Mismatch repair gene mutations lead to lynch syndrome colorectal cancer in rhesus macaques.

TitleMismatch repair gene mutations lead to lynch syndrome colorectal cancer in rhesus macaques.
Publication TypeJournal Article
Year of Publication2018
AuthorsDray, BK, Raveendran, M, R Harris, A, Benavides, F, Gray, SB, Perez, CJ, McArthur, MJ, Williams, LE, Baze, WB, Doddapaneni, H, Muzny, DM, Abee, CR, Rogers, J
JournalGenes Cancer
Volume9
Issue3-4
Pagination142-152
Date Published2018 Mar
ISSN1947-6019
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 () 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 and/or 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.

DOI10.18632/genesandcancer.170
Alternate JournalGenes Cancer
PubMed ID30108684
PubMed Central IDPMC6086002
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
R24 OD011173 / OD / NIH HHS / United States