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Aug 2014

Shared Resource Spotlight: Gene Expression + Genotyping Core Facility

Marty Veigl, PhDWhen a team of researchers at the Case Comprehensive Cancer Center wanted to study the link between genetic variants and the risk of developing colon cancer, they relied on the expertise of the Gene Expression + Genotyping Facility (GEGF) and its director, Marty Veigl, PhD, Associate Professor of General Medical Sciences (Oncology).

Recent studies identified 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) as a novel colon cancer suppressor, which means that loss of the gene function could result in an increased risk of colon cancer. A team of researchers led by Li Li, MD, PhD, Associate Director for Prevention Research at the Case CCC and Professor of Family Medicine at the CWRU SOM, hoped to build upon these findings to determine whether 15-PGDH is a colon cancer susceptibility gene, and if it plays a role in colon cancer carcinogenesis in the general population.

Researchers Dr. Li and Sandy Markowitz, MD, PhD, Co-Leader of the Case CCC Cancer Genetics Program and Markowitz-Ingalls Professor of Cancer Genetics at the CWRU SOM, partnered with the GEGF to design a three-stage study where they identified a genetic variant, then tested it in a validation population. In this study, the GEGF played a critical scientific role in designing the genetic study, identifying single nucleotide polymorphisms, and completing all of the genetic analyses. Specifically, the GEGF performed TaqMan assays to genotype PGDH for 102 SNPs in colon cancer cases and controls.

Steve Fink, PhD, Instructor in the Division of Hematology/Oncology at the CWRU SOM, working with Dr. Markowitz, assessed changes in expression of the PGDH gene in a subset of the colon cancer patients that were genotyped by the GEGF. Review of the genotyping data by Cheryl Thompson, PhD, Assistant Professor in the CWRU SOM Department of Family Medicine, and Robert Elston, PhD, Professor of Epidemiology & Biostatistics at CWRU, identified an allele associated with increased risk of colon cancer. This data further suggested that carriers of this risk allele exhibit decreased expression of 15-PGDH in the colon.

In addition to the important findings of this study, two additional projects stemmed from this research. Dr. Li used these findings as preliminary data to obtain a four-year U01 from the National Cancer Institute to search for more biomarkers, and to determine whether additional genetic polymorphisms in the 15-PGDH pathway are linked to susceptibility to early colon neoplasia. Dr. Veigl and the GEGF staff will again lead the genotyping and the expression analyses for this project.

Study co-authors Drs. Markowitz and Fink have also extended this observation and partnered with researchers at Harvard University to examine material from two long-term studies involving nearly 128,000 participants. This work discovered that aspirin can reduce colorectal cancer risks for those with high levels of 15-PGDH. The findings were reported in a high profile publication and received a great deal of media attention.

Citation: Thompson CL, Fink SP, Lutterbaugh JD, Elston RC, Veigl ML, Markowitz, SD and Li L. (2013) Genetic Variation in 15-Hydroxyprostaglandin Dehydrogenase and Colon Cancer Susceptibility. PLoS ONE 8(5): e64122.doi:10.1371/journal.pone.0064122.