Heat Selection Enables Highly Scalable Methylome Profiling in Cell-free DNA for Noninvasive Monitoring of Cancer Patients

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2022 Sep 9

PMID 36083902

Authors

Elsie Cheruba

Ramya Viswanathan

Pui-Mun Wong

Howard John Womersley

Shuting Han

Brenda Tay

Yiting Lau

Anna Gan

Polly S Y Poon

Anders Skanderup

Sarah B Ng

Aik Yong Chok

Dawn Qingqing Chong

Iain Beehuat Tan

Lih Feng Cheow

Affiliations

Soon will be listed here.

Abstract

Genome-wide analysis of cell-free DNA methylation profile is a promising approach for sensitive and specific detection of many cancers. However, scaling such assays for clinical translation is impractical because of the high cost of whole-genome bisulfite sequencing. We show that the small fraction of GC-rich genome is highly enriched in CpG sites and disproportionately harbors most of the cancer-specific methylation signature. Here, we report on the simple and effective heat enrichment of CpG-rich regions for bisulfite sequencing (Heatrich-BS) platform that allows for focused methylation profiling in these highly informative regions. Our novel method and bioinformatics algorithm enable accurate tumor burden estimation and quantitative tracking of colorectal cancer patient's response to treatment at much reduced sequencing cost suitable for frequent monitoring. We also show tumor epigenetic subtyping using Heatrich-BS, which could enable patient stratification. Heatrich-BS holds great potential for highly scalable screening and monitoring of cancer using liquid biopsy.

Citing Articles

Pioneering noninvasive colorectal cancer detection with an AI-enhanced breath volatilomics platform.

Liu Y, Ji Y, Chen J, Zhang Y, Li X, Li X Theranostics. 2024; 14(11):4240-4255.

PMID: 39113791 PMC: 11303087. DOI: 10.7150/thno.94950.

Programmable melanoma-targeted radio-immunotherapy via fusogenic liposomes functionalized with multivariate-gated aptamer assemblies.

Ren X, Xue R, Luo Y, Wang S, Ge X, Yao X Nat Commun. 2024; 15(1):5035.

PMID: 38866788 PMC: 11169524. DOI: 10.1038/s41467-024-49482-9.

Erasable and Field Programmable DNA Circuits Based on Configurable Logic Blocks.

Liu Y, Zhai Y, Hu H, Liao Y, Liu H, Liu X Adv Sci (Weinh). 2024; 11(26):e2400011.

PMID: 38698560 PMC: 11234411. DOI: 10.1002/advs.202400011.

DARESOME enables concurrent profiling of multiple DNA modifications with restriction enzymes in single cells and cell-free DNA.

Viswanathan R, Cheruba E, Wong P, Yi Y, Ngang S, Chong D Sci Adv. 2023; 9(37):eadi0197.

PMID: 37713482 PMC: 10881072. DOI: 10.1126/sciadv.adi0197.

Liquid biopsies for cancer: From bench to clinic.

Chen Z, Li C, Zhou Y, Yao Y, Liu J, Wu M MedComm (2020). 2023; 4(4):e329.

PMID: 37492785 PMC: 10363811. DOI: 10.1002/mco2.329.

References

Doherty A, Wigley D . Functional domains of an ATP-dependent DNA ligase. J Mol Biol. 1999; 285(1):63-71. DOI: 10.1006/jmbi.1998.2301. View

Carter S, Cibulskis K, Helman E, McKenna A, Shen H, Zack T . Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012; 30(5):413-21. PMC: 4383288. DOI: 10.1038/nbt.2203. View

Sproul D, Meehan R . Genomic insights into cancer-associated aberrant CpG island hypermethylation. Brief Funct Genomics. 2013; 12(3):174-90. PMC: 3662888. DOI: 10.1093/bfgp/els063. View

Li W, Li Q, Kang S, Same M, Zhou Y, Sun C . CancerDetector: ultrasensitive and non-invasive cancer detection at the resolution of individual reads using cell-free DNA methylation sequencing data. Nucleic Acids Res. 2018; 46(15):e89. PMC: 6125664. DOI: 10.1093/nar/gky423. View

Sun K, Jiang P, Chan K, Wong J, Cheng Y, Liang R . Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments. Proc Natl Acad Sci U S A. 2015; 112(40):E5503-12. PMC: 4603482. DOI: 10.1073/pnas.1508736112. View

Liu M, Oxnard G, Klein E, Swanton C, Seiden M . Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2021; 31(6):745-759. PMC: 8274402. DOI: 10.1016/j.annonc.2020.02.011. View

Leary R, Lin J, Cummins J, Boca S, Wood L, Parsons D . Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers. Proc Natl Acad Sci U S A. 2008; 105(42):16224-9. PMC: 2571022. DOI: 10.1073/pnas.0808041105. View

Nazemalhosseini Mojarad E, Kuppen P, Aghdaei H, Zali M . The CpG island methylator phenotype (CIMP) in colorectal cancer. Gastroenterol Hepatol Bed Bench. 2014; 6(3):120-8. PMC: 4017514. View

Mo Y . Probing the nature of hydrogen bonds in DNA base pairs. J Mol Model. 2006; 12(5):665-72. DOI: 10.1007/s00894-005-0021-y. View

10.

. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487(7407):330-7. PMC: 3401966. DOI: 10.1038/nature11252. View

11.

Lehmann-Werman R, Neiman D, Zemmour H, Moss J, Magenheim J, Vaknin-Dembinsky A . Identification of tissue-specific cell death using methylation patterns of circulating DNA. Proc Natl Acad Sci U S A. 2016; 113(13):E1826-34. PMC: 4822610. DOI: 10.1073/pnas.1519286113. View

12.

Weisenberger D, Siegmund K, Campan M, Young J, Long T, Faasse M . CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006; 38(7):787-93. DOI: 10.1038/ng1834. View

13.

Heyn H, Vidal E, Ferreira H, Vizoso M, Sayols S, Gomez A . Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer. Genome Biol. 2016; 17:11. PMC: 4728783. DOI: 10.1186/s13059-016-0879-2. View

14.

Cibulskis K, Lawrence M, Carter S, Sivachenko A, Jaffe D, Sougnez C . Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013; 31(3):213-9. PMC: 3833702. DOI: 10.1038/nbt.2514. View

15.

Ludgate J, Wright J, Stockwell P, Morison I, Eccles M, Chatterjee A . A streamlined method for analysing genome-wide DNA methylation patterns from low amounts of FFPE DNA. BMC Med Genomics. 2017; 10(1):54. PMC: 5580311. DOI: 10.1186/s12920-017-0290-1. View

16.

Wang J, Duan Y, Meng Q, Gong R, Guo C, Zhao Y . Integrated analysis of DNA methylation profiling and gene expression profiling identifies novel markers in lung cancer in Xuanwei, China. PLoS One. 2018; 13(10):e0203155. PMC: 6171826. DOI: 10.1371/journal.pone.0203155. View

17.

Adalsteinsson V, Ha G, Freeman S, Choudhury A, Stover D, Parsons H . Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat Commun. 2017; 8(1):1324. PMC: 5673918. DOI: 10.1038/s41467-017-00965-y. View

18.

Juo Y, Johnston F, Zhang D, Juo H, Wang H, Pappou E . Prognostic value of CpG island methylator phenotype among colorectal cancer patients: a systematic review and meta-analysis. Ann Oncol. 2014; 25(12):2314-2327. PMC: 4239805. DOI: 10.1093/annonc/mdu149. View

19.

Zhang X, Zhang W, Cao P . Advances in CpG Island Methylator Phenotype Colorectal Cancer Therapies. Front Oncol. 2021; 11:629390. PMC: 7952756. DOI: 10.3389/fonc.2021.629390. View

20.

Shinkins B, Nicholson B, Primrose J, Perera R, James T, Pugh S . The diagnostic accuracy of a single CEA blood test in detecting colorectal cancer recurrence: Results from the FACS trial. PLoS One. 2017; 12(3):e0171810. PMC: 5345794. DOI: 10.1371/journal.pone.0171810. View