Sporadic MSI cancers also differ in that they arise on a background of widespread gene promoter hypermethylation termed the CpG island methylator phenotype (CIMP).7 Of the mismatch repair gene family, only MLH1 is targeted for promoter hypermethylation,

so sporadic MSI cancers are all MLH1-deficient, unlike Lynch syndrome cancers where the mission protein may be MLH1, MSH2, MSH6 or PMS2. A clinical, histological and molecular testing algorithm for the identification of Lynch syndrome is suggested in Figure 1. The article by Yoon and colleagues in this issue of the Journal focuses on sporadic MSI cancer, methods of identification and clinicopathological associations.8 Critical selleck compound library to the findings of any such studies are the methods used to identify MSI cancers and the protocols in place to select a homogeneous DMXAA manufacturer study population. Immunohistochemical staining for

mismatch repair proteins is inexpensive and offered routinely in pathology laboratories. MLH1 and MSH2 are the two most commonly targeted proteins in Lynch syndrome, although the addition of MSH6 and PMS2 to the staining panel increases the number of Lynch cancers identified and where possible should be undertaken. MLH1 immunostaining is sufficient to detect sporadic disease. It is therefore surprising that Yoon et al. chose to include 85 patients (41% of study cases) with loss of MSH2 expression as these cases most likely represent Lynch syndrome despite the family history not meeting the Amsterdam criteria. The MLH1 immunostain in particular may be subject to technical variation. Yoon et al. make the important observation that technical issues, such as delayed fixation, are important for Urease staining efficacy. Some difficult-to-interpret cases may be resolved if staining is scored by a specialist pathologist, and

further clarified by addition of PCR-based MSI testing of tumors with indefinite staining patterns.9 PCR-based MSI testing is more expensive to perform and available in fewer testing centers. The MSI five-marker panel used by Yoon et al. and criteria of two positive markers to determine MSI reflects standard practice and the recommendations of the NCI Workshop on Microsatellite Instability conducted in 1998.10 In 2008, Nagasaka and colleagues subtly refined this definition of MSI to require at least one positive mononucleotide repeat tract mutation and one other marker of the NCI panel.11 This modified definition highlights the specificity of mononucleotide repeat tracts in detecting MSI and would reduce the small number of false positives arising due to mutation of two dinucleotide markers. Patient exclusion is as important as inclusion when designing a study to better understand a particular tumor subgroup. Yoon et al. used Amsterdam I or II criteria to exclude hereditary cases.