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

Nature Genetics volume 33, pages 33–39 (2003)Cite this article

Abstract

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.

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Figure 1: Rb9 acts as a suppressor of tumor multiplicity in ApcMin/+ mice.
Figure 2: Rb9 does not affect tumor size or regional distribution.
Figure 3: Formal evaluation of the hypothesis of a principal non-disjunctional LOH pathway.
Figure 4: Nuclear localization of centromeres.

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Acknowledgements

We dedicate this work to the memory of G. Pontecorvo, who insisted long ago on the importance of somatic recombination for mammalian genetics. The authors thank M. Haigis, L. Clipson, N. Drinkwater, A. Shedlovsky, R. Halberg and I. Riegel for critical reading of the manuscript; M. Newton for the statistical analysis in Web Note A; D. Threadgill for insightful discourse; C. Alexander for the gift of mouse embryonic fibroblasts; and J. Weeks and H. Edwards for histological preparations. This work was supported by grants from the US National Cancer Institute. K.M.H. was supported by a predoctoral training grant from the US National Institutes of Health. This is publication No. 3607 from the Laboratory of Genetics.

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  1. McArdle Laboratory for Cancer Research and Laboratory of Genetics, University of Wisconsin–Madison, 1400 University Avenue, Madison, 53706, Wisconsin, USA

    Kevin M. Haigis & William F. Dove

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Correspondence to William F. Dove.

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Haigis, K., Dove, W. A Robertsonian translocation suppresses a somatic recombination pathway to loss of heterozygosity. Nat Genet 33, 33–39 (2003). https://doi.org/10.1038/ng1055

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