Pitfalls in molecular analysis for mismatch repair deficiency in a family with biallelic pms2 germline mutations
Article first published online: 13 JAN 2011
© 2011 John Wiley & Sons A/S
Volume 80, Issue 6, pages 558–565, December 2011
How to Cite
Leenen, C., Geurts-Giele, W., Dubbink, H., Reddingius, R., van den Ouweland, A., Tops, C., van de Klift, H., Kuipers, E., van Leerdam, M., Dinjens, W. and Wagner, A. (2011), Pitfalls in molecular analysis for mismatch repair deficiency in a family with biallelic pms2 germline mutations. Clinical Genetics, 80: 558–565. doi: 10.1111/j.1399-0004.2010.01608.x
- Issue published online: 24 OCT 2011
- Article first published online: 13 JAN 2011
- Accepted manuscript online: 6 DEC 2010 08:13AM EST
- Received 20 August 2010, revised and accepted for publication 30 November 2010
- compound heterozygosity;
- constitutional mismatch repair deficiency;
- Lynch syndrome;
- microsatellite instability;
Leenen CHM, Geurts-Giele WRR, Dubbink HJ, Reddingius R, van den Ouweland AM, Tops CMJ, van de Klift HM, Kuipers EJ, van Leerdam ME, Dinjens WNM, Wagner A. Pitfalls in molecular analysis for mismatch repair deficiency in a family with biallelic pms2 germline mutations.
Heterozygous germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome. Biallelic mutations in the MMR genes are associated with a childhood cancer syndrome [constitutional mismatch repair deficiency (CMMR-D)]. This is predominantly characterized by hematological malignancies and tumors of the bowel and brain, often associated with signs of neurofibromatosis type 1 (NF1). Diagnostic strategies for selection of patients for MMR gene analysis include analysis of microsatellite instability (MSI) and immunohistochemical (IHC) analysis of MMR proteins in tumor tissue.
We report the clinical characterization and molecular analyses of tumor specimens from a family with biallelic PMS2 germline mutations. This illustrates the pitfalls of present molecular screening strategies. Tumor tissues of five family members were analyzed for MSI and IHC. MSI was observed in only one of the analyzed tissues. However, IHC analysis of brain tumor tissue of the index patient and his sister showed absence of PMS2 expression, and germline mutation analyses showed biallelic mutations in PMS2: p.Ser46IIe and p.Pro246fs. The same heterozygous mutations were confirmed in the father and mother, respectively.
These data support the conclusion that in case of a clinical phenotype of CMMR-D, it is advisable to routinely combine MSI analysis with IHC analysis for the expression of MMR proteins. With inconclusive or conflicting results, germline mutation analysis of the MMR genes should be considered after thorough counselling of the patients and/or their relatives.