Premium
Simple Detection of Germline Microsatellite Instability for Diagnosis of Constitutional Mismatch Repair Cancer Syndrome
Author(s) -
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.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22311
Subject(s) - pms2 , msh6 , lynch syndrome , msh2 , microsatellite instability , dna mismatch repair , germline mutation , biology , microsatellite , genetics , mlh1 , cancer , colorectal cancer , cancer research , mutation , allele , gene
Heterozygous mutations in DNA mismatch repair ( MMR ) genes result in predisposition to colorectal cancer (hereditary nonpolyposis colorectal cancer or L ynch 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 L ynch syndrome, but is also present in constitutional DNA of CMMRD patients. However, detection of constitutional or germline MSI (g MSI ) 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 g MSI 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 g MSI 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.