Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing

Ryland, Georgina L; Jones, K.L.; Chin, Melody; Markham, John; Aydogan, Elle; Kankanige, Yamuna; Caruso, Marisa Carmela; Guinto, Jerick; Dickinson, Michael; Prince, H. Miles; Yong, Kwee; Blombery, Piers

doi:10.1136/jclinpath-2018-205195

Cited by 30 publications

(16 citation statements)

References 29 publications

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“…Tumor samples were sequenced with the Peter MacCallum Cancer Centre (PMCC) PanHaem Panel as described previously [ 48 ]. Briefly, the PMCC PanHaem panel is a hybridisation based NGS panel targeting genes associated with haematological malignancy ( Supplementary Table 1 ), the entire IGH / TRA / TRB / TRG and TRD loci and genome-wide copy number assessment.…”

Section: Methodsmentioning

confidence: 99%

Frequent activating STAT3 mutations and novel recurrent genomic abnormalities detected in breast implant-associated anaplastic large cell lymphoma

et al. 2018

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Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare form of T-cell lymphoma that occurs after implantation of breast prostheses. We performed comprehensive next generation sequencing based genomic characterization of 11 cases of BIA-ALCL including sequence variant detection on 180 genes frequently mutated in haematological malignancy, genome-wide copy number assessment, structural variant detection involving the T-cell receptor loci and TRB deep-sequencing. We observed sequence variants leading to JAK/STAT activation in 10 out of 11 patients. We also observed germline TP53 mutations in two cases. In addition we detected a recurrent copy number loss involving RPL5 as well as copy number amplifications involving TNFRSF11A [RANK] (in 2 cases), MYC, P2RX7, TMEM119 and PDGFRA. In summary, our comprehensive genomic characterisation of 11 cases of BIA-ALCL has provided insight into potential pathobiological mechanisms (JAK/STAT, MYC and TP53) as well as identifying targets for future therapeutic intervention (TNFRSF11A, PDGFRA) in this rare entity.

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Section: Methodsmentioning

confidence: 99%

Frequent activating STAT3 mutations and novel recurrent genomic abnormalities detected in breast implant-associated anaplastic large cell lymphoma

et al. 2018

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“…Sanger sequencing was used to confirm selected variants. Sample CLL3 was sequenced with a hybridization-based (Agilent SureSelect) NGS panel targeting 363 genes with mean target read depth of ∼600×, as described previously (25). Whole-transcriptome sequencing was performed using TruSeq RNA Library Prep Kit v2 on patient CLL3 using RNA extracted from CD19 + selected tumor cells.…”

Section: Ngsmentioning

confidence: 99%

Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia

et al. 2019

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The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, leukemia recurs in most patients. To investigate the mechanisms of secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 patients with CLL progression enrolled on venetoclax clinical trials. The novel Gly101Val mutation in BCL2 was identifi ed at progression in 7 patients, but not at study entry. It was fi rst detectable after 19 to 42 months of therapy, and its emergence anticipated clinical disease progression by many months. Gly101Val reduces the affi nity of BCL2 for venetoclax by ∼180-fold in surface plasmon resonance assays, thereby preventing the drug from displacing proapoptotic mediators from BCL2 in cells and conferring acquired resistance in cell lines and primary patient cells. This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse. SIGNIFICANCE: Why CLL recurs in patients who achieve remission with the BCL2 inhibitor venetoclax has been unknown. We provide the fi rst description of an acquired point mutation in BCL2 arising recurrently and exclusively in venetoclax-treated patients. The mutation reduces venetoclax binding and is suffi cient to confer resistance.

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“…Additionally, 1q21 amplification is considered a high-risk genetic feature, which is the most common chromosomal aberration in MM [4,5]. In recent years, genetic biomarkers are starting to play an increasingly important role in the prognosis of myeloma [6,7]. Therefore, it is necessary to investigate novel biomarkers to predict the prognosis of MM, so as to help improve the prognostication and treatment of MM.…”

Section: Introductionmentioning

confidence: 99%

Enhanced expression of FCER1G predicts positive prognosis in multiple myeloma

Fu¹,

Cheng²,

Dong³

et al. 2020

J. Cancer

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Background: Multiple myeloma (MM) is the second most common hematologic malignancy worldwide and does not have sufficient prognostic indicators. FCER1G (Fc fragment Of IgE receptor Ig) is located on chromosome 1q23.3 and is involved in the innate immunity. Early studies have shown that FCER1G participates in many immune-related pathways encompassing multiple cell types. Meanwhile, it is associated with many malignancies. However, the relationship between MM and FCER1G has not been studied. Methods: In this study, we integrated nine independent gene expression omnibus (GEO) datasets and analyzed the associations of FCER1G expression and myeloma progression, ISS stage, 1q21 amplification and survival in 2296 myeloma patients and 48 healthy donors. Results: The expression of FCER1G showed a decreasing trend with the advance of myeloma. As ISS stage and 1q21 amplification level increased, the expression of FCER1G decreased (P = 0.0012 and 0.0036, respectively). MM patients with high FCER1G expression consistently had longer EFS and OS across three large sample datasets (EFS: P = 0.0057, 0.0049, OS: P = 0.0014, 0.00065, 0.0019 and 0.0029, respectively). Meanwhile, univariate and multivariate analysis indicated that high FCER1G expression was an independent favorable prognostic factor for EFS and OS in MM patients (EFS: P = 0.006, 0.027, OS: P =0.002,0.025, respectively). Conclusions:The expression level of FCER1G negatively correlated with myeloma progression, and high FCER1G expression may be applied as a favorable biomarker in MM patients.

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Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing

Cited by 30 publications

References 29 publications

Frequent activating STAT3 mutations and novel recurrent genomic abnormalities detected in breast implant-associated anaplastic large cell lymphoma

Frequent activating STAT3 mutations and novel recurrent genomic abnormalities detected in breast implant-associated anaplastic large cell lymphoma

Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia

Enhanced expression of FCER1G predicts positive prognosis in multiple myeloma

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