Microsatellite instability in radiation-induced murine tumours; influence of tumour type and radiation quality

Abstract

Purpose: To investigate microsatellite instability (MSI) in radiation-induced murine tumours, its dependence on tissue (haemopoietic, intestinal, mammary, brain and skin) and radiation type.

Materials and methods: DNA from spontaneous, X-ray or neutron-induced mouse tumours were used in Polymerase Chain Reactions (PCR) with mono- or di-nucleotide repeat markers. Deviations from expected allele size caused by insertion/deletion events were assessed by capillary electrophoresis.

Results: Tumours showing MSI increased from 16% in spontaneously arising tumours to 23% (P = 0.014) in X-ray-induced tumours and rising again to 83% (P ≪ 0.001) in neutron-induced tumours. X-ray-induced Acute Myeloid Leukaemias (AML) had a higher level of mono-nucleotide instability (45%) than di-nucleotide instability (37%). Fifty percent of neutron-induced tumours were classified as MSI-high for mono-nucleotide markers and 10% for di-nucleotide markers. Distribution of MSI varied in the different tumour types and did not appear random.

Conclusions: Exposure to ionising radiation, especially neutrons, promotes the development of MSI in mouse tumours. MSI may therefore play a role in mouse radiation tumourigenesis, particularly following high Linear Energy Transfer (LET) exposures. MSI events, for a comparable panel of genome-wide markers in different tissue types, were not randomly distributed throughout the genome.

Keywords:

• Microsatellite instability
• X-rays
• neutrons
• tumours

Acknowledgements

We thank Neils De Wind (LUMC, Leiden) for the Msh2^−/− cell line and Andrew Riches, Kazuko Yoshida for the AML cell lines. Paul Finnon, Naomi Robertson and Natalie Brown are thanked for their assistance with cell culture and isolation of clones and John Moody and Michele Ellender for providing DNA and tissue samples. This work was funded by EC RISC RAD contract FI6R-CT-2003-508842.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.