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Principal Investigator: John Kisiel
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2024
Award: $383,325
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT:
Gastrointestinal (GI) malignancies lead cancer deaths worldwide, killing ~3 million annually. In the U.S., only
colorectal cancers (CRC) are screened. Other GI cancers are not screened due to lack of accurate tests or because
prevalence is deemed too low for cost-effective screening. Consequently, most patients with GI cancers present at
late-stage and cure rates remain abysmally low. Effective early detection is desperately needed to improve
outcomes. Our group was central in development and validation of the FDA-approved multi- target stool DNA test
for CRC screening. We have begun to expand this approach, showing feasibility to detect supra-colonic GI cancers
by stool DNA testing. However, it is critical for a non-invasive molecular test to localize the site of a primary cancer
(“site-prediction”). Key preliminary data suggest that this may now be possible. First, we have completed
rigorous next-generation sequencing to identify differentially methylated regions (DMRs) which appear highly
discriminant for universal and site-specific detection of GI cancers. Second, we prioritized these DMRs by strict
filtering criteria and performed a confirmatory study with statistical cross-validation on an independent set of CRC,
gastroesophageal and pancreatico-biliary cancer, and normal control tissues. This showed that a panel of 8
selected DMRs could distinguish cancer from normal (95% accuracy) and assign organ site (94-95% accuracy for
each category) with overall site-prediction accuracy of 88%. Third, these findings have been confirmed with novel
DMRs assayed from stool specimens obtained from CRC and pancreatic cancer patients and normal controls (30,
each). Using a 2-stage analysis, cancers were distinguished from controls at 90% specificity in the first stage. At
stage 2, the markers accurately classified CRCs from pancreatic cancers with 90% accuracy. It is now our central
hypothesis that luminal and ductal adenocarcinomas can be detected and localized by stool assay of universal and
site-specific DMRs. This raises 3 key questions: 1) will stool assay of our novel DMRs show the high overall
cancer sensitivity and the site-prediction we have seen in preliminary data; 2) will the DMRs be specific for
cancer across a wide patient demographic spectrum and in the setting of non-malignant GI diseases; and 3) can
sensitivity and specificity be improved by novel assay technology? These will be addressed in the following
parallel, integrated, but independent specific aims: 1) Assess panel sensitivity and site-prediction accuracy in
stool specimens for adenocarcinoma at esophageal, pancreatic and colorectal sites; 2) Confirm and
evaluate DMR specificity in stool; and 3) Optimize novel assay conditions and marker selection for cancer
detection and site-prediction at esophageal, pancreatic and colorectal sites. With our team’s strong track
record, extensive stool archive, and unique access to a state-of-the art assay platform, we expect to demonstrate
in a cost-efficient manner the feasibility of a novel DMR panel for the detection and site prediction of specific GI
adenocarcinomas. Results will inform designs of future studies ranging from large- scale case-control studies
(phase 2) on early-stage cancer and pre-cursors to pivotal cohort validation (phase 4) of a non-invasive multi-GI
cancer screening test. The potential impacts on cancer control are far-reaching.
Terms: <Address><Adenocarcinoma><Alimentary Canal><Alleles><Allelomorphs><Anatomic Sites><Anatomic structures><Anatomy><Archives><Assay><BMI><BMI percentile><BMI z-score><Barrett Esophagus><Barrett Syndrome><Barrett Ulcer><Bioassay><Biological Assay><Biological Markers><Body System><Body Tissues><Body mass index><Buffers><CRC screening><Cancer Control><Cancer Control Science><Cancer Detection><Cancers><Case-Base Studies><Case-Comparison Studies><Case-Compeer Studies><Case-Referent Studies><Case-Referrent Studies><Case/Control Studies><Categories><Cell Communication and Signaling><Cell Signaling><Cessation of life><Classification><Clinical Evaluation><Clinical Testing><Colon><Colon or Rectum><Colonoscopy><Colorectal><Colorectal Cancer><Columnar Epithelial-Lined Lower Esophagus><Columnar-Lined Esophagus><Confidence Intervals><DNA><DNA Methylation><Data><Death><Deoxyribonucleic Acid><Detection><Development><Diagnostic><Digestive Tract><Duct><Duct (organ) structure><Early Diagnosis><Esophagus><Evaluation><FDA approved><Feces><Future><GI Tract><GI cancers><GI malignancies><GI tract cancers><Gastrointestinal Cancer><Gastrointestinal Diseases><Gastrointestinal Tract><Gastrointestinal Tract Cancer><Gastrointestinal tract structure><History><Incidence><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Intracellular Communication and Signaling><Knowledge><Laboratories><Lead><Life><Literature><Long-term Follow-up><Longterm Follow-up><Malignant Adenoma><Malignant Gastrointestinal Neoplasm><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of gastrointestinal tract><Malignant neoplasm of pancreas><Measurement><Measures><Methylation><Mission><Modeling><Modification><Molecular><NGS Method><NGS system><NIH><NSAIDs><National Institutes of Health><Non-Malignant><Non-Steroidal Anti-Inflammatory Agents><Organ><Organ System><Pancreas><Pancreas Cancer><Pancreatic><Pancreatic Cancer><Patients><Pb element><Phase><Positive Test Result><Prevalence><Quetelet index><Race><Races><Recording of previous events><Reproducibility><Sampling><Screening for cancer><Sensitivity and Specificity><Signal Transduction><Signal Transduction Systems><Signaling><Site><Specificity><Systematics><Technology><Testing><Time><Tissues><Tobacco><Training><United States National Institutes of Health><Validation><age associated effects><age effect><age related effects><aging effect><alcohol exposed><alcohol exposure><alimentary tract><bio-markers><biologic marker><biological signal transduction><biomarker><burden of disease><burden of illness><cancer location><cancer site><case-controlled studies><chronic pancreatitis><clinical test><cohort><colon cancer patients><colorectal cancer detection><colorectal cancer early detection><colorectal cancer patients><colorectal cancer screening><colorectum><cost effective><cost efficient><design><designing><detect colorectal cancer><developmental><digestive canal><disease burden><disease control><disorder control><early cancer detection><early detection><esophageal intestinal metaplasia><ethanol exposed><ethanol exposure><exposed to alcohol><exposed to ethanol><exposure to alcohol><exposure to ethanol><fecal sample><gastrointestinal><gastrointestinal disorder><gastrointestinal malignancies><heavy metal Pb><heavy metal lead><histories><impact of age><improved><improved outcome><inflammatory disease of the intestine><inflammatory disorder of the intestine><influence of age><intestinal autoinflammation><long-term followup><longterm followup><malignancy><molecular sequence database><neoplasm/cancer><next gen sequencing><next generation sequencing><nextgen sequencing><non-steroidal anti-inflammatory drugs><nonmalignant><novel><pancreatic cancer patients><pancreatic malignancy><patients with pancreatic cancer><performance tests><preservation><public health relevance><racial><racial background><racial origin><recurrent pancreatitis><research clinical testing><screening><screening cancer patients><screenings><sequence database><sequencing database><sex><stool><stool sample><stool specimen><upper GI cancer><upper gastrointestinal cancer><validation studies><validations>