title: The mutator pathway is a feature of immunodeficiency-related lymphomas.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U434, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France. alex.duval@cephb.fr
authors.forename: Alex
authors.initials: A
authors.lastname: Duval
authors.forename: Martine
authors.initials: M
authors.lastname: Raphael
authors.forename: Caroline
authors.initials: C
authors.lastname: Brennetot
authors.forename: Helene
authors.initials: H
authors.lastname: Poirel
authors.forename: Olivier
authors.initials: O
authors.lastname: Buhard
authors.forename: Alban
authors.initials: A
authors.lastname: Aubry
authors.forename: Antoine
authors.initials: A
authors.lastname: Martin
authors.forename: Amor
authors.initials: A
authors.lastname: Krimi
authors.forename: Veronique
authors.initials: V
authors.lastname: Leblond
authors.forename: Jean
authors.initials: J
authors.lastname: Gabarre
authors.forename: Frederic
authors.initials: F
authors.lastname: Davi
authors.forename: Frederic
authors.initials: F
authors.lastname: Charlotte
authors.forename: Francoise
authors.initials: F
authors.lastname: Berger
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Daniela
authors.initials: D
authors.lastname: Capello
authors.forename: Danielle
authors.initials: D
authors.lastname: Canioni
authors.forename: Dominique
authors.initials: D
authors.lastname: Bordessoule
authors.forename: Jean
authors.initials: J
authors.lastname: Feuillard
authors.forename: Philippe
authors.initials: P
authors.lastname: Gaulard
authors.forename: Marie Helene
authors.initials: MH
authors.lastname: Delfau
authors.forename: Sophie
authors.initials: S
authors.lastname: Ferlicot
authors.forename: Virginie
authors.initials: V
authors.lastname: Eclache
authors.forename: Sophie
authors.initials: S
authors.lastname: Prevot
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.forename: Pascale Cornillet
authors.initials: PC
authors.lastname: Lefevre
authors.forename: Francoise
authors.initials: F
authors.lastname: Adotti
authors.forename: Richard
authors.initials: R
authors.lastname: Hamelin
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D016368:Frameshift Mutation; D015658:HIV Infections / Q000150:complications*; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006801:Humans; D016867:Immunocompromised Host; D008228:Lymphoma, Non-Hodgkin / Q000150:complications / Q000235:genetics* / Q000821:virology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype
chemical_list: D017931:DNA Primers