Research article

A mitotic recombination map proximal to the APC locus on chromosome 5q and assessment of influences on colorectal cancer risk

Kimberley Howarth¹ , Susanna Ranta² , Eitan Winter² , Ana Teixeira¹ , Helmut Schaschl² , John J Harvey² , Andrew Rowan² , Angela Jones¹ , Sarah Spain¹ , Susan Clark³ , Thomas Guenther⁴ , Aengus Stewart² , Andrew Silver⁵ and Ian Tomlinson¹

¹Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK

²London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London, WC2A 3PX, UK

³Polyposis Registry St Mark's and Northwick Park Hospitals, Watford Road, Harrow, HA1 3UJ, UK

⁴Academic Histopathology, St Mark's and Northwick Park Hospitals, Watford Road, Harrow, HA1 3UJ, UK

⁵Colorectal Cancer Genetics Group, Institute of Cell and Molecular Sciences, Bart's and the London Medical School, Queen Mary College, University of London, London, UK

author email corresponding author email

BMC Medical Genetics 2009, 10:54doi:10.1186/1471-2350-10-54

Published:	10 June 2009

Abstract

Background

Mitotic recombination is important for inactivating tumour suppressor genes by copy-neutral loss of heterozygosity (LOH). Although meiotic recombination maps are plentiful, little is known about mitotic recombination. The APC gene (chr5q21) is mutated in most colorectal tumours and its usual mode of LOH is mitotic recombination.

Methods

We mapped mitotic recombination boundaries ("breakpoints") between the centromere (~50 Mb) and APC (~112 Mb) in early colorectal tumours.

Results

Breakpoints were non-random, with the highest frequency between 65 Mb and 75 Mb, close to a low copy number repeat region (68–71 Mb). There were, surprisingly, few breakpoints close to APC, contrary to expectations were there constraints on tumorigenesis caused by uncovering recessive lethal alleles or if mitotic recombination were mechanistically favoured by a longer residual chromosome arm. The locations of mitotic and meiotic recombination breakpoints were correlated, suggesting that the two types of recombination are influenced by similar processes, whether mutational or selective in origin. Breakpoints were also associated with higher local G+C content. The recombination and gain/deletion breakpoint maps on 5q were not, however, associated, perhaps owing to selective constraints on APC dosage in early colorectal tumours. Since polymorphisms within the region of frequent mitotic recombination on 5q might influence the frequency of LOH, we tested the 68–71 Mb low copy number repeat and nearby tagSNPs, but no associations with colorectal cancer risk were found.

Conclusion

LOH on 5q is non-random, but local factors do not greatly influence the rate of LOH at APC or explain inter differential susceptibility to colorectal tumours.