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Received on ,
Accepted on ,
Technical Briefs |
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
* To whom correspondence should be addressed. E-mail: tshuber{at}molecularinstincts.com.
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 compare 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.
The following articles in journals at HighWire Press have cited this article:
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  D. A. Ahlquist, D. J. Sargent, C. L. Loprinzi, T. R. Levin, D. K. Rex, D. J. Ahnen, K. Knigge, M. P. Lance, L. J. Burgart, S. R. Hamilton, et al. Stool DNA and Occult Blood Testing for Screen Detection of Colorectal Neoplasia Ann Intern Med, October 7, 2008; 149(7): 441 - 450. [Abstract] [Full Text] [PDF]
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 K. Oda, J. Okada, L. Timmerman, P. Rodriguez-Viciana, D. Stokoe, K. Shoji, Y. Taketani, H. Kuramoto, Z. A. Knight, K. M. Shokat, et al. PIK3CA Cooperates with Other Phosphatidylinositol 3'-Kinase Pathway Mutations to Effect Oncogenic Transformation Cancer Res., October 1, 2008; 68(19): 8127 - 8136. [Abstract] [Full Text] [PDF]
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 Y. Ito, T. Koessler, A. E.K. Ibrahim, S. Rai, S. L. Vowler, S. Abu-Amero, A.-L. Silva, A.-T. Maia, J. E. Huddleston, S. Uribe-Lewis, et al. Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer Hum. Mol. Genet., September 1, 2008; 17(17): 2633 - 2643. [Abstract] [Full Text] [PDF]
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 H. Zou, J. J. Harrington, A. M. Shire, R. L. Rego, L. Wang, M. E. Campbell, A. L. Oberg, and D. A. Ahlquist Highly Methylated Genes in Colorectal Neoplasia: Implications for Screening Cancer Epidemiol. Biomarkers Prev., December 1, 2007; 16(12): 2686 - 2696. [Abstract] [Full Text] [PDF]
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