Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and ...prognostication.
We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed.
We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (
,
, and
) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with
mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within
- and
-related MDS. MDS with complex karyotype and/or
gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of
mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features.
Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.
Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the ...diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome sequencing, whole-genome sequencing, and whole-transcriptome sequencing or RNA sequencing. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are used not only for detecting somatically acquired gene mutations but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification of myeloid neoplasms and acute leukemias makes extensive use of genomic data. The aim of this report is to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with hematologic neoplasms.
Complementing the recently published Blood articles outlining the 2022 International Consensus Classifications for hematological malignancies (Vol. 140, Issue 11), this pair of Special Reports illustrates how molecular pathology can be applied to precision medicine. de Leval and colleagues summarize the potential of DNA sequencing of tumors and cell-free plasma, epigenetic profiling, and single-cell analyses to inform clinical decision-making about diagnosis, prognosis, and treatment for patients with lymphoid neoplasms. Similarly, Duncavage and colleagues cover genomic profiling for myeloid neoplasms and the acute leukemias, focusing principally on somatic changes but also with emphasis on the emerging importance of germline gene mutations in certain diseases. Both articles provide up-to-date references for how to apply genomic information to practice.
The primary aim of this reprint is to describe the genomics of splenic lymphomas, hairy cell leukemia, Cutaneous lymphomas, plasma cell leukemia, MDS with deletion 5q, mastocytosis, hypodiploid acute ...lymphoblastic leukemia, CLL with complex karyotype and other rare hematologic cancers.
Cytogenetics has long represented a critical component in the clinical evaluation of hematologic malignancies. Chromosome banding studies provide a simultaneous snapshot of genome-wide copy number ...and structural variation, which have been shown to drive tumorigenesis, define diseases, and guide treatment. Technological innovations in sequencing have ushered in our present-day clinical genomics era. With recent publications highlighting novel sequencing technologies as alternatives to conventional cytogenetic approaches, we, an international consortium of laboratory geneticists, pathologists, and oncologists, describe herein the advantages and limitations of both conventional chromosome banding and novel sequencing technologies and share our considerations on crucial next steps to implement these novel technologies in the global clinical setting for a more accurate cytogenetic evaluation, which may provide improved diagnosis and treatment management. Considering the clinical, logistic, technical, and financial implications, we provide points to consider for the global evolution of cytogenetic testing.
Monosomy 7 -7 and/or partial loss of chromosome 7 del(7q) are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a ...key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with -7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with -7). Patients with del(7q) or -7 had similar demographic and disease-related characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in -7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0-8). There was no difference in mutation frequency between the two groups. Patients harbouring ≥2 mutations had a worse outcome than patients with <2 or no mutations (leukaemic transformation at 24 months, 38% and 20%, respectively, p = 0.044). Untreated patients with del(7q) had better overall survival (OS) compared with -7 (median OS, 34 vs 17 months, p = 0.034). In multivariable analysis, blast count, TP53 mutations and number of mutations were independent predictors of OS, whereas the cytogenetic subgroups did not retain prognostic relevance. This study highlights the importance of mutational analysis in terms of prognosis in MDS patients with isolated -7 or del(7q).
Optical Genome Mapping (OGM) is rapidly emerging as an exciting cytogenomic technology both for research and clinical purposes. In the last 2 years alone, multiple studies have demonstrated that OGM ...not only matches the diagnostic scope of conventional standard of care cytogenomic clinical testing but it also adds significant new information in certain cases. Since OGM consolidates the diagnostic benefits of multiple costly and laborious tests (e.g., karyotyping, fluorescence in situ hybridization, and chromosomal microarrays) in a single cost‐effective assay, many clinical laboratories have started to consider utilizing OGM. In 2021, an international working group of early adopters of OGM who are experienced with routine clinical cytogenomic testing in patients with hematological neoplasms formed a consortium (International Consortium for OGM in Hematologic Malignancies, henceforth “the Consortium”) to create a consensus framework for implementation of OGM in a clinical setting. The focus of the Consortium is to provide guidance for laboratories implementing OGM in three specific areas: validation, quality control and analysis and interpretation of variants. Since OGM is a complex technology with many variables, we felt that by consolidating our collective experience, we could provide a practical and useful tool for uniform implementation of OGM in hematologic malignancies with the ultimate goal of achieving globally accepted standards.
Real-world data have revealed that a substantial portion of patients with myelodysplastic syndromes (MDS) does not respond to epigenetic therapy with hypomethylating agents (HMAs). The cellular and ...molecular reasons for this resistance to the demethylating agent and biomarkers that would be able to predict the treatment refractoriness are largely unknown. In this study, we shed light on this enigma by characterizing the epigenomic profiles of patients with MDS treated with azacitidine. Our approach provides a comprehensive view of the evolving DNA methylation architecture of the disease and holds great potential for advancing our understanding of MDS treatment responses to HMAs.
This paper assesses university efficiency from a multidimensional perspective. First, the study scrutinizes universities using an efficiency measure that incorporates knowledge transfer outputs in ...the objective function. Second, a cluster analysis complements the efficiency model giving a more comprehensive image of universities' performance. The empirical application considers the Spanish higher education system during 2006–2009. The results point to the presence of heterogeneous orientations among Spanish universities and that universities integrate knowledge transfer in their operations at different intensities. The findings reveal that regional factors related to technological development and entrepreneurial culture strongly influence universities' efficiency and their involvement in knowledge transfer activities. As regards knowledge transfer across Spanish universities, results tend to give ammunition to the argument that effective support policies should have the capacity to be customized to fit the profile of the targeted universities and regions.
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