Detection and characterization of lung cancer using cell-free DNA fragmentomes

Mathios, Dimitrios; Johansen, J.; Cristiano, Stephen; Medina, Jamie E.; Phallen, Jillian; Larsen, Klaus; Bruhm, Daniel C.; Niknafs, Noushin; Ferreira, Leonardo Miziara Barboza; Adleff, Vilmos; Chiao, Elaine Jiayuee; Leal, Alessandro; Noë, Michaël; White, James R.; Arun, Adith S.; Hruban, Carolyn; Annapragada, Akshaya V.; Jensen, Sarah Østrup; Ørntoft, Mai-Britt W.; Madsen, Anders Husted; Carvalho, Beatriz; Wit, Meike de; Carey, Jacob; Dracopoli, Nicholas C.; Maddala, Tara; Fang, Kenneth C.; Hartman, Anne‐Renee; Forde, Patrick M.; Anagnostou, Valsamo; Brahmer, Julie R.; Fijneman, Remond J.A.; Nielsen, Hans Jørgen; Meijer, Gerrit A.; Andersen, Claus Lindbjerg; Mellemgaard, Anders; Bojesen, Stig E.; Scharpf, Robert B.; Velculescu, Victor E.

doi:10.1038/s41467-021-24994-w

Cited by 201 publications

(196 citation statements)

References 62 publications

Supporting

Mentioning

189

Contrasting

Order By: Relevance

“…3 a), and the average lengths of fragments of 5hmC-enriched cfDNA from cancer patients were smaller than those from healthy individuals (168.4968 bp and 168.5556 bp, respectively). As previously described [ 31 ], quality-controlled mapped reads were analyzed in non-overlapping 5-megabase (Mb) windows to create genome-wide patterns. Within each window, we examined the short, long and total 5hmC-enriched cfDNA fragments and calculated the ratio of short to long fragments (RoSL).…”

Section: Resultsmentioning

confidence: 99%

“…The pattern of different cfDNA fragment sizes could be defined as fragmentation, a feature with potential diagnostic power. Recent studies [ 29 – 31 ] depicted a large number of abnormalities in the cfDNA of cancer patients through genome-wide analysis of fragmentation patterns. Methods based on fragmentation, such as DELFI (DNA evaluation of fragments for early interception) [ 31 ], were developed to increase sensitivity of noninvasive detection of cancer, which to some extent could remedy shortcomings of methods based on mutations in circulating tumor DNA [ 32 ], i.e., individuals with cancer may be missed by targeted high coverage sequencing.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Integrated 5-hydroxymethylcytosine and fragmentation signatures as enhanced biomarkers in lung cancer

Luo

Shi

Yan³

et al. 2022

Clin Epigenet

View full text Add to dashboard Cite

Background Lung cancer is one of most common cancers worldwide, with a 5-year survival rate of less than 20%, which is mainly due to late-stage diagnosis. Noninvasive methods using 5-hydroxymethylation of cytosine (5hmC) modifications and fragmentation profiles from 5hmC cell-free DNA (cfDNA) sequencing provide an opportunity for lung cancer detection and management. Results A total of 157 lung cancer patients were recruited to generate the largest lung cancer cfDNA 5hmC dataset, which mainly consisted of 62 lung adenocarcinoma (LUAD), 48 lung squamous cell carcinoma (LUSC) and 25 small cell lung cancer (SCLC) patients, with most patients (131, 83.44%) at advanced tumor stages. A 37-feature 5hmC model was constructed and validated to distinguish lung cancer patients from healthy controls, with areas under the curve (AUCs) of 0.8938 and 0.8476 (sensitivity = 87.50% and 72.73%, specificity = 83.87% and 80.60%) in two distinct validation sets. Furthermore, fragment profiles of cfDNA 5hmC datasets were first explored to develop a 48-feature fragmentation model with good performance (AUC = 0.9257 and 0.822, sensitivity = 87.50% and 78.79%, specificity = 80.65% and 76.12%) in the two validation sets. Another diagnostic model integrating 5hmC signals and fragment profiles improved AUC to 0.9432 and 0.8639 (sensitivity = 87.50% and 83.33%, specificity = 90.30% and 77.61%) in the two validation sets, better than models based on either of them alone and performing well in different stages and lung cancer subtypes. Several 5hmC markers were found to be associated with overall survival (OS) and disease-free survival (DFS) based on gene expression data from The Cancer Genome Atlas (TCGA). Conclusions Both the 5hmC signal and fragmentation profiles in 5hmC cfDNA data are sensitive and effective in lung cancer detection and could be incorporated into the diagnostic model to achieve good performance, promoting research focused on clinical diagnostic models based on cfDNA 5hmC data. Graphical abstract

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Integrated 5-hydroxymethylcytosine and fragmentation signatures as enhanced biomarkers in lung cancer

Luo

Shi

Yan³

et al. 2022

Clin Epigenet

View full text Add to dashboard Cite

show abstract

“…The test has detection capability for any cancer (a pan-cancer test) and is good enough to identify the cancer primary lesion with about 80% accuracy [ 25 ]. The techniques that Grail uses to analyze ctDNA include targeted sequencing of about 500 genes previously associated with cancer, whole-genome sequencing, and copy number variations, whole-genome bisulfite sequencing to study methylation status [ 22 ], while other investigators are using DNA fragmentation to study the sizes of ctDNA [ 26 , 27 , 28 , 29 ]. Academic investigators have also published on the detection of early cancer by using ctDNA [ 13 , 30 ].…”

Section: Early Cancer Diagnosismentioning

confidence: 99%

Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm

2021

View full text Add to dashboard Cite

Circulating tumor DNA (ctDNA) is a new pan-cancer tumor marker with important applications for patient prognosis, monitoring progression, and assessing the success of the therapeutic response. Another important goal is an early cancer diagnosis. There is currently a debate if ctDNA can be used for early cancer detection due to the small tumor burden and low mutant allele fraction (MAF). We compare our previous calculations on the size of detectable cancers by ctDNA analysis with the latest experimental data from Grail’s clinical trial. Current ctDNA-based diagnostic methods could predictably detect tumors of sizes greater than 10–15 mm in diameter. When tumors are of this size or smaller, their MAF is about 0.01% (one tumor DNA molecule admixed with 10,000 normal DNA molecules). The use of 10 mL of blood (4 mL of plasma) will likely contain less than a complete cancer genome, thus rendering the diagnosis of cancer impossible. Grail’s new data confirm the low sensitivity for early cancer detection (<30% for Stage I–II tumors, <20% for Stage I tumors), but specificity was high at 99.5%. According to these latest data, the sensitivity of the Grail test is less than 20% in Stage I disease, casting doubt if this test could become a viable pan-cancer clinical screening tool.

show abstract

“…More recently, Mathios et al evaluated the cell free fragmentomes instead of ctDNA and reported good performances to detect lung cancer even at early stages (91% of stages I/II, and 96% of stages III/IV), thus opening a new paradigm for liquid biopsy [ 20 ].…”

Section: Molecular Aspectsmentioning

confidence: 99%

Role of Circulating Tumor DNA in Gastrointestinal Cancers: Current Knowledge and Perspectives

Moati¹,

Taly

Garinet

et al. 2021

Cancers

View full text Add to dashboard Cite

Gastrointestinal (GI) cancers are major health burdens worldwide and biomarkers are needed to improve the management of these diseases along their evolution. Circulating tumor DNA (ctDNA) is a promising non-invasive blood and other bodily-fluid-based biomarker in cancer management that can help clinicians in various cases for the detection, diagnosis, prognosis, monitoring and personalization of treatment in digestive oncology. In addition to the well-studied prognostic role of ctDNA, the main real-world applications appear to be the assessment of minimal residual disease to further guide adjuvant therapy and predict relapse, but also the monitoring of clonal evolution to tailor treatments in metastatic setting. Other challenges such as predicting response to treatment including immune checkpoint inhibitors could also be among the potential applications of ctDNA. Although the level of advancement of ctDNA development in the different tumor localizations is still inhomogeneous, it might be now reliable enough to be soon used in clinical routine for colorectal cancers and shows promising results in other GI cancers.

show abstract

Detection and characterization of lung cancer using cell-free DNA fragmentomes

Cited by 201 publications

References 62 publications

Integrated 5-hydroxymethylcytosine and fragmentation signatures as enhanced biomarkers in lung cancer

Integrated 5-hydroxymethylcytosine and fragmentation signatures as enhanced biomarkers in lung cancer

Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm

Role of Circulating Tumor DNA in Gastrointestinal Cancers: Current Knowledge and Perspectives

Contact Info

Product

Resources

About