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Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):2806-2811. doi: 10.1073/pnas.1722106115. Epub 2018 Feb 28.

MLH1-rheMac hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques.

Author information

1
Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
2
Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center MD Anderson Cancer Center, Houston, TX 77030.
3
Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
4
Keeling Center for Comparative Medicine and Research, The University of Texas MD Anderson Cancer Center MD Anderson Cancer Center, Bastrop, TX 78602.
5
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center MD Anderson Cancer Center, Smithville, TX 78957.
6
Department of Pathology, The University of Texas MD Anderson Cancer Center MD Anderson Cancer Center, Houston, TX 77030.
7
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center MD Anderson Cancer Center, Houston, TX 77030.
8
Department of Neurology, Harvard Medical School, Boston, MA 02115; richard_sidman@hms.harvard.edu juri.gelovani@wayne.edu.
9
Rutgers Cancer Institute of New Jersey at University Hospital, Newark, NJ 07103.
10
Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103.
11
Division of Hematology/Oncology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103.
12
Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center MD Anderson Cancer Center, Houston, TX 77030; richard_sidman@hms.harvard.edu juri.gelovani@wayne.edu.
13
Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI 48201.
14
Department of Biomedical Engineering, College of Engineering and School of Medicine, Wayne State University, Detroit, MI 48201.

Abstract

Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques (Macaca mulatta) at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon. These colon carcinoma lesions selectively accumulated [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoroacetate ([18F]FACE) at high levels, reflecting elevated carbohydrate and fatty acid metabolism in these tumors. In contrast, the accumulation of [18F]fluorothymidine ([18F]FLT) was less significant, reflecting slow proliferative activity in these tumors. The diagnoses of colon carcinomas were confirmed by endoscopy. The expression of MLH1, MSH2, and MSH6 proteins and the degree of microsatellite instability (MSI) was assessed in colon carcinomas. The loss of MLH1 protein expression was observed in all tumors and was associated with a deletion mutation in the MLH1 promoter region and/or multiple single-nucleotide polymorphism (SNP) mutations in the MLH1 gene. All tumors exhibited various degrees of MSI. The pedigree analysis of this rhesus macaque population revealed several clusters of affected animals related to each other over several generations, suggesting an autosomal dominant transmission of susceptibility for colon cancer. The newly discovered hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques, termed MLH1-rheMac, may serve as a model for development of novel approaches to diagnosis and therapy of Lynch syndrome in humans.

KEYWORDS:

MLH1; colon carcinoma; hereditary; rhesus macaque; single-nucleotide polymorphism

PMID:
29490919
PMCID:
PMC5856559
DOI:
10.1073/pnas.1722106115
[Indexed for MEDLINE]
Free PMC Article

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