Simple Detection of Germline Microsatellite Instability for Diagnosis of Constitutional Mismatch Repair Cancer Syndrome

ABSTRACT Heterozygous mutations in DNA mismatch repair (MMR) genes result in predisposition to colorectal cancer (hereditary nonpolyposis colorectal cancer or Lynch syndrome). Patients with biallelic mutations in these genes, however, present earlier, with constitutional mismatch repair deficiency c...

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Published inHuman mutation Vol. 34; no. 6; pp. 847 - 852
Main Authors Ingham, Danielle, Diggle, Christine P., Berry, Ian, Bristow, Claire A., Hayward, Bruce E., Rahman, Nazneen, Markham, Alexander F., Sheridan, Eamonn G., Bonthron, David T., Carr, Ian M.
Format Journal Article
LanguageEnglish
Published United States Blackwell Publishing Ltd 01.06.2013
Hindawi Limited
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Summary:ABSTRACT Heterozygous mutations in DNA mismatch repair (MMR) genes result in predisposition to colorectal cancer (hereditary nonpolyposis colorectal cancer or Lynch syndrome). Patients with biallelic mutations in these genes, however, present earlier, with constitutional mismatch repair deficiency cancer syndrome (CMMRD), which is characterized by a spectrum of rare childhood malignancies and café‐au‐lait skin patches. The hallmark of MMR deficiency, microsatellite instability (MSI), is readily detectable in tumor DNA in Lynch syndrome, but is also present in constitutional DNA of CMMRD patients. However, detection of constitutional or germline MSI (gMSI) has hitherto relied on technically difficult assays that are not routinely applicable for clinical diagnosis. Consequently, we have developed a simple high‐throughput screening methodology to detect gMSI in CMMRD patients based on the presence of stutter peaks flanking a dinucleotide repeat allele when amplified from patient blood DNA samples. Using the three different microsatellite markers, the gMSI ratio was determined in a cohort of normal individuals and 10 CMMRD patients, with biallelic germline mutations in PMS2 (seven patients), MSH2 (one patient), or MSH6 (two patients). Subjects with either PMS2 or MSH2 mutations were easily identified; however, this measure was not altered in patients with CMMRD due to MSH6 mutation. Mutations in the DNA mismatch repair genes predispose to childhood cancers. However, detection of constitutional or germline MSI (gMSI) has hitherto relied on technically difficult assays that are not routinely applicable for clinical diagnosis. Consequently, we have developed a simple high throughput screening methodology to detect gMSI in CMMRD patients based on the presence of stutter peaks flanking a dinucleotide repeat allele when amplified from patient blood DNA samples.
Bibliography:ArticleID:HUMU22311
istex:39CED17E12A2FE71AC115005C7BB537D687283D9
Cancer Research UK - No. 600130
ark:/67375/WNG-F81JX63C-5
Wellcome Trust Clinical Research Fellowship - No. 076461/Z/05/Z
Sir Jules Thorn Charitable Trust - No. 09/JTA
EPSRC - No. FP/I000623/1
Additional Supporting Information may be found in the online version of this article.
Contract grant sponsors: Sir Jules Thorn Charitable Trust (Grant 09/JTA); EPSRC (Grant FP/I000623/1); Cancer Research UK (Grant 600130); Wellcome Trust Clinical Research Fellowship (076461/Z/05/Z).
Communicated by A. Jamie Cutichhia
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ISSN:1059-7794
1098-1004
DOI:10.1002/humu.22311