Human Molecular Genetics Advance Access originally published online on October 24, 2006
Human Molecular Genetics 2006 15(23):3429-3435; doi:10.1093/hmg/ddl419
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Genetic determinants modulate susceptibility to pregnancy-associated tumourigenesis in a recombinant line of Min mice
1 ICMS, Barts and The London Queen Mary's School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK, 2 Cancer Research UK Colorectal Cancer Unit, 3 Cancer Research UK Colorectal Cancer Unit and Polyposis Registry and 4 Academic Department of Pathology, St Mark's Hospital, Harrow, Middx HA1 3UJ, UK, 5 Radiation Protection Division of Health Protection Agency, Chilton, Didcot, Oxon OX11 ORQ, UK, 6 Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK and 7 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK
* To whom correspondence should be addressed. Tel: +44 2078822590; Fax: +44 2078822200; Email: a.r.silver{at}qmul.ac.uk
Received September 14, 2006; Accepted October 18, 2006
Min mice provide a good model of human familial adenomatous polyposis. Recently, we have reported on two recombinant inbred lines (I and V) and the location of a modifier (Mom3) close to Apc, which altered polyp numbers in our mice possibly by modifying the frequency of wild-type (WT) allele loss at Apc; mice with severe disease (line V) showed elevated rates of loss. We now show that in line I only, a single pregnancy caused a significant increase in adenoma multiplicity compared with virgin controls (P<0.001) and that an additional pregnancy conferred a similar risk. Pregnancy was linked to both adenoma initiation and enhanced tumour growth in line I mice, and interline crosses indicated that susceptibility to pregnancy-associated adenomas was under genetic control. We found no evidence for the involvement of oestrodial metabolizing genes or the oestrogen receptors (Esr1 and 2) in tumour multiplicity. Importantly, a significantly elevated frequency of WT allele loss at Apc was observed in adenomas from parous mice (line and backcrossed) carrying the line I Min allele relative to equivalent virgin controls (P=0.015). Our results provide the first experimental evidence for genetic determinants controlling pregnancy-associated tumourigenesis; analogous genetic factors may exist in humans.
These authors contributed equally to this work.
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