期刊
HUMAN MUTATION
卷 34, 期 6, 页码 847-852出版社
WILEY-BLACKWELL
DOI: 10.1002/humu.22311
关键词
mismatch repair; microsatellite instability; germline; software
资金
- Sir Jules Thorn Charitable Trust [09/JTA]
- EPSRC [FP/I000623/1]
- Cancer Research UK [600130]
- Wellcome Trust Clinical Research Fellowship [076461/Z/05/Z]
- EPSRC [EP/I000623/1] Funding Source: UKRI
- Cancer Research UK [15106] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/I000623/1] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [09JTA] Funding Source: researchfish
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 cafe-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.
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