Biology subjects

Auclair, D.

Publications and source records attributed to Auclair, D..

4 recordsLinked to original sources

bioRxiv2019

Revealing the impact of recurrent and rare structural variants in multiple myeloma

The landscape of structural variants (SVs) in multiple myeloma remains poorly understood. Here, we performed comprehensive classification and analysis of SVs in multiple myeloma, interrogating a large cohort of 762 patients with whole genome and RNA sequencing. We identified 100 SV hotspots involving 31 new candidate driver genes, including drug targets BCMA (TNFRSF17) and SLAMF7. Complex SVs, including chromothripsis and templated insertions, were present in 61 % of patients and frequently resulted in the simultaneous acquisition of multiple drivers. After accounting for all recurrent events, 63 % of SVs remained unexplained. Intriguingly, these rare SVs were associated with up to 7-fold enrichment for outlier gene expression, indicating that many rare driver SVs remain unrecognized and are likely important in the biology of individual tumors.

genomics↗

bioRxiv2019

Multiple Myeloma DREAM Challenge Reveals Epigenetic Regulator PHF19 As Marker of Aggressive Disease

While the past decade has seen meaningful improvements in clinical outcomes for multiple myeloma patients, a subset of patients do not benefit from current therapeutics for unclear reasons. Many gene expression-based models of risk have been developed, but each model uses a different combination of genes and often involve assaying many genes making them difficult to implement. We organized the Multiple Myeloma DREAM Challenge, a crowdsourced effort to develop models of rapid progression in newly diagnosed myeloma patients and to benchmark these against previously published models. This effort lead to more robust predictors and found that incorporating specific demographic and clinical features improved gene expression-based models of high risk. Furthermore, post challenge analysis identified a novel expression-based risk marker and histone modifier, PHF19, which featured prominently in several independent models. Lastly, we show that a simple four feature predictor composed of age, International Staging System stage (ISS), and expression of PHF19 and MMSET performs similarly to more complex models with many more gene expression features included.\n\nKey pointsO_LIMost comprehensive and unbiased assessment of prognostic biomarkers in MM resulting in a robust and parsimonious model.\nC_LIO_LIIdentification of PHF19 as the expression based biomarker most strongly associated with rapid progression in MM patients.\nC_LI

cancer biology↗

bioRxiv2019

Microhomology-mediated end joining drives complex rearrangements and over expression of MYC and PVT1 in multiple myeloma

MYC is a widely acting transcription factor and its deregulation is a crucial event in many human cancers. MYC is important biologically and clinically in multiple myeloma, but the mechanisms underlying its dysregulation are poorly understood. We show that MYC rearrangements are present in 36.0% of newly diagnosed myeloma patients, as detected in the largest set of next generation sequencing data to date (n=1267). Rearrangements were complex and associated with increased expression of MYC and PVT1, but not other genes at 8q24. The highest effect on gene expression was detected in cases where the MYC locus is juxtaposed next to super-enhancers associated with genes such as IGH, IGK, IGL, TXNDC5/BMP6, FAM46C and FOXO3. We identified three hotspots of recombination at 8q24, one of which is enriched for IGH-MYC translocations. Breakpoint analysis indicates primary myeloma rearrangements involving the IGH locus occur through non-homologous end joining, whereas secondary MYC rearrangements occur through microhomology-mediated end joining. This mechanism is different to lymphomas, where non-homologous end joining generates MYC rearrangements. Rearrangements resulted in over-expression of key genes and ChIP-seq identified that HK2, a member of the glucose metabolism pathway, is directly over-expressed through binding of MYC at its promoter.

cancer biology↗

bioRxiv2018

Multiple myeloma immunoglobulin lambda translocations portend poor prognosis

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high-risk. To better understand and identify high-risk myeloma, we analyzed the translocation landscape of 826 newly-diagnosed patients by whole genome sequencing as part of the CoMMpass study. Translocations at the IgL locus were present in 10% of myeloma patients, and corresponded with poor prognosis. Importantly, 70% of IgL translocations co-occurred with hyperdiploid disease, a marker of standard risk, which is routinely diagnosed clinically whereas IgL-translocations are not. Thus, it is likely that the majority of IgL-translocated myeloma is being misclassified. The IgL enhancer is among the strongest in myeloma cells, indicating it can robustly drive oncogene expression when translocated. Consistent with this, IgL-translocated patients failed to benefit from immunomodulatory imide drugs (IMiDs), which target the lymphocyte-specific transcription factor Ikaros. These data implicate the IgL enhancer as resistant to IMiD-inhibition, and when translocated, as a driver of poor prognosis.

genomics↗