Prevalence and dynamics of clonal hematopoiesis caused by leukemia-associated mutations in elderly individuals without hematologic disorders

Midic, Danica; Rinke, Jenny; Perner, Florian; Müller, Violetta; Hinze, Anna; Pester, F. R. N.; Landschulze, Jürgen; Ernst, Jochen; Gruhn, Bernd; Matziolis, Georg; Heidel, Florian H.; Hochhaus, Andreas; Ernst, Thomas

doi:10.1038/s41375-020-0869-y

Cited by 35 publications

(25 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…While many laboratories lack the appropriate resources to perform secondary tissue testing, the cases demonstrated here support the analysis of secondary tissues in certain clinical scenarios. This could include buccal swabs as an alternative to skin biopsy to distinguish CH from germline variants 42 .…”

Section: Discussionmentioning

confidence: 99%

Incidental findings from cancer next generation sequencing panels

et al. 2021

View full text Add to dashboard Cite

Next-generation sequencing (NGS) technologies have facilitated multi-gene panel (MGP) testing to detect germline DNA variants in hereditary cancer patients. This sensitive technique can uncover unexpected, non-germline incidental findings indicative of mosaicism, clonal hematopoiesis (CH), or hematologic malignancies. A retrospective chart review was conducted to identify cases of incidental findings from NGS-MGP testing. Inclusion criteria included: 1) multiple pathogenic variants in the same patient; 2) pathogenic variants at a low allele fraction; and/or 3) the presence of pathogenic variants not consistent with family history. Secondary tissue analysis, complete blood count (CBC) and medical record review were conducted to further delineate the etiology of the pathogenic variants. Of 6060 NGS-MGP tests, 24 cases fulfilling our inclusion criteria were identified. Pathogenic variants were detected in TP53, ATM, CHEK2, BRCA1 and APC. 18/24 (75.0%) patients were classified as CH, 3/24 (12.5%) as mosaic, 2/24 (8.3%) related to a hematologic malignancy, and 1/24 (4.2%) as true germline. We describe a case-specific workflow to identify and interpret the nature of incidental findings on NGS-MGP. This workflow will provide oncology and genetic clinics a practical guide for the management and counselling of patients with unexpected NGS-MGP findings.

show abstract

Section: Discussionmentioning

confidence: 99%

Incidental findings from cancer next generation sequencing panels

et al. 2021

View full text Add to dashboard Cite

show abstract

“…In this experiment, the none-zero mutations were all C>T or G>A substitutions, which are possibly results of clonal hematopoiesis 26,27 (Fig. 2b).…”

Section: Qbda Aml Panel For Mrd Detectionmentioning

confidence: 72%

“…The specificity of AML panel was assessed using a "negative sample". Because QBDA is highly sensitive to mutations below 0.01% VAF, and even healthy blood donors have low-level mutations in their PBMC DNA as a result of DNA damage or clonal hematopoiesis, such as C>T or G>A substitutions 26,27 , there is no perfect "negative sample" for MRD detection (Supplementary Fig. S3).…”

Section: Qbda Aml Panel For Mrd Detectionmentioning

confidence: 99%

Calibration-free NGS Quantitation of Mutations below 0.01% VAF

Dai

Chen

et al. 2021

Preprint

View full text Add to dashboard Cite

The quantitation of rare somatic mutations is essential for basic research and translational clinical applications including minimal residual disease (MRD) detection. Though unique molecular identifier (UMI) has suppressed sequencing error and allowed detection rare mutation, the sequencing depth requirement is high. The blocker displacement amplification (BDA) allele enrichment method allows detection of rare mutations using low sequencing depth, but requires calibration to accurately quantitate the VAF of novel mutations. Here, we present Quantitative Blocker Displacement Amplification (QBDA), a method that allows accurate detection and quantitation of mutations below 0.01% VAF at only 23,000X depth. QBDA integrates sequence-selective variant enrichment into UMI quantitation allowing confident detection of rare mutations and reduced sequencing depth. Using a panel of 20 genes recurrently altered in acute myeloid leukemia, we demonstrate quantitation of various mutations including single base substitutions and indels down to a VAF of 0.001% at a single locus with less than 4 million sequencing reads, allowing a sensitive minimal residual disease (MRD) detection in patients during complete remission. In a comprehensive pan-cancer panel covering 61 genes and a melanoma hotspot panel covering 8 genes, we detect mutations down to 0.1% VAF using only 1 million reads in a broad range of clinical samples including cell-free DNA and FFPE DNA, enabling tissue or liquid biopsy genetic tests with de-centralized sequencing instruments. QBDA thus provides a convenient and versatile method for sensitive mutation quantitation using low-depth sequencing.

show abstract

“…2a. In this experiment, the non-zero mutations were all C > T or G > A substitutions, which are possibly results of clonal hematopoiesis 26,27 (Fig. 2b).…”

Section: Development Of Qbdamentioning

confidence: 74%

Calibration-free NGS quantitation of mutations below 0.01% VAF

Dai

Chen

et al. 2021

Nat Commun

View full text Add to dashboard Cite

Quantitation of rare somatic mutations is essential for basic research and translational clinical applications including minimal residual disease (MRD) detection. Though unique molecular identifier (UMI) has suppressed errors for rare mutation detection, the sequencing depth requirement is high. Here, we present Quantitative Blocker Displacement Amplification (QBDA) which integrates sequence-selective variant enrichment into UMI quantitation for accurate quantitation of mutations below 0.01% VAF at only 23,000X depth. Using a panel of 20 genes recurrently altered in acute myeloid leukemia, we demonstrate quantitation of various mutations including single base substitutions and indels down to 0.001% VAF at a single locus with less than 4 million sequencing reads, allowing sensitive MRD detection in patients during complete remission. In a pan-cancer panel and a melanoma hotspot panel, we detect mutations down to 0.1% VAF using only 1 million reads. QBDA provides a convenient and versatile method for sensitive mutation quantitation using low-depth sequencing.

show abstract

Prevalence and dynamics of clonal hematopoiesis caused by leukemia-associated mutations in elderly individuals without hematologic disorders

Cited by 35 publications

References 35 publications

Incidental findings from cancer next generation sequencing panels

Incidental findings from cancer next generation sequencing panels

Calibration-free NGS Quantitation of Mutations below 0.01% VAF

Calibration-free NGS quantitation of mutations below 0.01% VAF

Contact Info

Product

Resources

About