Abstract
The hallmarks of Lynch syndrome (LS) include a positive family history of colorectal cancer (CRC), germline mutations in the DNA mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression. However, in ∼10–15% of clinically suspected LS cases, MMR mutation analyses cannot explain MSI-H and abnormal immunohistochemistry (IHC) results. The highly variable phenotype of MUTYH-associated polyposis (MAP) can overlap with the LS phenotype, but is inherited recessively. We analysed the MUTYH gene in 85 ‘unresolved’ patients with tumours showing IHC MMR-deficiency without detectable germline mutation. Biallelic p.(Tyr179Cys) MUTYH germline mutations were found in one patient (frequency 1.18%) with CRC, urothelial carcinoma and a sebaceous gland carcinoma. LS was suspected due to a positive family history of CRC and because of MSI-H and MSH2–MSH6 deficiency on IHC in the sebaceous gland carcinoma. Sequencing of this tumour revealed two somatic MSH2 mutations, thus explaining MSI-H and IHC results, and mimicking LS-like histopathology. This is the first report of two somatic MSH2 mutations leading to an MSI-H tumour lacking MSH2–MSH6 protein expression in a patient with MAP. In addition to typical transversion mutations in KRAS and APC, MAP can also induce tumourigenesis via the MSI-pathway.
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Acknowledgements
We would like to thank the German Cancer Aid (Deutsche Krebshilfe grant 110780) and the Wilhelm Sander-Stiftung grant 2012.081.1 as well as grants P30 16058 and P01 CA124570 from the National Cancer Institute, USA, for support of this work. We also thank all patients for their participation in this study, as well as their respective doctors for contributing clinical information.
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Morak, M., Heidenreich, B., Keller, G. et al. Biallelic MUTYH mutations can mimic Lynch syndrome. Eur J Hum Genet 22, 1334–1337 (2014). https://doi.org/10.1038/ejhg.2014.15
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DOI: https://doi.org/10.1038/ejhg.2014.15
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