Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas Journal Article
| Authors: | Pasqualucci, L.; Neumeister, P.; Goossens, T.; Nanjangud, G.; Chaganti, R. S. K.; Küppers, R.; Dalla-Favera, R. |
| Article Title: | Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas |
| Abstract: | Genomic instability promotes tumorigenesis and can occur through various mechanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repair. Although B-cell lymphomas are associated with chromosomal translocations that deregulate oncogene expression, 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. 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. By mutating multiple genes, and possibly by favouring chromosomal translocations, aberrant hypermutation may represent the major contributor to lymphomagenesis. |
| Keywords: | controlled study; gene mutation; mutation; dna-binding proteins; proteins; gene; proto oncogene; oncology; carcinogenesis; b-lymphocytes; transcription factors; dna strand breakage; b cell lymphoma; germinal center; lymphoma, b-cell; dna; molecular sequence data; genetic engineering; tumors; genes, myc; chromosome translocation; large cell lymphoma; dna mutational analysis; chromosomes; hypermutation; proto-oncogenes; lymphoma, large-cell, diffuse; b-cell-specific activator protein; humans; human; priority journal; article |
| Journal Title: | Nature |
| Volume: | 412 |
| Issue: | 6844 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2001-07-19 |
| Start Page: | 341 |
| End Page: | 346 |
| Language: | English |
| DOI: | 10.1038/35085588 |
| PUBMED: | 11460166 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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