PMS2 involvement in patients suspected of Lynch syndrome

Abstract

It is well-established that germline mutations in the mismatch repair genes MLH1, MSH2, and MSH6 cause Lynch syndrome. However, mutations in these three genes do not account for all Lynch syndrome (suspected) families. Recently, it was shown that germline mutations in another mismatch repair gene, PMS2, play a far more important role in Lynch syndrome than initially thought. To explore this further, we determined the prevalence of pathogenic germline PMS2 mutations in a series of Lynch syndrome-suspected patients. Ninety-seven patients who had early-onset microsatellite instable colorectal or endometrial cancer, or multiple Lynch syndrome-associated tumors and/or were from an Amsterdam Criteria II-positive family were selected for this study. These patients carried no pathogenic germline mutation in MLH1, MSH2, or MSH6. When available, tumors were investigated for immunohistochemical staining (IHC) for PMS2. PMS2 was screened in all patients by exon-by-exon sequencing. We identified four patients with a pathogenic PMS2 mutation (4%) among the 97 patients we selected. IHC of PMS2 was informative in one of the mutation carriers, and in this case, the tumor showed loss of PMS2 expression. In conclusion, our study confirms the finding of previous studies that PMS2 is more frequently involved in Lynch syndrome than originally expected.

Clinical analysis ofPMS2: mutation detection and avoidance of pseudogenes

“…More importantly, pathogenic mutations were not detected in patients with other IHC profiles. Except for the recent report of a single case showing a pathogenic PMS2 mutation in a patient with isolated loss of MLH1 protein expression [Niessen et al, 2009], isolated loss of PMS2 is the only profile associated with pathogenic germline PMS2 mutations. Thus, the fact that pathogenic changes in patients with other IHC profiles were not seen supports the specificity of our evaluation of the actual PMS2 gene rather than the pseudogene.…”

Quantification of sequence exchange events betweenPMS2andPMS2CLprovides a basis for improved mutation scanning of Lynch syndrome patients

“…We quantified this problem to be able to better recognize the limitations of these methods still currently used [Jeske et al, 2008;Niessen et al, 2009]. As an alternative, we developed an RNA-based mutation detection protocol that recently has been implemented in the diagnostic lab.…”

Germline Genetics in Colorectal Cancer Susceptibility and Prognosis

“…The estimated risk of colorectal cancer in individuals with a MLH6 mutation is lower than some of the other mutations at 30-61% and the risk of endometrial cancer is higher with 65-70% of females developing endometrial cancer by the age of 70 (Talseth-Palmer et al, 2010;Ramsoekh et al, 2009). PMS2 mutations are less frequently the cause of LS accounting for only 2 to 14% of LS cases (Senter et al, 2008;Niessen et al, 2009b;Talseth-Palmer et al, 2010). The cumulative risk by the age of 70 of developing a colon cancer in mono-allelic PMS2 mutation carriers is 15-20%, endometrial cancer is 15% and other Lynch-related cancers is from 25-32% (Senter et al, 2008).…”