Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients

Shah, Vallari; Sherborne, Amy L.; Walker, Brian A.; Johnson, David C.; Boyle, Eileen M.; Ellis, Sidra; Begum, Dil; Proszek, Paula; Jones, J.; Pawlyn, Charlotte; Savola, Suvi; Jenner, Matthew; Drayson, Mark T.; Owen, Roger G.; Houlston, Richard S.; Cairns, David A.; Gregory, Walter M.; Cook, Gordon; Davies, Faith E.; Jackson, Graham; Morgan, Gareth J.; Kaiser, Martin

doi:10.1038/leu.2017.179

Cited by 185 publications

(253 citation statements)

References 41 publications

Supporting

Mentioning

215

Contrasting

Unclassified

Order By: Relevance

“…Two of the BIRC2 / BIRC3 biallelic losses occurred in patients with t(4;14), an association that has been previously noted 16. In addition, we observed that the biallelic loss was intragenic for MYH4 (exons 23–39), the three RB1 deletions (exons 5–17, exons 18–23, exons 8–11) and PTPRD (exons 15–26).…”

Section: Resultssupporting

confidence: 83%

Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing

et al. 2018

View full text Add to dashboard Cite

AimsMultiple myeloma is a genomically complex haematological malignancy with many genomic alterations recognised as important in diagnosis, prognosis and therapeutic decision making. Here, we provide a summary of genomic findings identified through routine diagnostic next-generation sequencing at our centre.MethodsA cohort of 86 patients with multiple myeloma underwent diagnostic sequencing using a custom hybridisation-based panel targeting 104 genes. Sequence variants, genome-wide copy number changes and structural rearrangements were detected using an inhouse-developed bioinformatics pipeline.ResultsAt least one mutation was found in 69 (80%) patients. Frequently mutated genes included TP53 (36%), KRAS (22.1%), NRAS (15.1%), FAM46C/DIS3 (8.1%) and TET2/FGFR3 (5.8%), including multiple mutations not previously described in myeloma. Importantly we observed TP53 mutations in the absence of a 17 p deletion in 8% of the cohort, highlighting the need for sequencing-based assessment in addition to cytogenetics to identify these high-risk patients. Multiple novel copy number changes and immunoglobulin heavy chain translocations are also discussed.ConclusionsOur results demonstrate that many clinically relevant genomic findings remain in multiple myeloma which have not yet been identified through large-scale sequencing efforts, and provide important mechanistic insights into plasma cell pathobiology.

show abstract

Section: Resultssupporting

confidence: 83%

Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Although the prognostic role of del17p is widely recognized in MM, 4,5 there has not been a systematic examination of the role of the extent of deletions spanning TP53 in terms of CCF level. Application of arbitrary CCF cutoffs 2 and double-hit phenomena 10,12,14 add further complexity to the prognostic impact of subclonal deletions in TP53. In addition, interaction with tumor (eg, 1q amplification) and nontumor (patient and immune) parameters may further influence the prognostic impact of TP53 deletion.…”

Section: Resultsmentioning

confidence: 99%

High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma

Thakurta¹,

Ortiz²,

Blecua³

et al. 2019

Blood

View full text Add to dashboard Cite

K E Y P O I N T S l Association of del17p CCF threshold and poor prognosis in NDMM is established via fluorescence in situ hybridization and sequencing methods. l TP53 mutations are enriched in a high-risk patient segment characterized by high del17p CCF.Deletions of chromosome 17p (del17p) that span the TP53 gene are associated with poor outcome in multiple myeloma (MM), but the prognostic value of del17p cancer clonal fraction (CCF) remains unclear. We applied uniform cytogenetic assessments in a large cohort of newly diagnosed MM (NDMM) patients carrying varying levels of del17p. Incremental CCF change was associated with shorter survival, and a robust CCF threshold of 0.55 was established in discovery and replication data sets. After stratification on the 0.55-CCF threshold, high-risk patients had statistically significantly poorer outcomes compared with low-risk patients (median progression-free survival [PFS] and overall survival [OS], 14 and 32 vs 23.1 and 76.2 months, respectively). Analyses of a third data set comprising whole-exome sequencing data from NDMM patients identified presence of TP53 deletions/mutations as a necessary requirement for high-risk stratification in addition to exceeding the del17p CCF threshold. Meta-analysis conducted across 3 data sets confirmed the robustness of the CCF threshold for PFS and OS. Our analyses demonstrate the feasibility of fluorescence in situ hybridization-and sequencingbased methods to identify TP53 deletions, estimate CCF, and establish that both CCF threshold of 0.55 and presence of TP53 deletion are necessary to identify del17p-carrying NDMM patients with poor prognosis. (Blood. 2019; 133(11):1217-1221

show abstract

“…One of the striking features of myeloma biology is the early observation that a dichotomous over-expression of the cell cycle regulators CCND1 and CCND2 over-arches genetic diversification (Bergsagel et al, 2005). While in the majority of MM cases overexpression of CCND1 can be explained by somatic structural variants i.e., juxtaposition to IGH@ enhancer or chr11q25 gain (Shah et al, 2018), no such aberrancies account for overexpression of CCND2. Our identification and functional validation of the distal cis and trans regulators of CCND2 expression addresses this gap in the biology of MM.…”

Section: Discussionmentioning

confidence: 99%

“…This heterogeneity converges, in most cases, to a functionally dichotomous, mutually exclusive overexpression of the cell cycle regulators CCND1 and CCND2 to which myeloma PC remain addicted, irrespective of primary or secondary genetic events (Bergsagel et al, 2005;Ely et al, 2005;Tiedemann et al, 2008). As well as over-expression by juxtaposition to the IgH enhancer in 20% of MM, CCND1 over-expression is associated with chr11q25 gain in over half of HD cases (Shah et al, 2018). However, the transcriptional mechanisms that result in CCND2 overexpression, seen in nearly 50% of MM cases and spanning all genetic subgroups except t(11;14), are not known.Chromatin accessibility profiling by ATAC-seq has been used to characterise the regulatory landscape of hundreds of different solid tumour cancers and in combination with other datatypes, has demonstrated its utility in categorising cancer and in the discovery of distal regulatory elements such as candidate enhancers of critical oncogenes (Corces et al, 2018).…”

mentioning

confidence: 99%

Over-accessible chromatin links myeloma initiating genetic events to oncogenic transcriptomes and aberrant transcription factor regulatory networks

Alvarez-Benayas

Katsarou

Trasanidis

et al. 2020

Preprint

View full text Add to dashboard Cite

Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Myeloma initiating genetic events define subgroups (MIE) and drivedistinct oncogenic transcriptomes that converge into a mutually exclusive overexpression of CCND1 and CCND2 oncogenes. Here, with reference to normal PC, we dissect how MIE impact the chromatin regulatory landscape of MM. We find that chromatin accessibility combined with transcriptome profiling classifies myeloma genetic subgroups, while in a topologically constrained manner, distal rather than proximal regulatory elements influence myeloma transcriptomes. Across and within MIE-defined subgroups, genes and pathways critical for myeloma biology can be linked to developmentally activated or de novo formed enhancers. We show that existing transcription factors, co-opted to organise highly ordered, aberrant regulatory networks, generate known and novel myeloma cell dependencies and help identify prognostic markers. Finally, we discover and functionally validate the critical enhancer that regulates ectopic expression of CCND2 in MM. 3MM is a common, genetically heterogeneous incurable cancer of the bone marrow plasma cells (PC), the terminally differentiated immunoglobulin-secreting B lineage cells (Palumbo and Anderson, 2011). Distinct transcriptome profiles in MM reflect two categories of myeloma initiating genetic events (MIE): Over-expression in up to half of cases of oncogenes such as CCND1, MAF and MMSET by their juxtaposition to the IgH enhancer in the t(11;14), t(14;16) and t(4;14) cytogenetic subgroups respectively; hyperdiploidy (HD) is the MIE driving oncogenic transcriptomes in the rest of cases (Manier et al., 2017;Morgan et al., 2012). High frequency secondary copy number aberrations, single nucleotide variants and indels further shape the distinct impact of the MIE and generate extensive genetic heterogeneity (Chapman et al., 2011;Lohr et al., 2014;Walker et al., 2015). This heterogeneity converges, in most cases, to a functionally dichotomous, mutually exclusive overexpression of the cell cycle regulators CCND1 and CCND2 to which myeloma PC remain addicted, irrespective of primary or secondary genetic events (Bergsagel et al., 2005;Ely et al., 2005;Tiedemann et al., 2008). As well as over-expression by juxtaposition to the IgH enhancer in 20% of MM, CCND1 over-expression is associated with chr11q25 gain in over half of HD cases (Shah et al., 2018). However, the transcriptional mechanisms that result in CCND2 overexpression, seen in nearly 50% of MM cases and spanning all genetic subgroups except t(11;14), are not known.Chromatin accessibility profiling by ATAC-seq has been used to characterise the regulatory landscape of hundreds of different solid tumour cancers and in combination with other datatypes, has demonstrated its utility in categorising cancer and in the discovery of distal regulatory elements such as candidate enhancers of critical oncogenes (Corces et al., 2018). Further, by means of transcription factor (TF) footprinting, ATAC-seq ...

show abstract

Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients

Cited by 185 publications

References 41 publications

Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing

Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing

High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma

Over-accessible chromatin links myeloma initiating genetic events to oncogenic transcriptomes and aberrant transcription factor regulatory networks

Contact Info

Product

Resources

About