CSF H3F3A K27M circulating tumor DNA copy number quantifies tumor growth and in vitro treatment response

Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC <0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma, renal, and pancreatic cancer was achieved with AUC > 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA.

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CIRCULATING TUMOR DNA BY HIGH‐THROUGHPUT SEQUENCING OF T CELL RECEPTOR MONITORED TREATMENT RESPONSE AND PREDICTED TREATMENT FAILURE IN T CELL LYMPHOMAS

Hematological Oncology ◽

10.1002/hon.136_2880 ◽

2021 ◽

Vol 39 (S2) ◽

Author(s):

W Wang ◽

W Zhang ◽

Y Zhang ◽

Y Gan ◽

L Qian ◽

...

Keyword(s):

T Cell ◽

Treatment Failure ◽

Treatment Response ◽

T Cell Receptor ◽

High Throughput ◽

High Throughput Sequencing ◽

Cell Receptor ◽

Circulating Tumor Dna ◽

T Cell Lymphomas ◽

Tumor Dna

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Circulating Tumor DNA Analysis in Blood for the Prediction of Treatment Response in Patientswith Advanced Non-Small Cell Lung Cancer

10.32388/n676np ◽

2022 ◽

Author(s):

Antonio Russo

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Treatment Response ◽

Cell Lung Cancer ◽

Dna Analysis ◽

Circulating Tumor Dna ◽

Small Cell ◽

Small Cell Lung ◽

Tumor Dna

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Promotion of Tumor Growth by ADAMTS4 in Colorectal Cancer: Focused on Macrophages

Cellular Physiology and Biochemistry ◽

10.1159/000489245 ◽

2018 ◽

Vol 46 (4) ◽

pp. 1693-1703 ◽

Cited By ~ 10

Author(s):

Jianjun Chen ◽

Yang Luo ◽

Yong Zhou ◽

Shaolan Qin ◽

Yier Qiu ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Tumor Growth ◽

Expression Profile ◽

Copy Number ◽

Copy Number Alterations ◽

Extracellular Proteases ◽

Proliferation And Invasion

Background/Aims: ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are a family of extracellular proteases that have been related to both oncogenic and tumor-suppressive functions. The aim of the present study was to investigate: 1) the mutation, copy-number alterations, and expression profile of ADAMTSs in colorectal cancer and 2) whether ADAMTSs participate in colorectal cancer (CRC) progression and invasion. Methods: The mutation, copy-number alterations, and expression profile of ADAMTSs in CRC were analyzed in the TCGA cohort using cBioportal. ADAMTS4 expression in tumor tissues and cell lines were determined by immunostaining and real-time quantitative PCR. The role of ADAMTS-4 in CRC progression and the underlying mechanisms were studied by using short hairpin RNA-mediated knockdown of ADAMTS4. The effects of ADAMTS4 in cell proliferation and invasion were determined by clone formation assay and transwell migration assay, respectively. Macrophages were depleted by liposomal clodronate in immune-competent BALB/c mice and tumor growth was analyzed. Results: ADAMTS4 was differentially expressed in CRC and predicted a poor prognosis. Elevated ADAMTS4 expression was closely associated with larger tumor size, enhanced TNM stage, and a poor clinical outcome in patients with CRC. ADAMTS4 knockdown had no inhibitory implications on cell proliferation and invasion in vitro, but significantly attenuated tumor growth in vivo. Mechanistically, we revealed that ADAMTS4 was associated macrophages infiltration and polarization in the tumor microenvironment of CRC. Macrophage depletion largely abolished the promotive effect of ADAMTS4 on tumor growth in the immune competent BALB/c mice. Conclusion: ADAMTS4 seemed to be a promising prognostic indicator in CRC. The novel link between ADAMTS4 and macrophages mirrors the potential regulatory roles of ADAMTSs in the inflammatory microenvironment of cancers.

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