Abstract
BackgroundMitotic 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.MethodsWe mapped mitotic recombination boundaries ("breakpoints") between the centromere (~50 Mb) and APC (~112 Mb) in early colorectal tumours.ResultsBreakpoints 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.ConclusionLOH 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.
Highlights
Mitotic recombination is important for inactivating tumour suppressor genes by copy-neutral loss of heterozygosity (LOH)
Further genotyping using highly polymorphic microsatellite markers and in/del polymorphisms confirmed the locations of these breakpoints and showed that they were likely to lie within or just distal to the low copy number repeat (LCR)
Mitotic breakpoint mapping using a custom single nucleotide polymorphism (SNP) array in colorectal tumours The preliminary observation from the colorectal cancer cell lines that there might be a non-random distribution of mitotic recombination breakpoints between the chromosome 5 centromere (~50 Mb) and adenomatous polyposis coli (APC) prompted us to examine this phenomenon in a larger set of tumours
Summary
Mitotic recombination is important for inactivating tumour suppressor genes by copy-neutral loss of heterozygosity (LOH). The APC gene (chr5q21) is mutated in most colorectal tumours and its usual mode of LOH is mitotic recombination. Germline mutations in the APC gene (chromosome 5q21) result in familial adenomatous polyposis (FAP, OMIM 175100), a dominantly inherited colorectal tumour predisposition syndrome. Somatic APC mutations occur in up to 85% of sporadic colorectal tumours and a similar association between "first hit" and "second hit" is seen. As a result of these selective constraints on APC in early tumours, LOH at APC occurs by mitotic recombination (break-induced replication), causing reduction to homozygosity but no copy number change [3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
