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Duval, A. et al.

Duval, Raphael, Brennetot, Poirel, Buhard, Aubry, Martin, Krimi, Leblond, Gabarre, Davi, Charlotte, Berger, Gaidano, Capello, Canioni, Bordessoule, Feuillard, Gaulard, Delfau, Ferlicot, Eclache, Prevot, Guettier, Lefevre, Adotti, Hamelin,

The mutator pathway is a feature of immunodeficiency-related lymphomas.

The mutator phenotype caused by defects in the mismatch repair system is observed in a subset of solid neoplasms characterized by widespread microsatellite instability-high (MSI-H). It is known to be very rare in non-Hodgkin lymphomas (NHL), whereas mutator NHL is the most frequent tumor subtype in mismatch repair-deficient mice. By screening a series of 603 human NHL with specific markers of the mutator phenotype, we found here 12 MSI-H cases (12/603, 2%). Of interest, we demonstrated that this phenotype was specifically associated with immunodeficiency-related lymphomas (ID-RL), because it was observed in both posttransplant lymphoproliferative disorders (9/111, 8.1%) and HIV infection-related lymphomas (3/128, 2.3%) but not in a large series of NHL arising in the general population (0/364) (P < 0.0001). The MSI pathway is known to lead to the production of hundreds of abnormal protein neoantigens that are generated in MSI-H neoplasms by frameshift mutations of a number of genes containing coding microsatellite sequences. As expected, MSI-H ID-RL were found to harbor such genetic alterations in 12 target genes with a putative role in lymphomagenesis. The observation that the MSI-H phenotype was restricted to HIV infection-related lymphomas and posttransplant lymphoproliferative disorders suggests the existence of the highly immunogenic mutator pathway as a novel oncogenic process in lymphomagenesis whose role is favored when host immunosurveillance is reduced. Because MSI-H-positive cases were found to be either Epstein-Barr virus-positive or -negative, the mutator pathway should act synergistically or not with this other oncogenic factor, playing an important role in ID-RL.[1]

References

The mutator pathway is a feature of immunodeficiency-related lymphomas. Duval, A., Raphael, M., Brennetot, C., Poirel, H., Buhard, O., Aubry, A., Martin, A., Krimi, A., Leblond, V., Gabarre, J., Davi, F., Charlotte, F., Berger, F., Gaidano, G., Capello, D., Canioni, D., Bordessoule, D., Feuillard, J., Gaulard, P., Delfau, M.H., Ferlicot, S., Eclache, V., Prevot, S., Guettier, C., Lefevre, P.C., Adotti, F., Hamelin, R. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]

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