Pairs of related bladder cancer cases who belong to pedigrees with an excess of bladder cancer were sequenced to identify rare, shared variants as candidate predisposition variants. Candidate variants were tested for association with bladder cancer risk. A validated variant was assayed for segregation to other related cancer cases, and the predicted protein structure of this variant was analyzed. This study of affected bladder cancer relative pairs from high-risk pedigrees identified 152 bladder cancer predisposition candidate variants. One variant in ERF (ETS Repressing Factor) was significantly associated with bladder cancer risk in an independent population, was observed to segregate with bladder and prostate cancer in relatives, and showed evidence for altering the function of the associated protein. This finding of a rare variant in ERF that is strongly associated with bladder and prostate cancer risk in an extended pedigree both validates ERF as a cancer predisposition gene and shows the continuing value of analyzing affected members of high-risk pedigrees to identify and validate rare cancer predisposition variants.
Cancers. 2021 May 15*** epublish ***
Lisa Anne Cannon-Albright, Craig Carl Teerlink, Jeff Stevens, Franklin W Huang, Csilla Sipeky, Johanna Schleutker, Rolando Hernandez, Julio Facelli, Neeraj Agarwal, Donald L Trump
Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA., Division of Hematology/Oncology, Department of Medicine, Helen Diller Family Comprehensive Cancer Center, Bakar Computational Health Sciences Institute, Institute for Human Genetics, University of California, San Francisco, CA 94143, USA., Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, Turku University Hospital, 20521 Turku, Finland., Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA., Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84108, USA., Inova Schar Cancer Institute, Inova Health System, 8081 Innovation Park Drive, Fairfax, VA 22031, USA.