Coding Microsatellite Frameshift Mutations Accumulate in Atherosclerotic Carotid Artery Lesions: Evaluation of 26 Cases and Literature Review.

Carolin Kurz,Maani Hakimi,Susanne Dihlmann,Magnus Von Knebel Doeberitz,Matthias Kloor,Dittmar Böckler,Marie-Luise Gross-Weissmann,Caspar Grond-Ginsbach

doi:10.2119/molmed.2014.00258

Abstract

Somatic DNA alterations are known to occur in atherosclerotic carotid artery lesions; however, their significance is unknown. The accumulation of microsatellite mutations in coding DNA regions may reflect a deficiency of the DNA mismatch repair (MMR) system. Alternatively, accumulation of these coding microsatellite mutations may indicate that they contribute to the pathology. To discriminate between these two possibilities, we compared the mutation frequencies in coding microsatellites (likely functionally relevant) with those in noncoding microsatellites (likely neutral). Genomic DNA was isolated from carotid endarterectomy (CEA) specimens of 26 patients undergoing carotid surgery and from 15 nonatherosclerotic control arteries. Samples were analyzed by DNA fragment analysis for instability at three noncoding (BAT25, BAT26, CAT25) and five coding (AIM2, ACVR2, BAX, CASP5, TGFBR2) microsatellite loci, with proven validity for detection of microsatellite instability in neoplasms. We found an increased frequency of coding microsatellite mutations in CEA specimens compared with control specimens (34.6 versus 0%; p = 0.0013). Five CEA specimens exhibited more than one frameshift mutation, and ACVR2 and CASP5 were affected most frequently (5/26 and 6/26). Moreover, the rate of coding microsatellite alterations (15/130) differed significantly from that of noncoding alterations (0/78) in CEA specimens (p = 0.0013). In control arteries, no microsatellite alterations were observed, neither in coding nor in noncoding microsatellite loci. In conclusion, the specific accumulation of coding mutations suggests that these mutations play a role in the pathogenesis of atherosclerotic carotid lesions, since the absence of mutations in noncoding microsatellites argues against general microsatellite instability, reflecting MMR deficiency.

Highlights

IntroductionAtherosclerosis is characterized by intimal lesions (atheromas or atheromatous plaque, consisting of a lipid core, inflammatory cells and a fibrous cap) affecting medium-sized muscular arteries
Atherosclerosis is characterized by intimal lesions affecting medium-sized muscular arteries
Frameshift mutations were detected in 9 of the 26 carotid endarterectomy (CEA) specimens, of which 5 were affected in more than one of the coding microsatellites (Table 3, Supplementary Table S1). Frameshift mutations in both ACVR2 and CASP5 were detected in three CEA specimens, whereas one specimen was affected in three of the markers

Summary

Introduction

Atherosclerosis is characterized by intimal lesions (atheromas or atheromatous plaque, consisting of a lipid core, inflammatory cells and a fibrous cap) affecting medium-sized muscular arteries. The contemporary model views atherosclerosis as a chronic inflammatory response to this damage, which involves macrophage and leukocyte adhesion to the endothelium, thrombosis, enhanced smooth muscle cell proliferation and excessive extracellular matrix production [1]. These processes are regulated by complex molecular mechanisms that remain mainly obscure. The observed alterations encompass large chromosomal alterations such as loss of heterozygosity, as well as small alterations (most notably nucleotide insertions and deletions in repetitive DNA regions, known as microsatellites or tandem repeats) [2,3] It remains to be demonstrated whether these alterations are cause or consequence of atherosclerosis

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Conclusion