Abstract
Heterozygous PMS2 germline mutations are associated with Lynch syndrome. Up to one third of these mutations are genomic deletions. Their detection is complicated by a pseudogene (PMS2CL), which – owing to extensive interparalog sequence exchange – closely resembles PMS2 downstream of exon 12. A recently redesigned multiplex ligation-dependent probe amplification (MLPA) assay identifies PMS2 copy number alterations with improved reliability when used with reference DNAs containing equal numbers of PMS2- and PMS2CL-specific sequences. We selected eight such reference samples – all publicly available – and used them with this assay to study 13 patients with PMS2-defective colorectal tumors. Three presented deleterious alterations: an Alu-mediated exon deletion; a 125-kb deletion encompassing PMS2 and four additional genes (two with tumor-suppressing functions); and a novel deleterious hybrid PMS2 allele produced by recombination with crossover between PMS2 and PMS2CL, with the breakpoint in intron 10 (the most 5′ breakpoint of its kind reported thus far). We discuss mechanisms that might generate this allele in different chromosomal configurations (and their diagnostic implications) and describe an allele-specific PCR assay that facilitates its detection. Our data indicate that the redesigned PMS2 MLPA assay is a valid first-line option. In our series, it identified roughly a quarter of all PMS2 mutations. © 2012 Wiley Periodicals, Inc.
Highlights
Lynch syndrome (MIM#120435) is the most common heritable cause of neoplastic disease in the large intestine
It is important to note that an unequal distribution of gene-derived and pseudogenederived sequences in the reference DNA set will reduce the accuracy of copy number assessments at these loci in patient DNA samples
Reference DNAs must harbor two PMS2specific copies and two PMS2CL-specific copies of each sequence bound by paralog-discriminating probes for exons 11-15
Summary
Lynch syndrome (MIM#120435) is the most common heritable cause of neoplastic disease in the large intestine. Referred to as hereditary nonpolyposis colorectal cancer, this syndrome accounts for approximately 2-3% of all colorectal malignancies and is associated with an increased risk for cancer at other sites as well (Cunningham et al, 2001; Lynch and de la Chapelle, 2003; Hampel et al, 2008; Lynch et al, 2009). It is caused mainly by heterozygous germline mutations in the mismatch repair (MMR) genes, in most cases MSH2 ($40% of cases) or MLH1 ($50%) (Liu et al, 1996; Peltomaki, 2003). In a large series of unselected colorectal carcinomas, evidence of primary alteration of PMS2
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