title: Mononucleotide precedes dinucleotide repeat instability during colorectal tumour development in Lynch syndrome patients.
abstract: A progressive accumulation of genetic alterations underlies the adenoma-carcinoma sequence of colorectal cancer. This accumulation of mutations is driven by genetic instability, of which there are different types. Microsatellite instability (MSI) is the predominant type present in the tumours of Lynch syndrome patients and in a subset of sporadic tumours. It is generally accepted that MSI can be found in the early stages of tumour progression, such as adenomas; however, the frequencies reported vary widely among studies. Moreover, data on the qualitative differences between adenomas and carcinomas, or between tumours of hereditary and sporadic origin, are scarce. We compared MSI in samples of colorectal adenoma and colorectal carcinoma in order to identify possible differences along the adenoma-carcinoma sequence. We compared germline mismatch repair (MMR) gene mutation carriers and non-carriers, to address possible differences of instability patterns between Lynch syndrome patients and patients with sporadic tumours. We found a comparable relative frequency of mono- and dinucleotide instability in sporadic colorectal adenomas and carcinomas, dinucleotide instability being observed most frequently in these sporadic tumours. In MMR gene truncating mutation carriers, the profile was different: colorectal adenomas showed predominantly mononucleotide instability and in colorectal carcinomas, also more mononucleotide than dinucleotide instability was detected. We conclude that MSI profiles differ between sporadic and Lynch syndrome tumours, and that mononucleotide marker instability precedes dinucleotide marker instability during colorectal tumour development in Lynch syndrome patients. As mononucleotide MSI proves to be highly sensitive for detecting mutation carriers, we propose the use of mononucleotide markers for the identification of possible Lynch syndrome patients.
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ferreira
authors.forename: Helga
authors.initials: H
authors.lastname: Westers
authors.forename: Sónia
authors.initials: S
authors.lastname: Sousa
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Renée C
authors.initials: RC
authors.lastname: Niessen
authors.forename: Maran
authors.initials: M
authors.lastname: Olderode-Berends
authors.forename: Tineke
authors.initials: T
authors.lastname: van der Sluis
authors.forename: Peter T W
authors.initials: PT
authors.lastname: Reuvekamp
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Jan H
authors.initials: JH
authors.lastname: Kleibeuker
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Sijmons
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D017668:Age of Onset; D014408:Biomarkers, Tumor / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D018900:Dinucleotide Repeats; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D008875:Middle Aged
chemical_list: D014408:Biomarkers, Tumor