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.
Highlights
Colorectal cancer (CRC) is a common, often fatal disease that ranks third in the United States and fourth in the world among all forms of cancer as a cause of death [1, 2]
We examined microsatellite instability (MSI) in tumoral DNA versus normal DNA from 9 of the rhesus macaques diagnosed with CRC, all drawn from the primary cohort of 20 cases
Among the 7 controls from the Keeling Center for Comparative Medicine and Research (KCCMR) colony, we found no individuals with predicted damaging mutations in MSH2, MSH6 or PMS2
Summary
Colorectal cancer (CRC) is a common, often fatal disease that ranks third in the United States and fourth in the world among all forms of cancer as a cause of death [1, 2]. Given their close phylogenetic position as Old World monkeys, rhesus macaques are genetically more similar to humans than are other widely used animal models [18] and provide translational models that share with humans more genetic, physiologic and pathophysiologic similarities than other laboratory species [19, 20] We anticipate that this spontaneous primate model will prove valuable for novel experiments intended to address some of the unanswered questions regarding pathogenesis and management of colorectal and other cancers in human carriers of MMR mutations
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
