosome 18 is increasingly disrupted. Our analysis shows that homologous somatic recombination is the principal pathway for LOH in adenomas in B6 ApcMin/+ mice. These studies provide additional evidence that neoplastic growth can initiate in the complete absence of canonical genomic instability.

[1]  M. Davisson,et al.  An improved method for preparing G-banded chromosomes from mouse peripheral blood. , 1987, Cytogenetics and cell genetics.

[2]  D. Falconer,et al.  Introduction to Quantitative Genetics. , 1962 .

[3]  A. Knudson,et al.  National Cancer Institute Workshop Report: the phakomatoses revisited. , 2000, Journal of the National Cancer Institute.

[4]  Charles W. Dunnett,et al.  Pairwise Multiple Comparisons in the Homogeneous Variance, Unequal Sample Size Case , 1980 .

[5]  P. Lichter,et al.  Identification of an interchromosomal compartment by polymerization of nuclear-targeted vimentin. , 1998, Journal of cell science.

[6]  A. Moser,et al.  Studies of neoplasia in the Min mouse. , 1997, Biochimica et biophysica acta.

[7]  E. Lander,et al.  Mom1 is a semi-dominant modifier of intestinal adenoma size and multiplicity in Min/+ mice. , 1996, Genetics.

[8]  L. Meisner,et al.  A juvenile polyposis tumor suppressor locus at 10q22 is deleted from nonepithelial cells in the lamina propria. , 1997, Gastroenterology.

[9]  J. Harbour,et al.  Molecular basis of low-penetrance retinoblastoma. , 2001, Archives of ophthalmology.

[10]  N. Frydman,et al.  Assisting reproduction of infertile men carrying a Robertsonian translocation. , 2001, Human reproduction.

[11]  A. Bradley,et al.  Cancer predisposition caused by elevated mitotic recombination in Bloom mice , 2000, Nature Genetics.

[12]  W. R. Robertson.  Chromosome studies. I. Taxonomic relationships shown in the chromosomes of tettigidae and acrididae: V‐shaped chromosomes and their significance in acrididae, locustidae, and gryllidae: Chromosomes and variation , 1916 .

[13]  L. Shaffer,et al.  Molecular mechanisms for constitutional chromosomal rearrangements in humans. , 2000, Annual review of genetics.

[14]  K. Kinzler,et al.  Erratum: Multiple Intestinal Neoplasia Caused By a Mutation in the Murine Homolog of the APC Gene , 1992, Science.

[15]  E. Wagner,et al.  Genetic interaction between PARP and DNA-PK in V(D)J recombination and tumorigenesis , 1997, Nature Genetics.

[16]  K. Haigis,et al.  Intestinal adenomas can develop with a stable karyotype and stable microsatellites , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[17]  K. Kinzler,et al.  Genetic instability in colorectal cancers , 1997, Nature.

[18]  T. Dryja,et al.  Mitotic recombination map of 13cen-13q14 derived from an investigation of loss of heterozygosity in retinoblastomas. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  W F Bodmer,et al.  The ABC of APC. , 2001, Human molecular genetics.

[20]  M. Jasin,et al.  Double-strand-break-induced homologous recombination in mammalian cells. , 2001, Biochemical Society transactions.

[21]  J. Nielsen,et al.  Chromosome abnormalities found among 34910 newborn children: results from a 13-year incidence study in Århus, Denmark , 2005, Human Genetics.

[22]  W. Dove,et al.  Dnmt1N/+ reduces the net growth rate and multiplicity of intestinal adenomas in C57BL/6-multiple intestinal neoplasia (Min)/+ mice independently of p53 but demonstrates strong synergy with the modifier of Min 1(AKR) resistance allele. , 2000, Cancer research.

[23]  C. Midgley,et al.  A resistant genetic background leading to incomplete penetrance of intestinal neoplasia and reduced loss of heterozygosity in ApcMin/+ mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  J. Tischfield,et al.  Mitotic recombination is suppressed by chromosomal divergence in hybrids of distantly related mouse strains , 2001, Nature Genetics.

[25]  S. Gangloff,et al.  Replication fork pausing and recombination or "gimme a break". , 2000, Genes & development.

[26]  W. Bodmer,et al.  Polyclonal Origin of Colonic Adenomas in an XO/XY Patient with FAP , 1996, Science.

[27]  A. Garcı́a-Bellido,et al.  The effect of inversions on mitotic recombination in Drosophila melanogaster , 1978, Molecular and General Genetics MGG.

[28]  L. Silver,et al.  Recombination suppression of mouse t-haplotypes due to chromatin mismatching , 1981, Nature.

[29]  C. Barlow,et al.  Solid tissues removed from ATM homozygous deficient mice do not exhibit a mutator phenotype for second-step autosomal mutations. , 1999, Cancer research.

[30]  C. Redi,et al.  Robertsonian karyotype variation in wild house mice from Rhaeto-Lombardia. , 1982, Cytogenetics and cell genetics.

[31]  J. Searle,et al.  Male meiosis and gametogenesis in wild house mice (Mus musculus domesticus) from a chromosomal hybrid zone; a comparison between "simple" Robertsonian heterozygotes and homozygotes. , 1992, Cytogenetics and cell genetics.

[32]  J. Eppig,et al.  Analysis of recombination in the centromere region of mouse chromosome 7 using ovarian teratoma and backcross methods. , 1988, The Journal of heredity.

[33]  M T Davisson,et al.  Recombination suppression by heterozygous Robertsonian chromosomes in the mouse. , 1993, Genetics.

[34]  A. Garcı́a-Bellido,et al.  Are dicentric anaphase bridges formed by somatic recombination in X chromosome inversion heterozygotes of Drosophila melanogaster? , 2004, Molecular and General Genetics MGG.

[35]  A. Garcı́a-Bellido,et al.  A model for somatic pairing derived from somatic crossing over with third chromosome rearrangements in Drosophila melanogaster , 2004, Molecular and General Genetics MGG.

[36]  S. Dudley,et al.  Mlh1 deficiency enhances several phenotypes of ApcMin/+ mice , 2000, Oncogene.

[37]  Jean Marx,et al.  Debate Surges Over the Origins of Genomic Defects in Cancer , 2002, Science.

[38]  A. Moser,et al.  Loss of Apc+ in intestinal adenomas from Min mice. , 1994, Cancer research.

[39]  A. Merritt,et al.  Polyclonal structure of intestinal adenomas in ApcMin/+ mice with concomitant loss of Apc+ from all tumor lineages. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[40]  J. Tischfield,et al.  Chromosome instability contributes to loss of heterozygosity in mice lacking p53. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[41]  A. Kuzminov.  DNA replication meets genetic exchange: Chromosomal damage and its repair by homologous recombination , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[42]  D. Smyth,et al.  Absence of silver bands in human Robertsonian translocation chromosomes. , 1979, Cytogenetics and cell genetics.

[43]  M. Radman,et al.  Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer , 1995, Cell.