scholarly journals Genetic and genomic analysis of acute lymphoblastic leukaemia in older adults reveals a distinct profile of abnormalities: analysis of 210 patients from the UKALL14 and UKALL60+ clinical trials

Haematologica ◽  
2021 ◽  
Author(s):  
Thomas Creasey ◽  
Emilio Barretta ◽  
Sarra L. Ryan ◽  
Ellie Butler ◽  
Amy A Kirkwood ◽  
...  
Keyword(s):  
Older Adults ◽  
Clinical Trials ◽  
Snp Array ◽  
Treatment Strategies ◽  
Genomic Analysis ◽  
Driver Genes ◽  
Single Nucleotide ◽  
Ras Pathway ◽  
Novel Therapeutic Strategies ◽  
Next Generation Sequencing Ngs

Despite being predominantly a childhood disease, the incidence of ALL has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterisation to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1 positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and 1% of patients respectively. Copy number abnormalities were common and deletions in ALL driver genes were seen in 77% of cases. IKZF1 deletion was present in 51% (40/78) of samples tested and the IKZF1plus profile identified in over a third (28/77) of BCP-ALL cases. The genetic good risk abnormalities high hyperdiploidy (n=2), ETV6-RUNX1 (no cases) and ERG deletion (no cases) were exceptionally rare in this cohort. RAS pathway mutations were seen in 17% (4/23) of screened samples. KDM6A abnormalities, including biallelic deletions, were discovered in 5% (4/78) of SNP array and 9% (2/23) of NGS samples, and represent a novel, potentially therapeutically actionable lesions using EZH2 inhibitors. Outcome remained poor with five-year event-free (EFS) and overall survival (OS) rates of 17% and 24% respectively across the cohort indicating a need for novel therapeutic strategies.

CoNCoS: Copy number estimation in cancer with controlled support

2015 ◽  
Vol 13 (05) ◽  
pp. 1550027 ◽  
Author(s):  
Ali T. Abdallah ◽  
Matthias Fischer ◽  
Peter Nürnberg ◽  
Michael Nothnagel ◽  
Peter Frommolt
Keyword(s):  
Copy Number ◽  
Genomic Analysis ◽  
Data Sets ◽  
Sequencing Data ◽  
Multiple Sources ◽  
Single Nucleotide ◽  
Copy Number Estimation ◽  
Coverage Quality ◽  
A Site ◽  
Next Generation Sequencing Ngs

Somatic copy number (CN) alterations are major drivers of tumorigenesis and growth. Although next-generation sequencing (NGS) technologies enable a deep genomic analysis of cancers, the analysis of the data remains subject to biases and multiple sources of error, including varying local read coverage. The currently existing algorithms for NGS-based detection of CN abberations do not incorporate information on the local coverage quality. We have developed a new algorithm, copy number estimation with controlled support (CoNCoS) that increases the accuracy of CN estimation in paired tumor/normal exome sequencing data sets by assessing and optimizing the support for a site-specific CN estimate. We show by simulations and in a benchmarking study against single nucleotide polymorphism (SNP) microarray data that our approach outperforms the commonly used methods CNAnorm and VarScan2. Our algorithm is suitable to increase the accuracy of somatic CN analysis by a support-optimized estimation approach.

scholarly journals Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma

Blood ◽  
2012 ◽  
Vol 120 (5) ◽  
pp. 1077-1086 ◽  
Author(s):  
Brian A. Walker ◽  
Christopher P. Wardell ◽  
Lorenzo Melchor ◽  
Sanna Hulkki ◽  
Nicola E. Potter ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Statistical Significance ◽  
Treatment Strategies ◽  
Specific Mechanism ◽  
Cell Level ◽  
Single Nucleotide ◽  
Ras Pathway ◽  
Whole Exome ◽  
Axonemal Dynein ◽  
Single Nucleotide Variations

Abstract We have used whole exome sequencing to compare a group of presentation t(4;14) with t(11;14) cases of myeloma to define the mutational landscape. Each case was characterized by a median of 24.5 exonic nonsynonymous single-nucleotide variations, and there was a consistently higher number of mutations in the t(4;14) group, but this number did not reach statistical significance. We show that the transition and transversion rates in the 2 subgroups are similar, suggesting that there was no specific mechanism leading to mutation differentiating the 2 groups. Only 3% of mutations were seen in both groups, and recurrently mutated genes include NRAS, KRAS, BRAF, and DIS3 as well as DNAH5, a member of the axonemal dynein family. The pattern of mutation in each group was distinct, with the t(4;14) group being characterized by deregulation of chromatin organization, actin filament, and microfilament movement. Recurrent RAS pathway mutations identified subclonal heterogeneity at a mutational level in both groups, with mutations being present as either dominant or minor subclones. The presence of subclonal diversity was confirmed at a single-cell level using other tumor-acquired mutations. These results are consistent with a distinct molecular pathogenesis underlying each subgroup and have important impacts on targeted treatment strategies. The Medical Research Council Myeloma IX trial is registered under ISRCTN68454111.

Perceived Voice Disorders in Older Adults and Impact on Social Interactions

2021 ◽  
pp. 1-8
Author(s):  
Connie K. Porcaro ◽  
Clare Singer ◽  
Boris Djokic ◽  
Ali A. Danesh ◽  
Ruth Tappen ◽  
...  
Keyword(s):  
Older Adults ◽  
Social Interactions ◽  
Social Engagement ◽  
Leisure Activities ◽  
Treatment Strategies ◽  
Voice Disorders ◽  
Community Dwelling ◽  
Vocal Performance ◽  
Older Individuals ◽  
Cross Sectional

Purpose Many aging individuals, even those who are healthy, report voice changes that can impact their ability to communicate as they once did. While this is commonly reported, most do not seek evaluation or management for this issue. The purpose of this study was to investigate the prevalence and differences in voice disorders in older adults, along with the effect of fatigue on their social interactions. Method This is a cross-sectional investigation of a community-dwelling sample of individuals aged 60 years or older. Participants completed the Questionnaire on Vocal Performance, the Social Engagement Index subset “Engagement in Social or Leisure Activities,” and the Fatigue Severity Scale. Results Results indicated 32.5% of the 332 participants reported symptoms of voice problems with no difference found between male and female respondents. A slight increase in report of voice problems was noted with each year of age. Participants who self-reported voice problems indicated less interaction in social activities involving communication than those who did not. Finally, as severity of self-reported voice problems increased, an increase was reported by the same individuals for signs of fatigue. Conclusions Voice problems and resulting decreased social interaction are commonly experienced by older individuals. Voice symptoms in older adults have been found to benefit from evidence-based treatment strategies. It is critical to provide education to encourage older individuals to seek appropriate evaluation and management for voice issues through a speech-language pathologist or medical professional.

scholarly journals Patient Derived Xenografts for Genome-Driven Therapy of Osteosarcoma

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 416
Author(s):  
Lorena Landuzzi ◽  
Maria Cristina Manara ◽  
Pier-Luigi Lollini ◽  
Katia Scotlandi
Keyword(s):  
Clinical Trials ◽  
Tumor Heterogeneity ◽  
Functional Studies ◽  
Ngs Data Analysis ◽  
The Many ◽  
Orthotopic Xenografts ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data ◽  
Generation Sequencing ◽  
Somatic Copy Number Alterations

Osteosarcoma (OS) is a rare malignant primary tumor of mesenchymal origin affecting bone. It is characterized by a complex genotype, mainly due to the high frequency of chromothripsis, which leads to multiple somatic copy number alterations and structural rearrangements. Any effort to design genome-driven therapies must therefore consider such high inter- and intra-tumor heterogeneity. Therefore, many laboratories and international networks are developing and sharing OS patient-derived xenografts (OS PDX) to broaden the availability of models that reproduce OS complex clinical heterogeneity. OS PDXs, and new cell lines derived from PDXs, faithfully preserve tumor heterogeneity, genetic, and epigenetic features and are thus valuable tools for predicting drug responses. Here, we review recent achievements concerning OS PDXs, summarizing the methods used to obtain ectopic and orthotopic xenografts and to fully characterize these models. The availability of OS PDXs across the many international PDX platforms and their possible use in PDX clinical trials are also described. We recommend the coupling of next-generation sequencing (NGS) data analysis with functional studies in OS PDXs, as well as the setup of OS PDX clinical trials and co-clinical trials, to enhance the predictive power of experimental evidence and to accelerate the clinical translation of effective genome-guided therapies for this aggressive disease.

scholarly journals Prenatal diagnosis of 7 cases with uniparental disomy by utilization of single nucleotide polymorphism array

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lili Zhou ◽  
Zhaoke Zheng ◽  
Yunzhi Xu ◽  
Xiaoxiao Lv ◽  
Chenyang Xu ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Prenatal Diagnosis ◽  
Molecular Analysis ◽  
Correct Diagnosis ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Chromosome 1 ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Rescue Mechanism

Abstract Background The phenotypes of uniparental disomy (UPD) are variable, which may either have no clinical impact, lead to clinical signs and symptoms. Molecular analysis is essential for making a correct diagnosis. This study involved a retrospective analysis of 4512 prenatal diagnosis samples and explored the molecular characteristics and prenatal phenotypes of UPD using a single nucleotide polymorphism (SNP) array. Results Out of the 4512 samples, a total of seven cases of UPD were detected with an overall frequency of 0.16%. Among the seven cases of UPD, two cases are associated with chromosomal aberrations (2/7), four cases (4/7) had abnormal ultrasonographic findings. One case presented with iso-UPD (14), and two case presented with mixed hetero/iso-UPD (15), which were confirmed by Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as maternal UPD (15) associated with Prader-Willi syndrome (PWS). Four cases had iso-UPD for chromosome 1, 3, 14, and 16, respectively; this is consistent with the monosomy rescue mechanism. Another three cases presented with mixed hetero/isodisomy were consistent with a trisomy rescue mechanism. Conclusion The prenatal phenotypes of UPD are variable and molecular analysis is essential for making a correct diagnosis and genetic counselling of UPD. The SNP array is a useful genetic test in prenatal diagnosis cases with UPD.

scholarly journals SNP array analysis in hematologic malignancies: avoiding false discoveries

Blood ◽  
2010 ◽  
Vol 115 (21) ◽  
pp. 4157-4161 ◽  
Author(s):  
Stefan Heinrichs ◽  
Cheng Li ◽  
A. Thomas Look
Keyword(s):  
Single Nucleotide Polymorphism ◽  
High Resolution ◽  
Snp Array ◽  
Hematologic Malignancies ◽  
Cancer Genome ◽  
Patient Specific ◽  
Nucleotide Polymorphism ◽  
Array Analysis ◽  
Single Nucleotide ◽  
Therapeutic Decisions

Comprehensive analysis of the cancer genome has become a standard approach to identifying new disease loci, and ultimately will guide therapeutic decisions. A key technology in this effort, single nucleotide polymorphism arrays, has been applied in hematologic malignancies to detect deletions, amplifications, and loss of heterozygosity (LOH) at high resolution. An inherent challenge of such studies lies in correctly distinguishing somatically acquired, cancer-specific lesions from patient-specific inherited copy number variations or segments of homozygosity. Failure to include appropriate normal DNA reference samples for each patient in retrospective or prospective studies makes it difficult to identify small somatic deletions not evident by standard cytogenetic analysis. In addition, the lack of proper controls can also lead to vastly overestimated frequencies of LOH without accompanying loss of DNA copies, so-called copy-neutral LOH. Here we use examples from patients with myeloid malignancies to demonstrate the superiority of matched tumor and normal DNA samples (paired studies) over multiple unpaired samples with respect to reducing false discovery rates in high-resolution single nucleotide polymorphism array analysis. Comparisons between matched tumor and normal samples will continue to be critical as the field moves from high resolution array analysis to deep sequencing to detect abnormalities in the cancer genome.

scholarly journals Mechanisms of Resistance to KRASG12C Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 151
Author(s):  
Victoria Dunnett-Kane ◽  
Pantelis Nicola ◽  
Fiona Blackhall ◽  
Colin Lindsay
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Current Evidence ◽  
Mechanisms Of Resistance ◽  
Ras Pathway ◽  
Early Evidence ◽  
Downstream Effectors ◽  
Direct Inhibitors

KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of “undruggable”. Recent efforts to produce subtype specific inhibitors have been more successful, and several KRASG12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors.

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