title: A mitotic recombination map proximal to the APC locus on chromosome 5q and assessment of influences on colorectal cancer risk.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. kimberley.howarth@well.ox.ac.uk
authors.forename: Kimberley
authors.initials: K
authors.lastname: Howarth
authors.forename: Susanna
authors.initials: S
authors.lastname: Ranta
authors.forename: Eitan
authors.initials: E
authors.lastname: Winter
authors.forename: Ana
authors.initials: A
authors.lastname: Teixeira
authors.forename: Helmut
authors.initials: H
authors.lastname: Schaschl
authors.forename: John J
authors.initials: JJ
authors.lastname: Harvey
authors.forename: Andrew
authors.initials: A
authors.lastname: Rowan
authors.forename: Angela
authors.initials: A
authors.lastname: Jones
authors.forename: Sarah
authors.initials: S
authors.lastname: Spain
authors.forename: Susan
authors.initials: S
authors.lastname: Clark
authors.forename: Thomas
authors.initials: T
authors.lastname: Guenther
authors.forename: Aengus
authors.initials: A
authors.lastname: Stewart
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D015179:Colorectal Neoplasms / Q000235:genetics*; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D008938:Mitosis; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA