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.
