Evaluation of an assay for methylated BCAT1 and IKZF1 in plasma for detection of colorectal neoplasiaReportar como inadecuado




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BMC Cancer

, 15:654

First Online: 06 October 2015Received: 01 March 2015Accepted: 01 October 2015DOI: 10.1186-s12885-015-1674-2

Cite this article as: Pedersen, S.K., Symonds, E.L., Baker, R.T. et al. BMC Cancer 2015 15: 654. doi:10.1186-s12885-015-1674-2

Abstract

BackgroundSpecific genes, such as BCAT1 and IKZF1, are methylated with high frequency in colorectal cancer CRC tissue compared to normal colon tissue specimens. Such DNA may leak into blood and be present as cell-free circulating DNA. We have evaluated the accuracy of a novel blood test for these two markers across the spectrum of benign and neoplastic conditions encountered in the colon and rectum.

MethodsCirculating DNA was extracted from plasma obtained from volunteers scheduled for colonoscopy for any reason, or for colonic surgery, at Australian and Dutch hospitals. The extracted DNA was bisulphite converted and analysed by methylation specific real-time quantitative PCR qPCR. A specimen was deemed positive if one or more qPCR replicates were positive for either methylated BCAT1 or IKZF1 DNA. Sensitivity and specificity for CRC were estimated as the primary outcome measures.

ResultsPlasma samples were collected from 2105 enrolled volunteers mean age 62 years, 54 % male, including 26 additional samples taken after surgical removal of cancers. The two-marker blood test was run successfully on 2127 samples. The test identified 85 of 129 CRC cases sensitivity of 66 %, 95 % CI: 57–74. For CRC stages I-IV, respective positivity rates were 38 % 95 % CI: 21–58, 69 % 95 % CI: 53–82, 73 % 95 % CI: 56–85 and 94 % 95 % CI: 70–100. A positive trend was observed between positivity rate and degree of invasiveness. The colonic location of cancer did not influence assay positivity rates. Gender, age, smoking and family history were not significant predictors of marker positivity. Twelve methylation-positive cancer cases with paired pre- and post-surgery plasma showed reduction in methylation signal after surgery, with complete disappearance of signal in 10 subjects. Sensitivity for advanced adenoma n = 338 was 6 % 95 % CI: 4–9. Specificity was 94 % 95 % CI: 92–95 in all 838 non-neoplastic pathology cases and 95 % 95 % CI: 92–97 in those with no colonic pathology detected n = 450.

ConclusionsThe sensitivity for cancer of this two-marker blood test justifies prospective evaluation in a true screening population relative to a proven screening test. Given the high rate of marker disappearance after cancer resection, this blood test might also be useful to monitor tumour recurrence.

Trial registrationACTRN12611000318987.

KeywordsDNA methylation Screening Colorectal cancer BCAT1 IKZF1 AbbreviationsCRCColorectal cancer

BCAT1Branched chain amino-acid transaminase 1

IKZF1IKAROS family zinc finger 1

qPCRquantitative PCR

PCRPolymerase chain reaction

HGDHigh-grade dysplasia

LGDLow-grade dysplasia

TVATubulovillous adenoma

TATubular adenoma

IBDInflammatory bowel disease

RCTRandomised controlled trial

FOBTFaecal occult blood test

FITFaecal immunochemical test

CtCycle threshold

Susanne K. Pedersen and Erin L. Symonds contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s12885-015-1674-2 contains supplementary material, which is available to authorized users.

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Autor: Susanne K. Pedersen - Erin L. Symonds - Rohan T. Baker - David H. Murray - Aidan McEvoy - Sascha C. Van Doorn - Marco 

Fuente: https://link.springer.com/







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