Prevalence and timing of TP53 mutations in del(17p) myeloma and effect on survival

Chin, Melody; Sive, Jonathan; Allen, Christopher; Roddie, Claire; Chavda, Selina J; Smith, Dean; Blombery, Piers; Jones, K.L.; Ryland, Georgina L; Popat, Rakesh; Rismani, Ali; D’Sa, Shirley; Rabin, Neil; Gale, Rosemary E.; Yong, Kwee

doi:10.1038/bcj.2017.76

Cited by 44 publications

(42 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In this subgroup of nine patients, the median age at diagnosis was 11 years (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and the median overall survival was 27.3 months (IQR 13.2; −). Two tumors were initially diagnosed as diffuse glioma grade IV (22.2%), five as grade III (55.6%) and two as grade II (22.2%).…”

Section: Histone Wild-type Subgroupmentioning

confidence: 94%

“…A total of 35 patients (79.5%) were identified with H3F3A or HIST1H3B mutation (Figure 2). In this subgroup, the median age at diagnosis was 9 years (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), and the median overall survival was 7.9 months ( IQR 3,8;13,9). Twenty-three patients (65.7%) had a tumor exclusively located in the brainstem, whereas 8 patients (22.9%) had a tumor in another midline location, as described previously.…”

Section: Main Molecular and Chromosomal Alterationsmentioning

confidence: 95%

See 1 more Smart Citation

Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant

et al. 2019

View full text Add to dashboard Cite

Pediatric diffuse midline gliomas are devastating diseases. Among them, diffuse midline gliomas H3K27M-mutant are associated with worse prognosis. However, recent studies have highlighted significant differences in clinical behavior and biological alterations within this specific subgroup. In this context, simple markers are needed to refine the prognosis of diffuse midline gliomas H3K27M-mutant and guide the clinical management of patients. The aims of this study were (i) to describe the molecular, immunohistochemical and, especially, chromosomal features of a cohort of diffuse midline gliomas and (ii) to focus on H3K27M-mutant tumors to identify new prognostic markers. Patients were retrospectively selected from 2001 to 2017. Tumor samples were analyzed by immunohistochemistry (including H3K27me3, EGFR, c-MET and p53), next-generation sequencing and comparative genomic hybridization array. Forty-nine patients were included in the study. The median age at diagnosis was 9 years, and the median overall survival (OS) was 9.4 months. H3F3A or HIST1H3B mutations were identified in 80% of the samples. Within the H3K27M-mutant tumors, PDGFRA amplification, loss of 17p and a complex chromosomal profile were significantly associated with worse survival. Three prognostic markers were identified in diffuse midline gliomas H3K27M-mutant: PDGFRA amplification, loss of 17p and a complex chromosomal profile. These markers are easy to detect in daily practice and should be considered to refine the prognosis of this entity.Dufour et al Prognostic markers in diffuse gliomas H3K27M-mutant Brain Pathology 30 (2020) [179][180][181][182][183][184][185][186][187][188][189][190]

show abstract

Section: Histone Wild-type Subgroupmentioning

confidence: 94%

Section: Main Molecular and Chromosomal Alterationsmentioning

confidence: 95%

Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Overall the genomic landscape of the cohort was consistent with the literature published to date. Of note, the cohort was enriched for TP53 abnormalities (with sequence variants and/or copy number changes detected in 57% (49/86) of patients), reflecting the inclusion of a previous cohort that had been selected for 17 p deletion detected by fluorescence in situ hybridisation (FISH) (n=47),7 as well as a high proportion of patients with relapsed/refractory disease. Both TP53 copy number loss (18/86, 21%) and TP53 mutation plus copy number loss (24/86, 28%) were more common compared with TP53 mutation alone (7/86, 8%).…”

Section: Resultsmentioning

confidence: 99%

“…Despite both deletion of 17 p detected by FISH and TP53 mutations being associated with inferior outcomes in myeloma,7 FISH for 17 p deletion alone is most commonly performed as part of routine prognostic investigation. Importantly, our analysis of patients in the CoMMpass data set with deletion of 17 p and those with TP53 mutation only (ie, without deletion of 17 p) demonstrated no statistically significant difference in progression-free or overall survival.…”

Section: Discussionmentioning

confidence: 99%

“…This includes a cohort of patients with deletion of 17 p, the outcomes of which have been previously described 7. DNA was extracted from bone marrow aspirate samples with at least 30% plasma cells (32 by morphological assessment and 54 enriched by immunomagnetic selection using CD138+ beads post mononuclear cell isolation by density centrifugation) using DNeasy Blood and Tissue Kit reagents (Qiagen, Hilden, Germany).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

Treatment patterns and clinical outcomes in high‐risk newly diagnosed multiple myeloma patients carrying the 17p deletion: An observational multi‐center retrospective study

et al. 2018

View full text Add to dashboard Cite

Del17p is a genomic imbalance occurring in ∼7%-10% of myeloma at diagnosis newly diagnosed myeloma patients (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008 and 1/2016 proven to carry 17p deletion by means of fluorescence in situ hybridization (FISH) were identified. Most received a bortezomib-based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance. Overall response rate (ORR) after induction was 85%; 94% for transplant eligible (TE); and 75% for transplant ineligible (NTE), and declined in subsequent treatment lines, 64% achieved ≥ VGPR. Median overall survival (OS) was 43 months; median progression free survival (PFS) was 11 months, 19 months for TE and 7 for NTE. In multivariate analysis: higher M-Spike, presence of extramedullary disease, and >50% of cells baring del17p were associated with adverse PFS; Autologous HCT and higher hemoglobin were associated with longer PFS; OS was 59 months for patients with early access to newer agents. Older age and higher M-Spike levels were associated with adverse OS, Autologous HCT was associated with favorable OS, 59.7 vs 28.7 months for NTE patients. Despite the improvement achieved with autologous HCT and new novel agents, the prognosis of patients with 17p deletion is still inferior, emphasizing the need for novel approaches.

show abstract

Prevalence and timing of TP53 mutations in del(17p) myeloma and effect on survival

Cited by 44 publications

References 14 publications

Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant

Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant

Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing

Treatment patterns and clinical outcomes in high‐risk newly diagnosed multiple myeloma patients carrying the 17p deletion: An observational multi‐center retrospective study

Contact Info

Product

Resources

About