Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas

• Published in: Nature (London) Vol. 412; no. 6844; pp. 341 - 346
• Main Authors: Pasqualucci, Laura, Neumeister, Peter, Goossens, Tina, Nanjangud, Gouri, Chaganti, R. S. K., Küppers, Ralf, Dalla-Favera, Riccardo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.07.2001; Nature Publishing; Nature Publishing Group
• Subjects: B-Lymphocytes; Biological and medical sciences; Chromosomes; Deoxyribonucleic acid; DNA; DNA Mutational Analysis; DNA-Binding Proteins; Genes; Genes, myc; Germinal Center - cytology; Hematologic and hematopoietic diseases; Humanities and Social Sciences; Humans; Immune system; Inactivation; letter; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - immunology; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - immunology; Medical sciences; Molecular Sequence Data; multidisciplinary; Mutation; Myc gene; PAX5 gene; PAX5 Transcription Factor; Proteins - genetics; Proto-Oncogenes; Pym1 gene; RhoH gene; Science; Science (multidisciplinary); Transcription Factors; TTF gene; Human; Germinative center; Pathogenesis; Malignant hemopathy; Large cell lymphoma; Non Hodgkin lymphoma; Carcinogenesis; Lymphoproliferative syndrome; C-Onc gene; Instability; Mutation; Genome; Protooncogene
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/35085588

Genomic instability promotes tumorigenesis and can occur through various mechanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repair 1 . Although B-cell lymphomas are associated with chromosomal translocations that deregulate oncogene expression 2 , a mechanism for genome-wide instability during lymphomagenesis has not been described. During B-cell development, the immunoglobulin variable (V) region genes are subject to somatic hypermutation in germinal-centre B cells 3 . Here we report that an aberrant hypermutation activity targets multiple loci, including the proto-oncogenes PIM1 , MYC , RhoH / TTF ( ARHH ) and PAX5, in more than 50% of diffuse large-cell lymphomas (DLCLs), which are tumours derived from germinal centres. Mutations are distributed in the 5′ untranslated or coding sequences, are independent of chromosomal translocations, and share features typical of V-region-associated somatic hypermutation. In contrast to mutations in V regions, however, these mutations are not detectable in normal germinal-centre B cells or in other germinal-centre-derived lymphomas, suggesting a DLCL-associated malfunction of somatic hypermutation. Intriguingly, the four hypermutable genes are susceptible to chromosomal translocations in the same region, consistent with a role for hypermutation in generating translocations by DNA double-strand breaks 4 , 5 , 6 . By mutating multiple genes, and possibly by favouring chromosomal translocations, aberrant hypermutation may represent the major contributor to lymphomagenesis.