TY - JOUR
T1 - Analysis of the coding genome of diffuse large B-cell lymphoma
AU - Pasqualucci, Laura
AU - Trifonov, Vladimir
AU - Fabbri, Giulia
AU - Ma, Jing
AU - Rossi, Davide
AU - Chiarenza, Annalisa
AU - Wells, Victoria A.
AU - Grunn, Adina
AU - Messina, Monica
AU - Elliot, Oliver
AU - Chan, Joseph
AU - Bhagat, Govind
AU - Chadburn, Amy
AU - Gaidano, Gianluca
AU - Mullighan, Charles G.
AU - Rabadan, Raul
AU - Dalla-Favera, Riccardo
N1 - Funding Information:
Among the vast array of genetic lesions identified in the DLBCL genome, alterations of MLL family members, and in particular MLL2, appear especially frequent. MLL2 encodes a trimethyltransferase residing in a complex with well-documented influence on the expression of a large number of genes. The pattern of monoallelic somatic inactivation observed in DLBCL suggests a role for MLL2 as a haplo-insufficient tumor suppressor, consistent with the observation that monoallelic MLL2 truncating mutations leading to decreased gene dosage have a pathogenic effect in Kabuki syndrome, a congenital disorder characterized by developmental and intellectual abnormalities56. A role for MLL genes in malignant transformation is supported by the involvement of MLL in the pathogenesis of acute leukemia57, although by a distinct and partially unclear mechanism, and by the recent finding of somatic inactivating mutations in both MLL2 and MLL3 in various cancers26,51,58. Collectively, alterations of chromatin-modifying enzymes, including HMTs and HATs, emerge as the most frequent alterations associated with DLBCL pathogenesis, being present in over one third of cases, independent of disease subtype (~50% in GCB DLBC and ~30% in ABC DLBCL).
PY - 2011/9
Y1 - 2011/9
N2 - Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. Although a number of structural alterations have been associated with the pathogenesis of this malignancy, the full spectrum of genetic lesions that are present in the DLBCL genome, and therefore the identity of dysregulated cellular pathways, remains unknown. By combining next-generation sequencing and copy number analysis, we show that the DLBCL coding genome contains, on average, more than 30 clonally represented gene alterations per case. This analysis also revealed mutations in genes not previously implicated in DLBCL pathogenesis, including those regulating chromatin methylation (MLL2; 24% of samples) and immune recognition by T cells. These results provide initial data on the complexity of the DLBCL coding genome and identify novel dysregulated pathways underlying its pathogenesis.
AB - Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. Although a number of structural alterations have been associated with the pathogenesis of this malignancy, the full spectrum of genetic lesions that are present in the DLBCL genome, and therefore the identity of dysregulated cellular pathways, remains unknown. By combining next-generation sequencing and copy number analysis, we show that the DLBCL coding genome contains, on average, more than 30 clonally represented gene alterations per case. This analysis also revealed mutations in genes not previously implicated in DLBCL pathogenesis, including those regulating chromatin methylation (MLL2; 24% of samples) and immune recognition by T cells. These results provide initial data on the complexity of the DLBCL coding genome and identify novel dysregulated pathways underlying its pathogenesis.
UR - http://www.scopus.com/inward/record.url?scp=80052269038&partnerID=8YFLogxK
U2 - 10.1038/ng.892
DO - 10.1038/ng.892
M3 - Article
SN - 1061-4036
VL - 43
SP - 830
EP - 837
JO - Nature Genetics
JF - Nature Genetics
IS - 9
ER -