Theodore R Levin1, Douglas A Corley2, Christopher D Jensen3, Amy R Marks2, Wei K Zhao2, Alexis M Zebrowski4, Virginia P Quinn5, Lawrence W Browne2, William R Taylor6, David A Ahlquist6, Graham P Lidgard7, Barry M Berger8. 1. Division of Research, Kaiser Permanente Walnut Creek Medical Center, Kaiser Permanente Northern California, 1425 South Main Street, Walnut Creek, CA, 94596, USA. 2. Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA. 3. Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA. christopher.d.jensen@kp.org. 4. Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Blockley Hall, 1st Floor, 423 Guardian Drive, Philadelphia, PA, 19104, USA. 5. Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA. 6. Gastroenterology Mayo Clinic, Mayo Building, 200 First St. NW, 19th Floor, Rochester, MN, 55905, USA. 7. Research and Development, Exact Sciences Corporation, 441 Charmany Dr., Madison, WI, 53719, USA. 8. Medical Affairs, Exact Sciences Corporation, 441 Charmany Dr., Madison, WI, 53719, USA.
Abstract
BACKGROUND: Fecal immunochemical test (FIT) screening detects most asymptomatic colorectal cancers. Combining FIT screening with stool-based genetic biomarkers increases sensitivity for cancer, but whether DNA biomarkers (biomarkers) differ for cancers detected versus missed by FIT screening has not been evaluated in a community-based population. AIMS: To evaluate tissue biomarkers among Kaiser Permanente Northern California patients diagnosed with colorectal cancer within 2 years after FIT screening. METHODS: FIT-negative and FIT-positive colorectal cancer patients 50-77 years of age were matched on age, sex, and cancer stage. Adequate DNA was isolated from paraffin-embedded specimens in 210 FIT-negative and 211 FIT-positive patients. Quantitative allele-specific real-time target and signal amplification assays were performed for 7 K-ras mutations and 10 aberrantly methylated DNA biomarkers (NDRG4, BMP3, SFMBT2_895, SFMBT2_896, SFMBT2_897, CHST2_7890, PDGFD, VAV3, DTX1, CHST2_7889). RESULTS: One or more biomarkers were found in 414 of 421 CRCs (98.3%). Biomarker expression was not associated with FIT status, with the exception of higher SFMBT2_897 expression in FIT-negative (194 of 210; 92.4%) than in FIT-positive cancers (180 of 211; 85.3%; p = 0.02). There were no consistent differences in biomarker expression by FIT status within age, sex, stage, and cancer location subgroups. CONCLUSIONS: The biomarkers of a currently in-use multi-target stool DNA test (K-ras, NDRG4, and BMP3) and eight newly characterized methylated biomarkers were commonly expressed in tumor tissue specimens, independent of FIT result. Additional study using stool-based testing with these new biomarkers will allow assessment of sensitivity, specificity, and clinical utility.
BACKGROUND: Fecal immunochemical test (FIT) screening detects most asymptomatic colorectal cancers. Combining FIT screening with stool-based genetic biomarkers increases sensitivity for cancer, but whether DNA biomarkers (biomarkers) differ for cancers detected versus missed by FIT screening has not been evaluated in a community-based population. AIMS: To evaluate tissue biomarkers among Kaiser Permanente Northern Californiapatients diagnosed with colorectal cancer within 2 years after FIT screening. METHODS: FIT-negative and FIT-positive colorectal cancerpatients 50-77 years of age were matched on age, sex, and cancer stage. Adequate DNA was isolated from paraffin-embedded specimens in 210 FIT-negative and 211 FIT-positive patients. Quantitative allele-specific real-time target and signal amplification assays were performed for 7 K-ras mutations and 10 aberrantly methylated DNA biomarkers (NDRG4, BMP3, SFMBT2_895, SFMBT2_896, SFMBT2_897, CHST2_7890, PDGFD, VAV3, DTX1, CHST2_7889). RESULTS: One or more biomarkers were found in 414 of 421 CRCs (98.3%). Biomarker expression was not associated with FIT status, with the exception of higher SFMBT2_897 expression in FIT-negative (194 of 210; 92.4%) than in FIT-positive cancers (180 of 211; 85.3%; p = 0.02). There were no consistent differences in biomarker expression by FIT status within age, sex, stage, and cancer location subgroups. CONCLUSIONS: The biomarkers of a currently in-use multi-target stool DNA test (K-ras, NDRG4, and BMP3) and eight newly characterized methylated biomarkers were commonly expressed in tumor tissue specimens, independent of FIT result. Additional study using stool-based testing with these new biomarkers will allow assessment of sensitivity, specificity, and clinical utility.
Entities:
Keywords:
Colorectal neoplasms/diagnosis; DNA mutational analysis; DNA neoplasm/analysis; Early detection of cancer/methods
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