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

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.

Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer

“…We detected the presence of a previously described heterozygous germline stop codon mutation in exon 11 of MLH1 (c.1029C>G; p.Tyr343Ter, Figs 2C and S2 ) in 8 animals (~20%) [ 10 ], thus confirming the presence of a causative pathogenic mutation previously described in humans (herein these animals are referred to as rhesus Lynch) [ 12 ].The remaining 33 animals (80%) had the wild-type germline sequence of MLH1 (herein referred to as sporadic rhesus, Fig 2C ). The pedigree of rhesus Lynch animals revealed the autosomal dominant inheritance pattern of the MLH1 mutation and an inheritance pattern concordant with the Amsterdam criteria (the 3-2-1 rule) originally described in human LS ( S3 Fig ) [ 13 ].…”

“…A cohort of specific pathogen free (SPF), Indian-origin rhesus macaques bred at The University of Texas MD Anderson Cancer Center (MDACC) Michale E. Keeling Center for Comparative Medicine and Research (KCCMR) spontaneously develops MSI/MMRd CRC, including a subset of animals harboring a pathogenic germline mutation in MLH1 (c.1029C<G, p.Tyr343Ter). This spontaneous mutation manifests into clinical and pathological features analogous to human LS, which suggests that these rhesus macaques may be an informative model organism for studying the biology of MMRd CRC [ 10 , 12 ].…”

Characteristics of cancer susceptibility genes mutations in 282 patients with gastric adenocarcinoma

“…CDH1 germline mutations were reported in 30%−50% of HDGC cases, with more than 100 pathogenic mutations in this gene identified ( 7 - 9 ). Other hereditary gastrointestinal cancer syndromes include Lynch syndrome caused by mutations in DNA mismatch repair genes ( 10 ), Peutz-Jeghers syndrome mostly associated with mutations in the Serine/Threonine Kinase ( STK11 ) and Li-Fraumeni syndrome associated with germline Tumor Protein P53 ( TP53 ) mutations ( 11 , 12 ). Furthermore, germline oncogenic mutations in A-T mutated ( ATM ), breast cancer susceptibility gene 2 ( BRCA2 ), and Partner and localizer of BRCA2 ( PALB2 ) which regulate DNA mismatch repair were also found in some families with HDGC ( 13 ).…”

Genomic resources for rhesus macaques (Macaca mulatta)

“…There are multiple different applications for information regarding genetic variation in rhesus populations, including studies of population genetics (Hernandez et al 2007 ; Liu et al 2018 ), analyses of the genetic causes of macaque pathology relevant to human disease (Bimber et al 2017 ; Dray et al 2018 ; Moshiri et al 2019 ; Peterson et al 2019 ; Rogers et al 2013 ), applications of genetic markers to assist in the genetic management of captive breeding colonies (Kanthaswamy et al 2014 , 2006 ; Petty et al 2021 ; Smith 1980 , 1982 ), or studies of functional variation influencing normal (non-pathogenic) phenotypic diversity (Warren et al 2020 ). Furthermore, while SNVs are the most common type of polymorphism in the macaque genome, gene copy number variants, structural variation, and other types of insertion/deletion polymorphisms may account for a larger number of affected base pairs.…”