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

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 microsat...

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Bibliographic Details
Published in:Nature communications 2014-09, Vol.5 (1), p.4988-4988, Article 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: Article
Language:English
Subjects:
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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
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Summary: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.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms5988