Inferring gene expression from cell-free DNA fragmentation profiles

Esfahani, Mohammad Shahrokh; Hamilton, Emily G.; Mehrmohamadi, Mahya; Nabet, Barzin Y.; Alig, Stefan; King, Dan; Steen, Chloé B.; Macaulay, Charles; Schultz, André; Nesselbush, Monica; Soo, Joanne; Schroers‐Martin, Joseph; Chen, Binbin; Binkley, Michael S.; Stehr, Henning; Chabon, Jacob J.; Sworder, Brian; Hui, Angela By; Frank, Matthew J.; Moding, Everett J.; Liu, Chih Long; Newman, Aaron M.; Isbell, James M.; Rudin, Charles M.; Li, Bob T.; Kurtz, David M.; Diehn, Maximilian; Alizadeh, Ash A.

doi:10.1038/s41587-022-01222-4

Cited by 114 publications

(82 citation statements)

References 103 publications

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“…We observed lowly accessible regions are associated with higher fragment length and increased local sequencing depth. This association was recently shown to become stronger with deeper sequencing of cfDNA 52 .…”

Section: Discussionmentioning

confidence: 95%

“…Furthermore, we and others have previously shown that chromatin accessibility affects fragmentation patterns observed in cfDNA 25 – 27 and targeting tissue-specific chromatin regions such as transcription factor binding sites allows for novel panel designs based on epigenetic patterns rather than genetic alterations 31 . A recent study further demonstrated the application of targeted sequencing of TSS regions in gene expression estimation and subtype classification for lung cancer and lymphoma 52 .…”

Section: Discussionmentioning

confidence: 99%

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Integrating chromatin accessibility states in the design of targeted sequencing panels for liquid biopsy

Taklifi

Palizban

Mehrmohamadi

2022

Sci Rep

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Dying tumor cells shed DNA fragments into the circulation that are known as circulating tumor DNA (ctDNA). Liquid biopsy tests aim to detect cancer using known markers, including genetic alterations and epigenetic profiles of ctDNA. Despite various advantages, the major limitation remains the low fraction of tumor-originating DNA fragments in a high background of normal blood-cell originating fragments in the cell-free DNA (cfDNA) pool in plasma. Deep targeted sequencing of cfDNA allows for enrichment of fragments in known cancer marker-associated regions of the genome, thus increasing the chances of detecting the low fraction variant harboring fragments. Most targeted sequencing panels are designed to include known recurrent mutations or methylation markers of cancer. Here, we propose the integration of cancer-specific chromatin accessibility states into panel designs for liquid biopsy. Using machine learning approaches, we first identify accessible and inaccessible chromatin regions specific to each major human cancer type. We then introduce a score that quantifies local chromatin accessibility in tumor relative to blood cells and show that this metric can be useful for prioritizing marker regions with higher chances of being detected in cfDNA for inclusion in future panel designs.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Integrating chromatin accessibility states in the design of targeted sequencing panels for liquid biopsy

Taklifi

Palizban

Mehrmohamadi

2022

Sci Rep

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“…8, 13, 20 . Third, differences in chromatin structure between neoplastic and non-neoplastic cells are known to alter the fragmentation patterns of cell-free DNA and could explain both cell-type specific and cancer-specific changes 7-8, 11, 14, 29-31 . Further research will be required to determine the relative importance of these three potential explanations.…”

Section: Discussionmentioning

confidence: 99%

identifying cancer patients from GC-patterned fragment ends of cell-free DNA

Curtis¹,

Summers

Cohen³

et al. 2022

Preprint

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One of the most intriguing characteristics of cell-free DNA (cfDNA) from plasma is the sequence at the ends of the fragments. Previous studies have shown that these end-sequences are somewhat different in cancer patients than in healthy individuals. While investigating this characteristic, we noticed that the bases at the 5-prime ends of a double-stranded fragment were highly correlated with the GC content of that particular fragment. This led us to develop a method, called MendSeqS (Modified End-based sequencing System), that incorporates the correlation between end-motifs and GC content into the analysis of shallow (0.5x) whole genome sequencing (WGS). MendSeqS was able to classify patients with a sensitivity of 96% at 98% specificity in a cohort comprised of 107 individuals evaluated in our laboratory (43 with cancer and 64 without). In cohorts evaluated in three other laboratories, comprising a total o4 401 individuals (193 with cancer and 208 without), MendSeqS achieved a sensitivity of 87% at 98% specificity. MendSeqS could in principle be combined with other methods of cfDNA analysis to enhance cancer detection.

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“…Most recently, a novel approach for analyzing expression based on cfDNA fragmentomics was developed that measured fragment length diversity to infer RNA expression levels at individual genes [ 40 ]. The working hypothesis was that cfDNA fragments from active promoters would display more random cleavage than fragments from inactive promoters due to the difference in nucleosome occupancy.…”

Section: Epigenetic-based Biomarkers In Liquid Biopsymentioning

confidence: 99%

“…Employing this analysis method to plasma samples could classify subtypes of lung carcinoma and diffuse large B cell lymphoma. Further, it was possible to correlate gene expression profiles with clinical response in serial blood samples from patients with PD-(L)1 immune checkpoint inhibitors treatment [ 40 ].…”

Section: Epigenetic-based Biomarkers In Liquid Biopsymentioning

confidence: 99%

Tracing the Origin of Cell-Free DNA Molecules through Tissue-Specific Epigenetic Signatures

et al. 2022

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All cell and tissue types constantly release DNA fragments into human body fluids by various mechanisms including programmed cell death, accidental cell degradation and active extrusion. Particularly, cell-free DNA (cfDNA) in plasma or serum has been utilized for minimally invasive molecular diagnostics. Disease onset or pathological conditions that lead to increased cell death alter the contribution of different tissues to the total pool of cfDNA. Because cfDNA molecules retain cell-type specific epigenetic features, it is possible to infer tissue-of-origin from epigenetic characteristics. Recent research efforts demonstrated that analysis of, e.g. methylation patterns, nucleosome occupancy, and fragmentomics determined the cell- or tissue-of-origin of individual cfDNA molecules. This novel tissue-of origin-analysis enables to estimate the contributions of different tissues to the total cfDNA pool in body fluids and find tissues with increased cell death (pathologic condition), expanding the portfolio of liquid biopsies towards a wide range of pathologies and early diagnosis. In this review, we summarize the currently available tissue-of-origin approaches and point out the next steps towards clinical implementation.

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Inferring gene expression from cell-free DNA fragmentation profiles

Cited by 114 publications

References 103 publications

Integrating chromatin accessibility states in the design of targeted sequencing panels for liquid biopsy

Integrating chromatin accessibility states in the design of targeted sequencing panels for liquid biopsy

identifying cancer patients from GC-patterned fragment ends of cell-free DNA

Tracing the Origin of Cell-Free DNA Molecules through Tissue-Specific Epigenetic Signatures

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