An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors.

Vasilis Bikos, Maria Karypidou, Evangelia Stalika, Panagiotis Baliakas, Aliki Xochelli, Lesley-Ann Sutton, George Papadopoulos, Andreas Agathangelidis, Evdoxia Papadopoulou, Zadie Davis, Patricia Algara, George Kanellis, Alexandra Traverse-Glehen, Manuela Mollejo, Achilles Anagnostopoulos, Maurilio Ponzoni, David Gonzalez, Sarka Pospisilova, Estella Matutes, Miguel Angel Piris, Theodora Papadaki, Paolo Ghia, Richard Rosenquist, David Oscier, Nikos Darzentas, Dimitrios Tzovaras, Chrysoula Belessi, Anastasia Hadzidimitriou, Kostas Stamatopoulos

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research 2016;22(8):2032-40

PMID: 26647217

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Abstract

PURPOSE

Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation.

EXPERIMENTAL DESIGN

We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM).

RESULTS

ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P= 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene).

CONCLUSIONS

These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.

Address: Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece. Central European Institute of Technology, Masaryk University, Brno, Czech Republic.; Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece. Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.; Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.; Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.; Institute of Applied Biosciences, CERTH, Thessaloniki, Greece. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.; Information Technologies Institute, CERTH, Thessaloniki, Greece.; Division of Experimental Oncology and Department of Onco-Hematology, Università Vita-Salute San Raffaele and Istituto Scientifico San Raffaele, Milan, Italy.; Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom.; Department of Pathology, Hospital Virgen de la Salud, Toledo, Spain.; Hematopathology Department, Evangelismos Hospital, Athens, Greece.; Department of Pathology and Hematology, Hospices Civils de Lyon, Universite Lyon, Lyon, France.; Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.; Pathology Unit, San Raffaele Scientific Institute, Milan, Italy.; Section of Haemato-Oncology, Institute of Cancer Research, London, United Kingdom.; Central European Institute of Technology, Masaryk University, Brno, Czech Republic.; Hospital Universitario Marques de Valdecilla, Santander, Cantabria, Spain.; Hematology Department, Nikea General Hospital, Pireaus, Greece.; Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece. Institute of Applied Biosciences, CERTH, Thessaloniki, Greece. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. [email protected].

DOI: 10.1158/1078-0432.CCR-15-1170

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MeSH Terms: Alleles, Amino Acid Motifs, Amino Acid Sequence, Amino Acid Substitution, Antigens, Complementarity Determining Regions, Gene Expression Profiling, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Humans, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Lymphoma, B-Cell, Marginal Zone, Models, Biological, Mutation, Receptors, Antigen, B-Cell, Splenic Neoplasms, Transcriptome