Activating somatic mutations in diffuse large B-cell lymphomas: lessons from next generation sequencing and key elements in the precision medicine era
Élodie BohersSylvain MareschalPhilìppe BertrandPierre‐Julien ViaillySydney DuboisCatherine MaingonnatPhilippe RuminyHervé TillyFabrice Jardin
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Abstract:
Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, accounting for 30-40% of newly diagnosed non-Hodgkin lymphomas. Historically, DLBCL has been thought to involve recurrent translocations of the immunoglobulin heavy (IGH) locus and the deregulation of rearranged oncogenes. Whole exome sequencing (WES) of more than 200 DLBCLs has completely redefined the genetic landscape of the disease by identifying recurrent single nucleotide variants and providing new therapeutic opportunities in DLBCL molecular subtypes. Some of these somatic mutations target genes that play a crucial role in B-cell function (B cell receptor [BCR] signaling, nuclear factor κB [NF-κB] pathway, Toll-like receptor [TLR] signaling and phosphatidylinositol 3-kinase [PI3K] pathway), immunity, cell cycle/apoptosis or chromatin modification. In this review, following an overview of the somatic mutations reported in DLBCL, we focus on activating and clustered mutations targeting genes including MYD88, CD79A/B, EZH2 and CARD11 and discuss their clinical and therapeutic relevance in the precision medicine era.Somatic mutation calling from next-generation sequencing data remains a challenge due to the difficulties of distinguishing true somatic events from artifacts arising from PCR, sequencing errors or mis-mapping. Tumor cellularity or purity, sub-clonality and copy number changes also confound the identification of true somatic events against a background of germline variants. We have developed a heuristic strategy and software (http://www.qcmg.org/bioinformatics/qsnp/) for somatic mutation calling in samples with low tumor content and we show the superior sensitivity and precision of our approach using a previously sequenced cell line, a series of tumor/normal admixtures, and 3,253 putative somatic SNVs verified on an orthogonal platform.
Copy number analysis
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Somatic and germline mutagenesis assayed by the unstable zeste-white test in Drosophila melanogaster
This investigtion is an attempt to compare mutation rates in germinal and somatic cells by the use of the unstable zeste-white assay in Drosophila melanogaster. In this system it is possible to use the same genetic end point to measure both somatic mutations (aberrantly pigmented spots in the eyes of adult flies) and germinal mutations (males with aberrantly pigmented eyes). We used two mutagens, formaldehyde and methylmethane sulphonate (MMS), to induce mutations and two different routes of mutagen administration, larval feeding and adult feeding, and scored mutations in somatic as well as germinal cells. Both types of tissues were susceptible to MMS mutagenesis, showing elevated frequencies of both germline mutations and eye spots. Formaldehyde, however, gave no increase in the germinal mutation rate but caused somatic mutations. These were found after larval exposure, but also among the offspring of exposed males, as formation of delayed somatic mutations. The results show that somatic cells are much more sensitive in monitoring induced mutations than germinal cells in this system. We also found that spontaneous mutation rate among germinal cells is 200 times higher than that in somatic cells, which presumably is due to the involvement of a mobile element.
Mutation frequency
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Germline mosaicism
Mendelian inheritance
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Discovery of the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome demonstrates that somatic mutations in haematological precursor cells can cause adult-onset, complex inflammatory disease. Unlike germline mutations, somatic mutations occur throughout the lifespan, are restricted to specific tissue types, and may play a causal role in non-heritable rheumatological diseases, especially conditions that start in later life. Improvements in sequencing technology have enabled researchers and clinicians to detect somatic mutations in various tissue types, especially blood. Understanding the relationships between cell-specific acquired mutations and inflammation is likely to yield key insights into causal factors that underlie many rheumatological diseases. The objective of this review is to detail how somatic mutations are likely to be relevant to clinicians who care for patients with rheumatological diseases, with particular focus on the pathogenetic mechanisms of the VEXAS syndrome.
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OBJECTIVE Germline mutations in 3 genes have been found in familial cases of cerebral cavernous malformations (CCMs). We previously discovered somatic and germline truncating mutations in the KRIT1 gene, supporting the “2-hit” mechanism of CCM lesion formation in a single lesion. The purpose of this study was to screen for somatic, nonheritable mutations in 3 more lesions from different patients and identify the cell type(s) in which somatic mutations occur. METHODS Somatic mutations were sought in DNA from 3 surgically excised, fresh-frozen CCM lesions by cloning and screening polymerase chain reaction products generated from KRIT1 or PDCD10 coding regions. Laser capture microdissection was used on isolated endothelial and nonendothelial cells to determine whether somatic mutations were found in endothelial cells. RESULTS CCM lesions harbor somatic and germline KRIT1 mutations on different chromosomes and are therefore biallelic. Both mutations are predicted to truncate the protein. The KRIT1 somatic mutations (novel c.1800delG mutation and previously identified 34 nucleotide deletion) in CCMs from 2 different patients were found only in the vascular endothelial cells lining caverns. No obvious somatic mutations were identified in the 2 other lesions; however, the results were inconclusive, possibly owing to the technical limitations or the fact that these specimens had a small proportion of vascular endothelial cells lining pristine caverns. CONCLUSION The “2-hit” mechanism occurs in vascular endothelial cells lining CCM caverns from 2 patients with somatic and Hispanic-American KRIT1 germline mutations. Methods for somatic mutation detection should focus on vascular endothelial cells lining pristine caverns.
Laser capture microdissection
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Druggability
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Brief Summary: This study investigated the mutational background of somatic cells and rates of mutation in 29 distinct anatomical structures and compared these with the male germline from the same donor. The rate of mutation was lowest in spermatogonia.
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