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Human Molecular Genetics Advance Access published online on October 24, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl419
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received September 14, 2006
Revised October 18, 2006
Accepted October 18, 2006

Article

Genetic determinants modulate susceptibility to pregnancy-associated tumourigenesis in a recombinant line of Min mice

N Suraweera 1, J Haines 2, A McCart 1, P Rogers 3, A Latchford 4, M Coster 2, G Polanco-Echeverry 1, T. Guenther 5, J Wang 6, O Sieber 7, I Tomlinson 8, and A Silver 9 *

1 ICMS, Barts and The London Queen Mary's School of Medicine and Dentistry, 4 Newark Street, London, E1 2AT, UK
2 Radiation Protection Division of Health Protection Agency, Chilton, Didcot, Oxon OX11 ORQ, UK
3 ICMS, Barts and The London Queen Mary's School of Medicine and Dentistry, 4 Newark Street, London, E1 2AT, UK; Cancer Research UK Colorectal Cancer Unit, St Mark's Hospital, Harrow, Middx HA1 3UJ, UK
4 Cancer Research UK Colorectal Cancer Unit and Polyposis Registry, St Mark's Hospital, Harrow, Middx HA1 3UJ, UK
5 Academic Department of Pathology, St Mark's Hospital, Harrow , Middx HA1 3UJ, UK
6 Cancer Research UK Colorectal Cancer Unit, St Mark's Hospital, Harrow, Middx HA1 3UJ, UK
7 Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU
8 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, WC2A 3PX, UK, and Cancer Research UK Colorectal Cancer Unit, St Mark's Hospital, Harrow, Middx HA1 3UJ, UK
9 Cancer Research UK Colorectal Cancer Unit and Polyposis Registry, St Mark's Hospital, Harrow, Middx HA1 3UJ, UK; Institute of Cell and Molecular Science, Barts and The London, Queen Mary's School of Medicine and Dentistry, 4 Newark Street, London, E1 2AT

* To whom correspondence should be addressed.
A Silver, E-mail: a.r.silver{at}qmul.ac.uk


  Abstract

Min mice provide a good model of human Familial adenomatous polyposis (FAP). We have reported recently on two recombinant inbred lines (I and V) and the location of a modifier (Mom3) close to Apc that altered polyp numbers in our mice possibly by modifying the frequency of wild type 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 to 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 estrogen receptors (Esr1 and 2) in tumour multiplicity. Importantly, a significantly elevated frequency of wild type (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.


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