Non Hodgkin Lymphomas Showing Microsatellite Instability (MSI-H NHL) Are Characterized by Both Specific Biological and Clinical Features.

Cancers showing microsatellite instability (MSI-H) constitute a frequent subset of human tumors characterized by mismatch repair (MMR) deficiency. This phenotype is well known to occur in the Human Non Polyposis Colorectal Cancer (HNPCC) syndrome, as well as in about 10–15% of sporadic colorectal, gastric and endometrial cancers. Of interest, we recently demonstrated that it was also strikingly associated with a subset of Non Hodgkin Lymphomas (NHL) developed in either HIV positive (HIV-RL, e.g. HIV-related Lymphomas) or iatrogenically immunosuppressed (PTLD, e.g. Post-Transplantation Lymphoprolipherative Disorders) patients. We here further characterize this new subset of immunodeficiency-related lymphomas (ID-RL) at both the biological and clinical levels. By using specific markers of the MSI-H phenotype, we extended our molecular screening to a series of 161 NHL developed in either immunocompetent (n = 136) or immunodeficient (n =25, including 4 HIV-RL and 21 PTLD) hosts. Clinically, MSI-H NHL were found to be:

• mostly PTLD (12/114, e.g 10%), and more rarely HIV-RL (4/131, e.g. 3%) (p = 0;05; fisher’s exact test):

• mostly T-cell NHL (4/17, e.g. 24% of T-cell ID-RL, as compared to 10/224, e.g 4% of B-cell ID-RL);

• late occurring PTLD after organ transplantation associated or not with EBV (52% EBV negative and 48% EBV positive).

Biologically, MSI-H NHL presented with:

• primary MMR defects involving MLH1, MSH2 or MSH6;

• secondary mutational events at target genes for instability, as already reported (RAD-50, BAX, CASP-5 and others…);

• frequent V599E activating mutation within the BRAF gene (3/9, e.g. 30%);

• stable cytogenetic profiles characterized by only few chromosomal rearrangements if any.

Taken together, these data show that oncogenic mechanisms involved in MSI-H NHL differ from those already known to be associated with other ID-RL, e.g. Chromosomal Instability or EBV-related pathways, and that they should now be considered as a distinct tumor entity.