title: Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Pritchard
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Akash
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Xiaotun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Smith
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.affiliation: 1] Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA [2] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Salipante
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Milbank
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Tait
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Corey
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
mesh_terms: D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D011485:Protein Binding
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein