Mismatch repair gene mutations lead to lynch syndrome colorectal cancer in rhesus macaques
Beth K. Dray1, Muthuswamy Raveendran2, R. Alan Harris2, Fernando Benavides3, Stanton B. Gray1, Carlos J. Perez3, Mark J. McArthur4, Lawrence E. Williams1, Wallace B. Baze1, Harsha Doddapaneni2, Donna M. Muzny2, Christian R. Abee1 and Jeffrey Rogers2
1 Michale E. Keeling Center for Comparative Medicine and Research, Department of Veterinary Sciences, University of Texas MD Anderson Cancer Center, Bastrop, Texas, USA
2 Human Genome Sequencing Center and Dept. of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
3 The Virginia Harris Cockrell Cancer Research Center, Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, Texas, USA
4 Department of Veterinary Medicine and Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Correspondence:
Beth K. Dray, email:
Keywords: colorectal cancer; Lynch syndrome; rhesus macaque; MLH1; MSH6
Received: February 12, 2018 Accepted: April 16, 2018 Published: April 28, 2018
Abstract
Colorectal cancer accounts for a substantial number of deaths each year worldwide. Lynch Syndrome is a genetic form of colorectal cancer (CRC) caused by inherited mutations in DNA mismatch repair (MMR) genes. Although researchers have developed mouse models of Lynch Syndrome through targeted mutagenesis of MMR genes, the tumors that result differ in important ways from those in Lynch Syndrome patients. We identified 60 cases of CRC in rhesus macaques (Macaca mulatta) at our facility since 2001. The tumors occur at the ileocecal junction, cecum and proximal colon and display clinicopathologic features similar to human Lynch Syndrome. We conducted immunohistochemical analysis of CRC tumors from several rhesus macaques, finding they frequently lack expression of MLH1 and PMS2 proteins, both critical MMR proteins involved in Lynch Syndrome. We also found that most macaque cases we tested exhibit microsatellite instability, a defining feature of Lynch Syndrome. Whole genome sequencing of rhesus macaque CRC cases identified mutations in MLH1 and/or MSH6 that are predicted to disrupt protein function. We conclude that this population of rhesus macaques constitutes a spontaneous model of Lynch Syndrome, matching the human disease in several significant characteristics, including genetic risk factors that parallel human Lynch Syndrome.
