scholarly journals SNP array–based karyotyping: differences and similarities between aplastic anemia and hypocellular myelodysplastic syndromes

Blood ◽  
2011 ◽  
Vol 117 (25) ◽  
pp. 6876-6884 ◽  
Author(s):  
Manuel G. Afable ◽  
Marcin Wlodarski ◽  
Hideki Makishima ◽  
Mohammed Shaik ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Myelodysplastic Syndromes ◽  
Immune Escape ◽  
Neutral Loss ◽  
Clonal Evolution ◽  
Snp Array ◽  
Single Nucleotide ◽  
Genomic Aberrations ◽  
Disease Entities ◽  
N 93

Abstract In aplastic anemia (AA), contraction of the stem cell pool may result in oligoclonality, while in myelodysplastic syndromes (MDS) a single hematopoietic clone often characterized by chromosomal aberrations expands and outcompetes normal stem cells. We analyzed patients with AA (N = 93) and hypocellular MDS (hMDS, N = 24) using single nucleotide polymorphism arrays (SNP-A) complementing routine cytogenetics. We hypothesized that clinically important cryptic clonal aberrations may exist in some patients with BM failure. Combined metaphase and SNP-A karyotyping improved detection of chromosomal lesions: 19% and 54% of AA and hMDS cases harbored clonal abnormalities including copy-neutral loss of heterozygosity (UPD, 7%). Remarkably, lesions involving the HLA locus suggestive of clonal immune escape were found in 3 of 93 patients with AA. In hMDS, additional clonal lesions were detected in 5 (36%) of 14 patients with normal/noninformative routine cytogenetics. In a subset of AA patients studied at presentation, persistent chromosomal genomic lesions were found in 10 of 33, suggesting that the initial diagnosis may have been hMDS. Similarly, using SNP-A, earlier clonal evolution was found in 4 of 7 AA patients followed serially. In sum, our results indicate that SNP-A identify cryptic clonal genomic aberrations in AA and hMDS leading to improved distinction of these disease entities.

scholarly journals Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4552-4560 ◽  
Author(s):  
Ramon V. Tiu ◽  
Lukasz P. Gondek ◽  
Christine L. O'Keefe ◽  
Paul Elson ◽  
Jungwon Huh ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Diagnostic Yield ◽  
Neutral Loss ◽  
Snp Array ◽  
Hematologic Malignancies ◽  
Prognostic Impact ◽  
Myeloid Malignancies ◽  
Genomic Aberrations ◽  
Chromosomal Defects

Abstract Single nucleotide polymorphism arrays (SNP-As) have emerged as an important tool in the identification of chromosomal defects undetected by metaphase cytogenetics (MC) in hematologic cancers, offering superior resolution of unbalanced chromosomal defects and acquired copy-neutral loss of heterozygosity. Myelodysplastic syndromes (MDSs) and related cancers share recurrent chromosomal defects and molecular lesions that predict outcomes. We hypothesized that combining SNP-A and MC could improve diagnosis/prognosis and further the molecular characterization of myeloid malignancies. We analyzed MC/SNP-A results from 430 patients (MDS = 250, MDS/myeloproliferative overlap neoplasm = 95, acute myeloid leukemia from MDS = 85). The frequency and clinical significance of genomic aberrations was compared between MC and MC plus SNP-A. Combined MC/SNP-A karyotyping lead to higher diagnostic yield of chromosomal defects (74% vs 44%, P < .0001), compared with MC alone, often through detection of novel lesions in patients with normal/noninformative (54%) and abnormal (62%) MC results. Newly detected SNP-A defects contributed to poorer prognosis for patients stratified by current morphologic and clinical risk schemes. The presence and number of new SNP-A detected lesions are independent predictors of overall and event-free survival. The significant diagnostic and prognostic contributions of SNP-A–detected defects in MDS and related diseases underscore the utility of SNP-A when combined with MC in hematologic malignancies.

Recurrent Novel Regions of Uniparental Disomy and Homozygous Deletions in Mycosis Fungoides Identified Using High Resolution Single Nucleotide Polymorphism Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2644-2644
Author(s):  
Azim M Mohamedali ◽  
Tracey J Mitchell ◽  
Silvia Ferreira ◽  
Barbara A Guinn ◽  
Robin M. Ireland ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
High Resolution ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genomic Aberrations ◽  
Homozygous Deletions

Abstract Abstract 2644 Poster Board II-620 Mycosis Fungoides (MF) is the commonest form of primary cutaneous T-cell lymphoma but our understanding of the underlying molecular pathogenesis remains limited. Cytogenetic studies remain limited due to difficulties in obtaining analysable mitotic chromosomes for metaphase G-band analysis from MF patients. We have utilised high resolution 250k Affymetrix single nucleotide polymorphism (SNP) arrays to analyse tumour samples from 34 MF patients including 12 paired skin samples using and identified 156 chromosomal aberrations in ten patients (29%). Compared with previous studies using comparative genomic hybridization (CGH) in both MF and Sezary syndrome (SS), SNP array analysis detected a greater frequency of deletions and amplifications on chromosomes 1, 2, 3, 4, 5, 6, 11, and 16. Heterozygous deletions of chromosome 8 were also detected in 3 patients which have been undetected by CGH studies. A particular feature of SNP array technology is the detection of uniparental disomy (UPD) which are copy neutral regions of homozygosity. UPD (median size 32.3Mb (range: 6.6Mb – 159Mb)) was detected in 21% of our MF patients affecting either chromosome 7 (whole chromosome), 8p, 9p/9q, 10q, 12p, 14q, 16p/16q, 17q and 19q. Of note, two patients shared a common UPD region on chromosome 9p that specifically encompassed the p14 and p16 tumour suppressor genes. Thirteen regions of homozygous deletions were also observed in six patients (18%) on chromosomes 1p21.1, 7q34, 9p22.1-21.3, 10p12.1/p12.2/p14/q23.31/q23.1 and 16q23.1-q23.2. Common minimal homozygously deleted regions at 9p21-p22.3 and 16q23.1, suggest the presence of tumour suppressor gene in these regions. Interestingly, all the homozygous regions appeared within a larger region of the UPD or heterozygous deletion. Grouping patients with UPD/deletions or UPD/amplification identified eleven common minimal regions of genomic aberrations occurring in at least 3 patients; 3p24.1-14.2, 7p22.3-12.2, 7q31.1-31.2, 9p21.3-22.1, 10q21.2-26.13, 12p13.33-13.31, 13q14.2-21.1, 16p13.13, 16q23.1, 17p13.3-13.1 and 17q21.32-25.1. The detection of these recurrent abnormalities associated with UPD suggests a series of candidate genes selected for dysregulation through mutational or epigenetic modulation such as MLH, CDKN2A/B, RB1 and TP53. Paired plaque samples were also analysed from 12 patients. Of note, SNP analysis did not always show identical aberrations between these samples. Six patients had multiple aberrant regions in at least one of their samples. Of these, three patients had unique aberrations which were present in only one. This discordance in the distribution of genomic aberrations between the samples may reflect clonal evolution of the disease. To our knowledge, this is the first high resolution SNP array study in MF that has provided additional insight into the pathogenesis of MF. We have identified distinct aberrations not detected by previous studies as well as frequent and widespread UPD harbouring important oncogenes and tumour suppressor genes likely to play key roles in the dysregulation of MF cells. Disclosures: No relevant conflicts of interest to declare.

Clonal Evolution in Aplastic Anemia

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 90-95 ◽  
Author(s):  
Manuel G. Afable ◽  
Ramon V. Tiu ◽  
Jaroslaw P. Maciejewski
Keyword(s):  
Aplastic Anemia ◽  
Chromosomal Abnormalities ◽  
Clonal Evolution ◽  
Immunosuppressive Treatment ◽  
Snp Array ◽  
Term Survival ◽  
Strong Argument ◽  
Monosomy 7 ◽  
Definitive Therapy

Abstract Current immunosuppressive treatment (IST) induces remissions in 50%-70% of patients with aplastic anemia (AA) and result in excellent long-term survival. In recent years, the survival of refractory patients has also improved. Apart from relapse and refractoriness to IST, evolution of clonal diseases, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndrome (MDS), are the most serious long-term complications and constitute a strong argument for definitive therapy with BM transplantation if possible. Consequently, the detection of diagnostic chromosomal abnormalities (mostly monosomy 7) is of great clinical importance. Newer whole-genome scanning technologies such as single nucleotide polymorphism (SNP) array–based karyotyping may be a helpful diagnostic test for the detection of chromosomal defects in AA due to its precision/resolution and lack of reliance on cell division.

scholarly journals Clonal evolution and clinical significance of copy number neutral loss of heterozygosity of chromosome arm 6p in acquired aplastic anemia

2016 ◽  
Vol 209 (1-2) ◽  
pp. 1-10 ◽  
Author(s):  
Marisol Betensky ◽  
Daria Babushok ◽  
Jacquelyn J. Roth ◽  
Philip J. Mason ◽  
Jaclyn A. Biegel ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Clinical Significance ◽  
Loss Of Heterozygosity ◽  
Copy Number ◽  
Neutral Loss ◽  
Clonal Evolution ◽  
Chromosome Arm

scholarly journals Clonal Evolution and Clinical Significance of Copy Number Neutral Loss of Heterozygosity of Chromosome Arm 6p in Acquired Aplastic Anemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4387-4387
Author(s):  
Marisol Betensky ◽  
Daria V. Babushok ◽  
Jacquelyn J. Roth ◽  
Philip J Mason ◽  
Jaclyn A. Biegel ◽  
...  
Keyword(s):  
T Cells ◽  
Clinical Outcome ◽  
Aplastic Anemia ◽  
Allele Frequency ◽  
Clinical Significance ◽  
Loss Of Heterozygosity ◽  
Copy Number ◽  
Pediatric Patients ◽  
Neutral Loss ◽  
Clonal Evolution

Abstract Acquired Aplastic Anemia (aAA) develops from the immune-mediated destruction of hematopoietic stem cells (HSCs) by auto-reactive T cells. Although the exact mechanisms remain incompletely defined, it is hypothesized that auto-reactive T cells target auto-antigens presented by human leukocyte antigens (HLA), leading to HSC destruction. Acquired genetic alterations resulting in clonal hematopoiesis may therefore emerge in patients with aAA as a means of evading this immune response. Well-recognized patterns of clonal cellular evolution in aAA include myelodysplastic syndrome (MDS) and paroxysmal nocturnal hemoglobinuria (PNH). Recent studies have identified acquired copy-number neutral loss of heterozygosity on the short arm of chromosome 6 (6p CN-LOH) as another recurrent abnormality. The HLA loci map to 6p, and deletions or LOH in this region result in the loss of alleles from one parental HLA haplotype. 6p CN-LOH may allow for immune escape and restoration of hematopoiesis in aAA by deleting the HLA haplotype to which the HLA-restricted auto-reactive T cell response is targeted. The effect of 6p CN-LOH on clinical outcome and further clonal evolution in aAA is not well described. Thus, the aim of our study was to investigate the frequency, evolution and clinical significance of clonal 6p CN-LOH in our institutional cohort of adult and pediatric patients diagnosed with aAA. Bone marrow (BM) or peripheral blood (PB) samples were collected for genome wide single nucleotide polymorphism (SNP) arrays (Illumina Human OMNI1 or 850K BeadChip), and analyzed for the presence of copy number abnormalities and loss of heterozygosity, with specific reference to 6p CN-LOH. Clinical outcome data were extracted from patient charts. High Resolution HLA typing information was obtained from patient charts or performed on a research basis. HLA allele frequency in our cohort was compared to that of published control populations from the National Marrow Donor Program. Quantitative comparison of HLA haplotype allele frequency in patients with 6p CN-LOH was performed by next generation sequencing to determine the identity of clonally deleted parental alleles. Our cohort was comprised of 71 patients with aAA and related conditions including PNH and hypoplastic MDS (AA (n=64), PNH (n=5), MDS (n=2); median age 14 years, range 8 months to 68 years; 52% females). A total of 68 patients (96%) had a SNP array performed. 6p CN-LOH (n=8) or acquired clonal deletion of 6p (n=1) was detected in 13% of these patients, with the prevalence significantly higher in adult versus pediatric patients (29% versus 8.3%, p < 0.045). In all patients, clones were first identified at least 6 months after initial diagnosis. The majority of patients with 6p CN-LOH (n=7) received immunosuppressive therapy (IST). Of these, 43% failed IST requiring additional therapy while the rest achieved only a partial response. Importantly, no patient with 6p CN-LOH receiving IST alone achieved complete remission at the time of analysis. The characteristics of 6p CN-LOH varied considerably in terms of the number of clones with different sized regions of LOH, the percentage of cells with LOH, and the specific HLA loci included in the LOH region. 6p CN-LOH patients in whom follow-up SNP analyses were performed exhibited stable clone size, with no new clonal abnormalities. Quantitative analysis of HLA alleles in 6p CN-LOH patients revealed many distinct functionally deleted HLA alleles. While no specific allele was recurrently lost in the 6p CN-LOH clones, several of these deleted alleles occurred at increased frequency in our overall aAA cohort compared to ethnicity-matched control populations. In conclusion, the results from our institutional aAA cohort confirm the prevalence rates of clonal 6p CN-LOH described previously in ethnically distinct populations, while demonstrating an increased frequency of 6p CN-LOH in adult versus pediatric aAA patients. None of the aAA patients with 6p CN-LOH in our cohort achieved a complete response to IST alone, suggesting that 6p CN-LOH may be a risk factor or marker predicting poor response to IST. Taken together, our findings underscore the critical importance of understanding the mechanisms underlying clonal evolution in aAA and their effects on disease pathogenesis and response to therapy. Future multi-institutional studies are needed to define optimal therapeutic approaches for aAA patients with 6p CN-LOH. Disclosures No relevant conflicts of interest to declare.

High-Resolution SNP Array Profiling of Relapsed Acute Leukemia Identifies Genomic Abnormalities Distinct from Those Present at Diagnosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 234-234 ◽  
Author(s):  
Charles G. Mullighan ◽  
Ina Radtke ◽  
Jing Ma ◽  
Sheila A. Shurtleff ◽  
James R. Downing
Keyword(s):  
High Resolution ◽  
Acute Leukemia ◽  
Loss Of Heterozygosity ◽  
Copy Number ◽  
Neutral Loss ◽  
Clonal Evolution ◽  
Snp Array ◽  
Remission Induction ◽  
Dna Copy Number ◽  
Leukemic Clone

Abstract Failure of initial remission-induction therapy and disease recurrence remains a major problem in the management of acute leukemia, however the nature of the biologic factors promoting relapse are incompletely understood. To identify genomic abnormalities associated with relapse, we performed high-resolution, genome-wide analysis of DNA copy number abnormalities and loss-of heterozygosity using Affymetrix single nucleotide polymorphism (SNP) microarrays in 33 cases of relapsed acute leukemia. Sixteen ALL (2 ETV6-RUNX1, 2 MLL rearranged, 6 pseudodiploid or cytogenetically normal B-progenitor ALL, and 6 T-lineage) and 17 AML (two RUNX1-RUNX1T1 [AML1-ETO], two MLL-rearranged, one M7, and 12 with normal karyotype or miscellaneous cytogenetic abnormalities) were studied. Samples with less than 80% blasts were flow sorted to at least 90% purity prior to DNA extraction. Diagnostic samples were available for all cases, and germline samples for 22. DNA copy number and LOH analysis was performed using Affymetrix 250k Nsp and Sty arrays was performed for all samples. Data were analysed using a karyotype-guided normalization algorithm, dChipSNP, and circular binary segmentation. In a detailed comparative analysis of paired diagnostic and relapse samples, changes in DNA copy number abnormalities were identified in the relapse sample in 14 of 16 (87.5%) ALL cases. A striking finding was loss of copy number lesions present at diagnosis in 8/16 ALL relapse samples, and the acquisition of new copy number lesions in 4 of these 8 samples. In each case, the pattern of deletions at antigen receptor loci was comparable between relapse and diagnosis, suggesting the emergence of a related leukemic clone, rather than the development of a distinct second leukemia. An additional 8 ALL relapse samples retained the copy number lesions present at diagnosis, but 6 of these acquired additional copy number abnormalities at relapse, a finding further suggestive of significant clonal evolution. Of the newly acquired copy number abnormalities in the relapse samples, deletions (62.5% of cases) were more common than gains (12.5%). In constrast to ALL a more restricted range of copy number abnormalities was seen in AML, with new abnormalities at relapse seen in 5/17 (29.4%) cases, and deletions (29.4%) outnumbering gains (17.6%). The loss of lesions present at diagnosis was only observed in two AML relapse samples. Examining the entire cohort, the CDKN2A/B locus was most commonly involved (N=5), gains of 1q were noted in two cases, otherwise all observed copy number changes were noted in single cases only, and included focal deletions of ERG and RUNX1. Copy neutral loss of heterozygosity was uncommon, with the exception of three AML cases with UPD of the entire chromosome 13. These observations indicate that relapse is frequently the result of the emergence of a leukemic clone that shows significant genetic differences from the diagnostic clone. Whether these represent rare clones present at the time of diagnosis or are the emergence of new clones as the result of ongoing genomic abnormalities can now be determined using genomic probes specific for the newly acquired deletions.

Quantitative Whole Genome Analysis of Sequential Samples From Patients with B-CLL Identifies Novel Recurrent Copy Number Alterations Involving Critical B-Cell Transcription Factors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3590-3590
Author(s):  
Adele Timbs ◽  
Sam Knight ◽  
Elham SadighiAkha ◽  
Adam Burns ◽  
Helene Dreau ◽  
...  
Keyword(s):  
B Cell ◽  
Allele Frequency ◽  
Neutral Loss ◽  
Clonal Evolution ◽  
Snp Array ◽  
Chromosome 8 ◽  
Copy Number Alterations ◽  
Genome Wide ◽  
Sequential Samples ◽  
Pre Treatment

Abstract Abstract 3590 Genome-wide array or sequencing analyses are powerful tools for identifying genetic aberrations in cancers including leukaemias. However, the majority of these aberrations are likely to be random passenger events that do not drive clonal expansion. Currently, it is unknown whether cancers are maintained by a finite set of recurrent mutations similar for each patient or whether and to what extent malignancies are ‘personalised’, and also how molecular disease drivers evolve over time in the context of clinical intervention. The answers to these questions will determine whether future treatment modalities must be tailored according to individual and dynamic cancer characteristics. We hypothesized that differential quantitative high-resolution genome-wide array analysis of sequential samples from the same patients before treatment and at subsequent relapse would have the potential to identify emerging structural abnormalities with relevance to disease progression and/or response to treatment in a given patient. In order to test this hypothesis, we chose B-cell chronic lymphocytic leukaemia (CLL), because of its unique clinical characteristics, as our model to begin to evaluate the potential role of ‘companion diagnostics’ for this condition. We analysed DNA samples of 80 patients with CLL using a 1 million high resolution SNP array. On 34 of them, sequential pre-treatment and relapse samples were available. The raw data was analysed using the OncoSNP analysis tool designed in-house specifically for cancer samples as it enables quantification of copy number alterations (CNA) and copy neutral loss of heterozygosity (cnLOH) based on B-allele frequency plots in complex mixtures. This allows low levels of aberrations to be detected and for mosaic samples to be identified. Results were compared against the data from the Wellcome Trust Case Control Consortium, the DGA and germline DNA in selected cases. Large CNAs (>1Mb) and cnLOH (>5Mb) without deletions of 11q22.3 or 17p13.1 were identified in a third of patients. These patients had an intermediate clinical risk score that increased with the number of large CNAs. SNP array demonstrated clonal evolution in 32% of patients in the sequential sample cohort. These consisted of extension of the 13q abnormality (2), loss of the 13q deletion (1), a 10q23.1-q25.1 deletion (1), gain of 2pter-p14 (1), deletion of 2q33.1-q36.3, (1) a heterozygous deletion of 2q37.1 (1), gain of 8q22.2-qter (1), deletion of 8p (1), amplification of 8q (1), deletion of 8q (1), loss of 16p13.3 (2), mosaic deletion of 17q11.2 (1), an expansion of chromosomes carrying a 19p13.2-p13.11 gain and a 19p13.11 loss (1), deletions within 3p (1), conversion of a gain of 12p12.2-q21.31 to a copy neutral loss of heterozygosity (cnLOH) (1), deletion of 17pter-13.1 (1), increased proportion of chromosomes with the 7q33–34 deletion (1), expansion of cnLOH for 20q11.22-qter (1) and an increased number of cells with a deletion of 2q22.2-q24.1 (1) found at relapse. Importantly, most CNAs occurring at relapse were recurrent in the entire cohort implying that these are non-random events that are important in disease progression. Analysis of the minimal deleted region (MDR) of these recurrent and relapse associated CNAs revealed genes important in lymphoid development, such as NFκB2 and TRAP1 found in the alternative NFκB pathway and BLIMP1 involved in B-cell differentiation. There were also recurrent abnormalities in the region coding for SP140 which has been implicated in familial CLL. Known cancer genes were also affected by these recurrent and relapse-associated CNAs such as RND3, RIF1, RFXANK, and RHOT1, which are all members of the RAS pathway family. Using the OncoSNP program it was possible to determine that most of these emerging abnormalities were present in low numbers at diagnosis (fig. 1) suggesting that treatment does not induce the genetic alterations but may select for them. Fig .1 CNA and B-allele frequency plots of pre-treatment and relapse samples of a patient demonstrating clonal evolution. A low level of cnLOH can be seen in the B-allele frequency plot at diagnosis (a) at the end of chromosome 8 (dashed box) which becomes more apparent at relapse (b). Fig .1. CNA and B-allele frequency plots of pre-treatment and relapse samples of a patient demonstrating clonal evolution. A low level of cnLOH can be seen in the B-allele frequency plot at diagnosis (a) at the end of chromosome 8 (dashed box) which becomes more apparent at relapse (b). In conclusion, this is the first attempt to quantify CNAs in sequential leukaemia samples. The results demonstrate that recurrent and relapse associated CNAs affect genes important in B-cell development and cancer progression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3296
Author(s):  
Ioannis Chanias ◽  
Kristina Stojkov ◽  
Gregor Stehle ◽  
Michael Daskalakis ◽  
Helena Simeunovic ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Myelodysplastic Syndromes ◽  
Clonal Evolution ◽  
Driver Mutations ◽  
Future Perspectives ◽  
Hematopoietic Stem ◽  
Secondary Acute Myeloid Leukemia ◽  
Stem And Progenitor Cells ◽  
Unfit Patients ◽  
Generation Sequencing

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

scholarly journals Structural variant detection in cancer genomes: computational challenges and perspectives for precision oncology

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Ianthe A. E. M. van Belzen ◽  
Alexander Schönhuth ◽  
Patrick Kemmeren ◽  
Jayne Y. Hehir-Kwa
Keyword(s):  
Intratumor Heterogeneity ◽  
Precision Oncology ◽  
Single Nucleotide Variants ◽  
Full Spectrum ◽  
Single Nucleotide ◽  
Sequencing Technologies ◽  
Cancer Genomes ◽  
Genomic Aberrations

AbstractCancer is generally characterized by acquired genomic aberrations in a broad spectrum of types and sizes, ranging from single nucleotide variants to structural variants (SVs). At least 30% of cancers have a known pathogenic SV used in diagnosis or treatment stratification. However, research into the role of SVs in cancer has been limited due to difficulties in detection. Biological and computational challenges confound SV detection in cancer samples, including intratumor heterogeneity, polyploidy, and distinguishing tumor-specific SVs from germline and somatic variants present in healthy cells. Classification of tumor-specific SVs is challenging due to inconsistencies in detected breakpoints, derived variant types and biological complexity of some rearrangements. Full-spectrum SV detection with high recall and precision requires integration of multiple algorithms and sequencing technologies to rescue variants that are difficult to resolve through individual methods. Here, we explore current strategies for integrating SV callsets and to enable the use of tumor-specific SVs in precision oncology.

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