Researchers at Vanderbilt University Medical Center and the University of Calgary have established an analytical framework that integrates genomic, proteomic and electronic health record data to identify cancer risk proteins and therapeutics for cancer prevention.

Their study, reported Dec. 2 in the American Journal of Human Genetics, identifies previously unreported protein biomarkers and candidate drug targets across six major cancer types and highlights approved drugs with potential cancer preventive effects.

To date, genome-wide association studies (GWAS) have identified several hundred genetic variants associated with increased risk for breast, colorectal and prostate cancer, and several dozen risk variants for other cancers, including lung, pancreatic and ovarian cancer.

“Previous research, including our work, has identified hundreds of putative cancer susceptibility genes that could be regulated by these risk variants; however, most dysregulated gene expression has not been thoroughly investigated at the protein level,” said Xingyi Guo, PhD, associated professor of Medicine in the Division of Epidemiology at VUMC.

Guo is a co-senior author of the current study with Zhijun Yin, PhD, MS, associate professor of Biomedical Informatics at VUMC, and Quan Long, PhD, associate professor of Biochemistry and Molecular Biology at the University of Calgary.

“To deepen the understanding of causal mechanisms and enhance drug discovery efforts, it is imperative to explore data from transcriptomic to proteomic studies,” Yin said.

In the current study, the investigators integrated large GWAS data for breast, colorectal, lung, ovarian, pancreatic and prostate cancers and population-scale proteomics data from over 75,000 participants (combined from the Atherosclerosis Risk in Communities study, deCODE genetics, and UK Biobank Pharma Proteomics Project) to identify risk proteins associated with each cancer.

They identified 365 proteins associated with cancer risk, and through further analysis narrowed the list to 101 proteins, including 74 not reported in previous studies. Using a variety of pharmaceutical databases, the researchers comprehensively annotated the risk proteins as therapeutic targets of approved drugs or drugs in clinical testing. The idea, they said, is to find drugs that can potentially be repurposed for cancer prevention.

“Traditional drug discovery faces challenges of escalating costs, lengthy timelines, and high failure rates. Drug repurposing is a promising strategy to identify new applications for existing drugs with well-documented characteristics,” Guo said.

Among the 101 risk proteins, the researchers identified 36 druggable proteins potentially targeted by 404 drugs already approved or in clinical trials. Nineteen of the druggable proteins were targeted by drugs approved or in trials to treat cancer. The researchers compared drug effects using data from more than 3.5 million electronic health records (EHRs) from VUMC. They demonstrated in simulated trials with EHR data that several approved drugs, for example the diuretic medication acetazolamide, were associated with reduced colorectal cancer risk.

“Our findings offer additional insights into therapeutic drugs targeting risk proteins for cancer prevention and intervention. It is essential to evaluate the effects of the reported candidate drugs through both in vitro and in vivo assays in future research,” Yin said.

Co-first authors of the AJHG paper are Qing Li,PhD; Qingyuan Song; and Zhishan Chen, PhD. The research was supported by the National Institutes of Health (grants R37CA227130, R01CA269589, R01CA297582).

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A multidisciplinary team led by investigators at Vanderbilt University Medical Center has received a $4.2 million grant from the National Cancer Institute (NCI) to probe the genetics of colorectal adenomas — polyps that can develop into colon cancer — and to identify drug candidates that could reduce adenoma recurrence. 

Colorectal cancer is the second most common cause of cancer-related death in the United States, according to the NCI, part of the National Institutes of Health. Removing precancerous polyps during colonoscopy procedures significantly reduces the burden of colorectal cancer, but about 30% of patients who have a colorectal adenoma removed will develop recurrent adenomas. 

“Patients who have recurrent adenomas are at higher risk for developing cancer,” said Xingyi Guo, PhD, associate professor of Medicine in the Division of Epidemiology and lead principal investigator for the project. “We will integrate cutting-edge genomic research with real-world patient data from electronic health records, with the goal of translating genetic discoveries into actionable strategies to prevent colorectal cancer.” 

Zhijun Yin, PhD, MS, associate professor of Biomedical Informatics, is co-principal investigator for the four-year project. 

The team previously conducted genome-wide association studies (GWAS) of about 8,000 colorectal adenoma cases from European American and African American participants included in BioVU, VUMC’s de-identified DNA biobank and linked electronic health records. Using a large-scale analysis of electronic health records and pathology reports, the investigators also established the Vanderbilt Colonoscopy Cohort of colorectal adenoma cases after polyp removal, which includes 76,664 cases. 

With the new funding support, the team will extend its efforts to establish the largest-ever genetic study of colorectal adenoma, drawing on BioVU, the Mass General Brigham Biobank, and the NIH All of Us Research Program to include over 25,000 cases in European Americans and 6,500 cases in African Americans, with thousands of recurrences. African Americans are about 20% more likely to have colorectal cancer and about 40% more likely to die from it compared to other racial groups, according to the American Cancer Society. 

“Our approach will allow us to examine racial differences in adenoma recurrence and colorectal cancer risk,” Guo said. 

In addition to GWAS, the team will conduct transcriptome-wide, methylome-wide, and proteome-wide association studies to identify genes and proteins associated with colorectal adenomas and their recurrence. The investigators will integrate findings from these “omics” studies with electronic health record data from the Vanderbilt Colonoscopy Cohort and the Mass General Brigham Colonoscopy Cohort and use machine learning frameworks to identify candidate drugs that could prevent colorectal adenoma recurrence. They will test the most promising drug candidates in colorectal adenoma and cancer cells, patient-derived organoids, and animal models. 

“This project is an innovative integration of multiomics analyses with electronic health record-based real-world clinical evidence,” Yin said. “We anticipate that our findings will inform personalized colorectal polyp surveillance, guide therapeutic prevention strategies, and ultimately reduce the burden of colorectal cancer nationwide.” 

Guo holds a secondary appointment in the Department of Biomedical Informatics at VUMC, and Yin holds secondary appointments in the Department of Computer Science and the Department of Electrical and Computer Engineering at Vanderbilt University. Guo and Yin have both received NCI R37 MERIT Awards, which provide long-term grant support to outstanding investigators. 

Other collaborators for the new NCI grant (R01CA297582) include VUMC Department of Medicine investigators Wei Zheng, MD, PhD, MPH, Qiuyin Cai, MD, PhD, and Wanqing Wen, MD, MPH, Division of Epidemiology; Bhuminder Singh, PhD, Division of Gastroenterology, Hepatology and Nutrition; and Kristen Ciombor, MD, MSCI, Division of Hematology and Oncology; and Harvard T.H. Chan School of Public Health investigator Mingyang Song, ScD, Departments of Epidemiology and Nutrition.

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