Frequent mutation of histone modifying genes in non-Hodgkin lymphoma

By Ryan D. Morin, María Méndez-Lago, A. Mungall, R. Goya, K. Mungall, R. Corbett, N. Johnson, T. Severson, Readman Chiu, M. Field and 40 more. Nature, 2011

1,628 citations recorded by the source corpus.

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis.

Subfields: Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/1b4268886c62e98034608b03ca265878c06d31fd

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In Molecular Biology

1. S. Baylin
2. Peter A. Jones
3. Eric S. Lander
4. J. Audia
5. R. Campbell
6. J. You
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In Pathology and Forensic Medicine

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Citations in the corpus

• Epigenetic Determinants of Cancer. (2016, positive): “…H3K4 Bladder TCC, hematopoietic, nonHodgkin lymphoma, B-cell lymphoma, prostate (primary) Translocation, mutation, aberrant expression (Gui et al. 2011; Morin et al. 2011) Histone modification enzymes EZH2 Histone methyltransferase H3K27 Breast, prostate, bladder, colon, pancreas, liver, gastric,…”
• The clonal and mutational evolution spectrum of primary triple-negative breast cancers (2012, neutral): “Ina recentlymphomastudy,similarproportionswereobserved(137of329 somaticmutationsexpressedinRNA-seq) 11 .”
• Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas (2014, background): “MLL genes encode histone lysine methyltransferases that are involved in chromatin remodeling and recurrently mutated in several cancer types (43-46).”
• EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation (2013, background): “…the recent identification of frequent loss-of-function mutations in the histone methyltransferase protein MLL2 in B cell lymphomas (Lohr et al., 2012; Morin et al., 2011), suggest that the balance of H3K4me3 and H3K27me3 is disrupted and represents a therapeutic target in lymphoid malignancies.”
• Mutational heterogeneity in cancer and the search for new cancer genes (2013, neutral): “…(GBM) 2 and lung adenocarcinoma 1,4 ; CSMD3 in ovarian cancer 2 ; PCLO in diffuse large B-cell lymphoma (DLBCL) 9 ; MUC16 in lung squamous carcinoma 11 , breast cancer 12 and DLBCL 8 ; MUC4 in melanoma 13 ; olfactory receptor OR2L13 in GBM 14 ; and TTN in breast cancer 12 and other tumor types 15 .”
• Signatures of mutational processes in human cancer (2013, neutral): “6 and Supplementary Figs 97 and 98).”
• Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy (2014, neutral): “Of the remaining 18% of tumors lacking such obviously functionally important mutations, some are likely to be driven by rare mutations in bona fide driver genes (e.g., the tumors with mutations in MYD88 or CARD11, previously reported to be recurrently mutated in the B cell malignancy DLBCL [Lohr et ”
• Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing (2012, background): “As has been suggested previously, our data suggest that MLL2 may function as an important tumor suppressor in DLBCL (17, 29).”
• Lessons from the cancer genome. (2013, neutral): “Among the HATs, mutations affect CREBP and EP300 (Gui et al., 2011; Morin et al., 2011; Peifer et al., 2012).”
• Burkitt Lymphoma Pathogenesis and Therapeutic Targets from Structural and Functional Genomics (2012, methodology): “Viable BL cells were quantified by MTS assay following treatment for 4 days with the indicated concentrations of the pan-class I PI(3) kinase inhibitor BKM120.”