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Clinical Chemistry 52: 2299-2302, 2006. First published November 2, 2006; 10.1373/clinchem.2007.070896
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(Clinical Chemistry. 2006;52:2299-2302.)
© 2006 American Association for Clinical Chemistry, Inc.

Technical Briefs

Improved Marker Combination for Detection of De Novo Genetic Variation and Aberrant DNA in Colorectal Neoplasia

Lisa Kann1,1, James Han1, David Ahlquist2, Theodore Levin3, Douglas Rex4, Duncan Whitney1,1, Sanford Markowitz5 and Anthony Shuber1,a,1

1 EXACT Sciences Corporation, Marlborough, Massachusetts; 2 Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota;3 Division of Gastroenterology, Kaiser Permanente Medical Center, Walnut Creek, California;4 Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, Indiana;5 Howard Hughes Medical Institute, and Department of Medicine, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio

aaddress correspondence to this author at: Molecular Instincts, 6 Parker Rd., Mendon, MA 01756; fax 508-473-6832, e-mail tshuber{at}molecularinstincts.com


Abstract

Background: The genetic heterogeneity of sporadic colorectal cancer (CRC) makes the choice of genetic markers and sequence variation–detection technologies critical to the performance of screening assays. We have previously described the effectiveness of a CRC assay composed of 22 known variants in KRAS, APC, TP53, and BAT-26 (V1). We introduce a new marker formulation (V2) that includes detection of de novo variation in APC, PIK3CA, and CTNNB1, hypermethylated sequences within SMARCA3 and VIM, and a single-base variation within BRAF. We compared the abilities of the V1 and V2 markers to detect aberrant DNA in colorectal neoplasias.

Methods: V1 and V2 marker formulations were used to analyze 144 colorectal tissue samples comprising 50 precancerous adenomas, 94 carcinomas, and 11 nonpathologic tissues. V1 analysis consisted of single-base extension analysis of the 22 V1 variants. V2 analysis consisted of DNA scanning of the APC mutation cluster region, PIK3CA exons 9 and 20, CTNNB1 exon 3, analysis for the BRAF Val600Glu substitution, and methylation-specific PCR analysis of VIM and SMARCA3.

Results: The V2 marker formulation had significantly higher sensitivity than the V1 markers for carcinomas (93.6% and 72.3%, respectively; P = 0.0002) and adenomas (92.0% and 62.0%, respectively; P = 0.0006). None of the nonpathologic samples were positive for any marker.

Conclusions: We demonstrate improved sensitivity of a new marker formulation (V2) to detect aberrant DNA in CRC and precancerous adenoma tumor tissues.




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