A Two-Gene Blood Test for Methylated DNA Sensitive for Colorectal Cancer

Pedersen, Susanne K.; Baker, Rohan T.; McEvoy, Aidan; Murray, David H.; Thomas, Melissa L.; Molloy, Peter L.; Mitchell, Susan M.; Lockett, Trevor; Young, Graeme P.; LaPointe, Lawrence C.

doi:10.1371/journal.pone.0125041

Cited by 63 publications

(48 citation statements)

References 40 publications

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“…In combining biomarkers to improve assay sensitivity, it is critical that individual markers have minimal false positive detection rates in normal subjects in order to maintain good specificity. In a 218-person case/control study of two of our prospective biomarkers, BCAT1 and IKZF1 , the combination of two markers provided greater sensitivity (77%) compared to the two individual assays (65% and 67%) but at the cost of a higher false positive rate (7.6%) compared to the individual markers (3.5% and 4.9%) [28]. This combination has now been evaluated in two prospective clinical trials including more than 3900 subjects [29,30] and showed an overall sensitivity and specificity of 66% and 94% respectively for detection of colorectal cancer [30].…”

Section: Discussionmentioning

confidence: 99%

“…Buffy coat WBC DNA was obtained from nine male and nine female healthy donors under the age of 30, using the PAXgene blood DNA kit (QIAGEN, Hilden, Germany). Plasma samples were obtained from colonoscopy-confirmed patients from either Flinders Medical Centre (Adelaide, Australia) or sourced through Proteogenex Inc. (Culver City, CA, USA) as previously described in [28,30]. Clinical diagnosis was determined on the basis of colonoscopic findings and histological assessment.…”

Section: Methodsmentioning

confidence: 99%

“…Cancers were staged according to American Joint Committee on Cancer (AJCC) Cancer staging 7th edition [31]. ccfDNA was isolated from 4 mL plasma using the QIAamp circulating nucleic acid kit (QIAGEN), and bisulphite-converted using an Epitect Fast bisulphite conversion kit (QIAGEN) as previously described [28]. …”

Section: Methodsmentioning

confidence: 99%

“…Here we describe an approach to identifying candidate biomarkers that are most promising for development of plasma assays, and evaluate them in pilot plasma samples from colorectal cancer cases and control subjects. Subsequently, two candidate biomarkers selected using this approach, IKZF1 and BCAT1 [28,29], have been evaluated for detection of ctDNA in larger patient cohorts.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Methylation Biomarkers for Detection of Circulating Tumor DNA and Application to Colorectal Cancer

Mitchell

Brown

et al. 2016

Genes

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Solid tumors shed DNA into circulation, and there is growing evidence that the detection of circulating tumor DNA (ctDNA) has broad clinical utility, including monitoring of disease, prognosis, response to chemotherapy and tracking tumor heterogeneity. The appearance of ctDNA in the circulating cell-free DNA (ccfDNA) isolated from plasma or serum is commonly detected by identifying tumor-specific features such as insertions, deletions, mutations and/or aberrant methylation. Methylation is a normal cell regulatory event, and since the majority of ccfDNA is derived from white blood cells (WBC), it is important that tumour-specific DNA methylation markers show rare to no methylation events in WBC DNA. We have used a novel approach for assessment of low levels of DNA methylation in WBC DNA. DNA methylation in 29 previously identified regions (residing in 17 genes) was analyzed in WBC DNA and eight differentially-methylated regions (DMRs) were taken through to testing in clinical samples using methylation specific PCR assays. DMRs residing in four genes, BCAT1, GRASP, IKZF1 and IRF4, exhibited low positivity, 3.5% to 7%, in the plasma of colonoscopy-confirmed healthy subjects, with the sensitivity for detection of ctDNA in colonoscopy-confirmed patients with colorectal cancer being 65%, 54.5%, 67.6% and 59% respectively.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of Methylation Biomarkers for Detection of Circulating Tumor DNA and Application to Colorectal Cancer

Mitchell

Brown

et al. 2016

Genes

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“…42 In 2016, this test was narrowly FDA-approved. In another example, Pedersen et al 43 showed that a combination of mBCAT1 and mIKZF1 detected CRC with a sensitivity 77% (higher than either alone) and a combined specificity of 92.4%. Because BCAT1 and IKZF1 genes are both involved in tumor growth and invasiveness, the degree of their hypermethylation and the frequency of their combined detection closely corresponded to CRC stages I-IV, at 50%, 68%, 87%, and 100%, respectively.…”

Section: Dna Markersmentioning

confidence: 99%

Biomarkers in Colorectal Cancer Screening

Nguyen

Weinberg

2016

J Natl Compr Canc Netw

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Colorectal cancer (CRC) is the third most common cause of cancer death in men and women in the United States. The main goals of screening are to prevent carcinogenesis (via adenoma detection and removal) and detect cancer at an early, curable stage. CRC mortality is steadily dropping in the United States, partly because of greater screening utilization. However, nearly 1 in 3 average-risk people are not up to date with standard CRC screening recommendations. This review surveys a wide range of CRC biomarkers in various stages of development, which may offer attractive risk stratification tools; a few have reached the commercial stage. If widely accepted, these tools may contribute to shift CRC screening practices away from 1-step colonoscopy to a 2-step risk stratification process of predictive biomarker measurements followed by colonoscopy for lower-risk patients with a positive result. Such strategies could potentially increase the rate of CRC screening. J Natl Compr Canc Netw 2016;14(8):1033-1040 NCCN: Continuing Education Accreditation StatementThis activity has been designed to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center`s Commission on Accreditation.NCCN designates the education activity for a maximum of 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/ displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/ node/79280; and 4) view/print certificate.Release date: August 10, 2016; Expiration date: August 10, 2017 Learning ObjectivesUpon completion of this activity, participants will be able to:• Describe advances in biomarker technology as risk stratification tools for CRC screening • Evaluate the efficacy, safety, convenience, and cost of stool, imaging, and endoscopy-based CRC screening methods

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A cross‐sectional study comparing a blood test for methylated BCAT1 and IKZF1 tumor‐derived DNA with CEA for detection of recurrent colorectal cancer

Young

Pedersen²,

Mansfield

et al. 2016

Cancer Medicine

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Recurrence will develop in 30–50% of colorectal cancer (CRC) cases despite apparent clearance following treatment. Carcinoembryonic antigen (CEA) is the only guideline‐recommended blood test for monitoring cases for recurrence, but its sensitivity and specificity are suboptimal. This observational study compared a novel 2‐gene (methylated BCAT1 and IKZF1 DNA) blood test with CEA for detection of recurrent CRC. We conducted a paired comparison of the BCAT1/IKZF1 test with CEA (cut‐off 5 ng/mL) in blood from patients in remission after treatment for primary CRC and undergoing surveillance. Blood collected in the 12 months prior to or 3 months after complete investigational assessment of recurrence status were assayed and the results compared by McNemar's test. Of 397 patients enrolled, 220 underwent satisfactory assessment for recurrence and 122 had blood testing performed within the prescribed period. In 28 cases with recurrent CRC, CEA was positive in 9 (32%; 95% CI 16–52%) compared to 19 (68%; 95% CI 48–84%) positive for methylated BCAT1/IKZF1 (P = 0.002). All samples that were CEA positive were also BCAT1/IKZF1 positive. In 94 patients without clinically detectable recurrence, CEA was positive in 6 (6%, 95% CI 2–13%) and BCAT1/IKZF1 in 12 (13%, 95% CI 7–21%), P = 0.210. The odds ratio of a positive CEA test for recurrence was 6.9 (95% CI 2–22) compared to 14.4 (5–39) for BCAT1/IKZF1. The BCAT1/IKZF1 test was more sensitive for recurrence than CEA and the odds of recurrence given a positive test was twice that of CEA. The BCAT1/IKZF1 test should be further considered for monitoring cases for recurrence.

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A Two-Gene Blood Test for Methylated DNA Sensitive for Colorectal Cancer

Cited by 63 publications

References 40 publications

Evaluation of Methylation Biomarkers for Detection of Circulating Tumor DNA and Application to Colorectal Cancer

Evaluation of Methylation Biomarkers for Detection of Circulating Tumor DNA and Application to Colorectal Cancer

Biomarkers in Colorectal Cancer Screening

A cross‐sectional study comparing a blood test for methylated BCAT1 and IKZF1 tumor‐derived DNA with CEA for detection of recurrent colorectal cancer

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