Noninvasive stool test for colorectal cancer unaffected by variables

Public release date: 3-Apr-2012
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Contact: Jeremy Moore
Jeremy.Moore@aacr.org
215-446-7109
American Association for Cancer Research

Noninvasive stool test for colorectal cancer unaffected by medications, lifestyle factors and other variables

CHICAGO Research on an investigational DNA methylation test for colorectal cancer demonstrated that the only clinical variable that influenced test results was age, according to results presented at the AACR Annual Meeting 2012, held here March 31 - April 4.

"There was a progressive increase in background methylation levels that varied widely between methylation markers tested as a patient aged," said David Ahlquist, M.D., professor of medicine and a consultant in gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. "For example, median background methylation levels of the TFPI2 gene increased 49 percent in patients from age 50 to age 80, whereas levels for the BMP3 gene increased by only 0.2 percent across this age range."

His group at the Mayo Clinic, in collaboration with Exact Sciences, developed the multimarker molecular stool test, which is highly sensitive to the critical cancer screening targets of early-stage cancers and precancerous adenomas, he said.

"This test, if broadly applied, should have a very important impact on reducing both the mortality and incidence of colorectal cancer," Ahlquist said.

The researchers examined common patient variables, including age, sex, race, alcohol consumption, tobacco use, body mass and medication use in 500 patients undergoing screening colonoscopy or polyp follow-up. Patients had a normal colonoscopy in the last three years.

With the exception of age, none of the variables influenced test results, nor did family history of colorectal cancer or polyps or personal history of polyps. These results mean that "patients don't have to change their lifestyle to have this test," Ahlquist said. "That was important from a patient-friendly standpoint for a test like this and could benefit compliance."

Researchers have selected the two markers least affected by age for further test development and validation based on these study results.

"If we can minimize the false positives, that will reduce the cost of the whole screening program by avoiding unnecessary colonoscopies," Ahlquist said.

The screening test is currently undergoing FDA validation in a multicenter study in the United States and Canada, which is expected to be completed in the fall. The Mayo Clinic and Ahlquist have a financial interest in the technology referenced in this announcement.

###

Press registration for the AACR Annual Meeting 2012 is free to qualified journalists and public information officers: http://www.aacr.org/PressRegistration.

Follow the AACR on Twitter: @aacr #aacr

Follow the AACR on Facebook: http://www.facebook.com/aacr.org

About the AACR

Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR's membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of individual and team science grants in cancer research that have the potential for patient benefit. The AACR actively communicates with legislators and policy makers about the value of cancer research and related biomedical science in saving lives from cancer.

For more information about the AACR, visit http://www.AACR.org.

Presenter: David Ahlquist, M.D.

Abstract Number: 3572

Title: Methylated gene marker levels in stool: effects of demographic, drug, and body mass and other patient characteristics

Author Block: David A. Ahlquist1, William R. Taylor1, Tracy C. Yab1, Mary E. Devens1, Douglas W. Mahoney1, Lisa A. Boardman1, Steven N. Thibodeau1, Hongzhi Zou2, Domanico Michael2, Barry M. Berger2, Graham P. Lidgard2. 1Mayo Clinic, Rochester, MN; 2EXACT Sciences, Madison, WI

Abstract: Aberrantly methylated genes represent attractive and broadly informative markers for colorectal cancer (CRC). As demographics, numerous ingestants, environmental exposures, and obesity variably influence both gene methylation rates and CRC incidence, it is important to understand the effects of such covariates on the clinical performance of CRC screening tests that incorporate assay of methylated gene markers. Based on a recent multicenter study (Ahlquist et al. Gastroenterology 2012 (in press)), stool assay of carefully selected methylated gene marker candidates (NDRG4, BMP3, vimentin, TFPI2), alone or in combination, yield high detection rates of both CRC and large adenomas.

Aim: To assess the impact of demographic, exposure, body mass, and other patient variables on stool levels of the above 4 methylated gene markers.

Methods: We studied buffered stools collected within 3 years of a normal colonoscopy from 500 patients undergoing average-risk screening or polyp surveillance (median age 64 (range 44-85); 53% women). Upon receipt, stools were promptly homogenized, aliquoted, and frozen at -80C. On supernatants from thawed/spun aliquots, target genes were purified by hybrid capture, bisulfite treated, and assayed using the analytically-sensitive QuARTS method (quantitative allele-specific real-time target and signal amplification), as described (above citation). The reference gene ?-actin was assayed along with methylation of NDRG4, BMP3, vimentin, TFPI2. Log-converted data were normalized to allow comparison of effects between markers, and effect size was expressed as % change relative to standard deviation for each marker (standardized relative change (SR?)).

Results: The only patient characteristic that significantly influenced all methylated marker levels in stool was age (pConclusions: Age significantly affects stool levels of tumor-associated methylated gene markers in colonoscopy-normal patients, and the degree of this age effect differs across markers. In contrast, other key patient variables had no effect on stool marker levels.

Comment: Optimal use of these methylation markers for stool screening of CRC may require age-adjustment of normal cutoff levels to maximize test specificity.

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Public release date: 3-Apr-2012
[ | E-mail | Share ]

Contact: Jeremy Moore
Jeremy.Moore@aacr.org
215-446-7109
American Association for Cancer Research

Noninvasive stool test for colorectal cancer unaffected by medications, lifestyle factors and other variables

CHICAGO Research on an investigational DNA methylation test for colorectal cancer demonstrated that the only clinical variable that influenced test results was age, according to results presented at the AACR Annual Meeting 2012, held here March 31 - April 4.

"There was a progressive increase in background methylation levels that varied widely between methylation markers tested as a patient aged," said David Ahlquist, M.D., professor of medicine and a consultant in gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. "For example, median background methylation levels of the TFPI2 gene increased 49 percent in patients from age 50 to age 80, whereas levels for the BMP3 gene increased by only 0.2 percent across this age range."

His group at the Mayo Clinic, in collaboration with Exact Sciences, developed the multimarker molecular stool test, which is highly sensitive to the critical cancer screening targets of early-stage cancers and precancerous adenomas, he said.

"This test, if broadly applied, should have a very important impact on reducing both the mortality and incidence of colorectal cancer," Ahlquist said.

The researchers examined common patient variables, including age, sex, race, alcohol consumption, tobacco use, body mass and medication use in 500 patients undergoing screening colonoscopy or polyp follow-up. Patients had a normal colonoscopy in the last three years.

With the exception of age, none of the variables influenced test results, nor did family history of colorectal cancer or polyps or personal history of polyps. These results mean that "patients don't have to change their lifestyle to have this test," Ahlquist said. "That was important from a patient-friendly standpoint for a test like this and could benefit compliance."

Researchers have selected the two markers least affected by age for further test development and validation based on these study results.

"If we can minimize the false positives, that will reduce the cost of the whole screening program by avoiding unnecessary colonoscopies," Ahlquist said.

The screening test is currently undergoing FDA validation in a multicenter study in the United States and Canada, which is expected to be completed in the fall. The Mayo Clinic and Ahlquist have a financial interest in the technology referenced in this announcement.

###

Press registration for the AACR Annual Meeting 2012 is free to qualified journalists and public information officers: http://www.aacr.org/PressRegistration.

Follow the AACR on Twitter: @aacr #aacr

Follow the AACR on Facebook: http://www.facebook.com/aacr.org

About the AACR

Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR's membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of individual and team science grants in cancer research that have the potential for patient benefit. The AACR actively communicates with legislators and policy makers about the value of cancer research and related biomedical science in saving lives from cancer.

For more information about the AACR, visit http://www.AACR.org.

Presenter: David Ahlquist, M.D.

Abstract Number: 3572

Title: Methylated gene marker levels in stool: effects of demographic, drug, and body mass and other patient characteristics

Author Block: David A. Ahlquist1, William R. Taylor1, Tracy C. Yab1, Mary E. Devens1, Douglas W. Mahoney1, Lisa A. Boardman1, Steven N. Thibodeau1, Hongzhi Zou2, Domanico Michael2, Barry M. Berger2, Graham P. Lidgard2. 1Mayo Clinic, Rochester, MN; 2EXACT Sciences, Madison, WI

Abstract: Aberrantly methylated genes represent attractive and broadly informative markers for colorectal cancer (CRC). As demographics, numerous ingestants, environmental exposures, and obesity variably influence both gene methylation rates and CRC incidence, it is important to understand the effects of such covariates on the clinical performance of CRC screening tests that incorporate assay of methylated gene markers. Based on a recent multicenter study (Ahlquist et al. Gastroenterology 2012 (in press)), stool assay of carefully selected methylated gene marker candidates (NDRG4, BMP3, vimentin, TFPI2), alone or in combination, yield high detection rates of both CRC and large adenomas.

Aim: To assess the impact of demographic, exposure, body mass, and other patient variables on stool levels of the above 4 methylated gene markers.

Methods: We studied buffered stools collected within 3 years of a normal colonoscopy from 500 patients undergoing average-risk screening or polyp surveillance (median age 64 (range 44-85); 53% women). Upon receipt, stools were promptly homogenized, aliquoted, and frozen at -80C. On supernatants from thawed/spun aliquots, target genes were purified by hybrid capture, bisulfite treated, and assayed using the analytically-sensitive QuARTS method (quantitative allele-specific real-time target and signal amplification), as described (above citation). The reference gene ?-actin was assayed along with methylation of NDRG4, BMP3, vimentin, TFPI2. Log-converted data were normalized to allow comparison of effects between markers, and effect size was expressed as % change relative to standard deviation for each marker (standardized relative change (SR?)).

Results: The only patient characteristic that significantly influenced all methylated marker levels in stool was age (pConclusions: Age significantly affects stool levels of tumor-associated methylated gene markers in colonoscopy-normal patients, and the degree of this age effect differs across markers. In contrast, other key patient variables had no effect on stool marker levels.

Comment: Optimal use of these methylation markers for stool screening of CRC may require age-adjustment of normal cutoff levels to maximize test specificity.

---

[ | E-mail | Share ]

?

AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

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