Abstract
Accumulation of frameshift mutations at genes containing coding mononucleotide repeats is thought to be the major molecular mechanism by which mismatch repair-deficient cells accumulate functional alterations. These mutations resulting from microsatellite instability (MSI) can affect genes involved in pathways with a putative oncogenic role, but may also arise in genes without any expected role in MSI carcinogenesis because of the high mutation background of these tumours. We here screened 39 MSI colorectal tumours for the presence of mutations in 25 genes involved in DNA damage signalling and repair pathways. Using a maximum likelihood statistical method, these genes were divided into two different groups that differed significantly in their mutation frequencies, and likely represent mutations that do or do not provide selective pressure during MSI tumour progression. Interestingly, the so-called real-target mutational events were found to be distributed among genes involved in different functional pathways of the DNA metabolism, for example, DNA damage signalling (DNA-PKcs, ATR), double-strand break (DSB) repair (DNA-PKcs, RAD50), mismatch repair (MSH3, MSH6, MBD4) and replication (POLD3). In particular, mutations in MRE11 and/or RAD50 were observed in the vast majority of the tumours and resulted in the concomitant loss of immunohistochemical expression of both proteins. These data might explain why MSI colorectal cancers (CRC) behave differently in response to a wide variety of chemotherapeutic agents, notably those targeting DNA. More generally, they give further insights into how MSI leads to functional changes with synergistic effects in oncogenic pathways.
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Acknowledgements
We thank Dr Brigitte Bressac-de-Paillerets and Dr Sylviane Olschwang for sharing data, and Valérie Velasco, Nadine Leonard, Joëlle Lacombe and Olivier Buhard for their expert technical assistance. We also thank Dr Pierre Duvillard, Professor Pierre Netter and Dr Filippo Rosselli for constant support and stimulating discussions. Financial supports have been provided by the ‘Fondation pour la Recherche Médicale’ (to CM), the ‘Ministère de l'Education Nationale de la Recherche et de la Technologie’, and by the ‘Ligue Nationale contre le Cancer’ (to SJ) and the ‘Association pour la Recherche sur le Cancer’ (to JV). This research was granted by the ‘Association pour la Recherche sur le Cancer’ (#4683 and 3835 to FP).
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Miquel, C., Jacob, S., Grandjouan, S. et al. Frequent alteration of DNA damage signalling and repair pathways in human colorectal cancers with microsatellite instability. Oncogene 26, 5919–5926 (2007). https://doi.org/10.1038/sj.onc.1210419
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DOI: https://doi.org/10.1038/sj.onc.1210419
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