Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer

• Published in: Nature communications Vol. 5; no. 1; p. 4988
• Main Authors: Pritchard, Colin C., Morrissey, Colm, Kumar, Akash, Zhang, Xiaotun, Smith, Christina, Coleman, Ilsa, Salipante, Stephen J., Milbank, Jennifer, Yu, Ming, Grady, William M., Tait, Jonathan F., Corey, Eva, Vessella, Robert L., Walsh, Tom, Shendure, Jay, Nelson, Peter S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.09.2014; Nature Publishing Group; Nature Pub. Group
• Subjects: 13/51; 631/208/68; 631/67/589/466; Autopsies; Cancer research; DNA Mismatch Repair; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endometrial cancer; Epigenetics; Genes; Genomes; Genomics; Humanities and Social Sciences; Humans; Male; Medical research; Metastasis; Microsatellite Instability; Middle Aged; multidisciplinary; Mutation; MutS Homolog 2 Protein - genetics; MutS Homolog 2 Protein - metabolism; Patients; Prostate cancer; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Protein Binding; Science; Science (multidisciplinary); Tumors; Yeast; United States > US
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms5988

A hypermutated subtype of advanced prostate cancer was recently described, but prevalence and mechanisms have not been well-characterized. Here we find that 12% (7 of 60) of advanced prostate cancers are hypermutated, and that all hypermutated cancers have mismatch repair gene mutations and microsatellite instability (MSI). Mutations are frequently complex MSH2 or MSH6 structural rearrangements rather than MLH1 epigenetic silencing. Our findings identify parallels and differences in the mechanisms of hypermutation in prostate cancer compared with other MSI-associated cancers. Several patients with metastatic prostate cancer have been shown to harbour tumours with markedly high mutation rates. Here, the authors characterise hypermutation in advanced prostate cancer samples and show that these samples have somatic mismatch repair gene mutations and microsatellite instability.