Dataset Information

Cost-effective methylome sequencing of cell-free DNA for accurately detecting and locating cancer.

ABSTRACT: Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our approach to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, allowing us to learn new features and expand to other cancer types as training cohorts grow.

SUBMITTER: Stackpole ML

PROVIDER: S-EPMC9522828 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Cost-effective methylome sequencing of cell-free DNA for accurately detecting and locating cancer.

Stackpole Mary L ML Zeng Weihua W Li Shuo S Liu Chun-Chi CC Zhou Yonggang Y He Shanshan S Yeh Angela A Wang Ziye Z Sun Fengzhu F Li Qingjiao Q Yuan Zuyang Z Yildirim Asli A Chen Pin-Jung PJ Winograd Paul P Tran Benjamin B Lee Yi-Te YT Li Paul Shize PS Noor Zorawar Z Yokomizo Megumi M Ahuja Preeti P Zhu Yazhen Y Tseng Hsian-Rong HR Tomlinson James S JS Garon Edward E French Samuel S Magyar Clara E CE Dry Sarah S Lajonchere Clara C Geschwind Daniel D Choi Gina G Saab Sammy S Alber Frank F Wong Wing Hung WH Dubinett Steven M SM Aberle Denise R DR Agopian Vatche V Han Steven-Huy B SB Ni Xiaohui X Li Wenyuan W Zhou Xianghong Jasmine XJ

Nature communications 20220929 1

Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational met ...[more]

PMID: 36175411

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Project description:BackgroundAccurate lung cancer classification is crucial to guide therapeutic decisions. However, histological subtyping by pathologists requires tumor tissue-a necessity that is often intrinsically associated with procedural difficulties. The analysis of circulating tumor DNA present in minimal-invasive blood samples, referred to as liquid biopsies, could therefore emerge as an attractive alternative.MethodsConcerning adenocarcinoma, squamous cell carcinoma, and small cell carcinoma, our proof of concept study investigates the potential of liquid biopsy-derived copy number alterations, derived from single-end shallow whole-genome sequencing (coverage 0.1-0.5×), across 51 advanced stage lung cancer patients.ResultsGenomic abnormality testing reveals anomalies in 86.3% of the liquid biopsies (16/20 for adenocarcinoma, 13/16 for squamous cell, and 15/15 for small cell carcinoma). We demonstrate that copy number profiles from formalin-fixed paraffin-embedded tumor biopsies are well represented by their liquid equivalent. This is especially valid within the small cell carcinoma group, where paired profiles have an average Pearson correlation of 0.86 (95% CI 0.79-0.93). A predictive model trained with public data, derived from 843 tissue biopsies, shows that liquid biopsies exhibit multiple deviations that reflect histological classification. Most notably, distinguishing small from non-small cell lung cancer is characterized by an area under the curve of 0.98 during receiver operating characteristic analysis. Additionally, we investigated how deeper paired-end sequencing, which will eventually become feasible for routine diagnosis, empowers tumor read enrichment by insert size filtering: for all of the 29 resequenced liquid biopsies, the tumor fraction could be increased in silico, thereby "rescuing" three out of five cases with previously undetectable alterations.ConclusionsCopy number profiling of cell-free DNA enables histological classification. Since shallow whole-genome sequencing is inexpensive and often fully operational at routine molecular laboratories, this finding has current diagnostic potential, especially for patients with lesions that are difficult to reach.

Dataset Information

Cost-effective methylome sequencing of cell-free DNA for accurately detecting and locating cancer.

Publications

Cost-effective methylome sequencing of cell-free DNA for accurately detecting and locating cancer.

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