title: Genetic alterations in periprosthetic soft-tissue masses from patients with metal-on-metal hip replacement.
abstract: Adverse soft tissue reactions in patients with metal-on-metal (MoM) hip replacement are associated with cobalt (Co) and chromium (Cr) particles released from the implant. Exposing the patients to long periods of increased metal ions concentrations resulting from the wear of these implants poses an increased risk of genotoxicity/mutagenicity. A variable proportion of patients develop periprosthetic soft-tissue masses or pseudotumors at the site of the implant. There is a concern that exposure to increased metal ions could increase the risk of cancer. In order to investigate whether the periprosthetic soft-tissue mass harbours any cancer- related genetic alterations, we studied DNA isolated from periprosthetic tissues of 20 patients with MoM hip replacement, for copy number alterations and mutations in hotspot regions of 50 cancer genes using aCGH and amplicon-based next generation sequencing. Our results showed copy number gains at 12q14.3 and 21q21.1in tumour from patient diagnosed with liposarcoma. Copy number alterations in periprosthetic tissues were seen in three other patients, one had a region of gain at 9q24.1 affecting JAK2 and INSL6, and two patients had region of gain at 6p21.1, affecting RUNX2. Mutation analysis showed V1578del mutation in NOTCH1 in two patients. The copy number alterations and mutations seen in periprosthetic soft-tissue masses are earlier reported in either haematological malignancies or in osteoblast related bone dysplasia. The presence of genetic anomalies was associated with longer in-situ time of the implant. Our findings warrant the need of similar studies in larger patient cohorts to evaluate the risk of development of neoplastic alterations in periprosthetic tissues of patients with MoM hip replacement.
authors.affiliation: University of Helsinki, Faculty of Medicine, Department of Pathology, Helsinki, Finland.
authors.forename: Virinder Kaur
authors.initials: VK
authors.lastname: Sarhadi
authors.affiliation: Coxa Hospital for Joint Replacement, Tampere, Finland; Department of Pathology, FIMLAB Laboratories, Tampere, Finland.
authors.forename: Jyrki
authors.initials: J
authors.lastname: Parkkinen
authors.affiliation: Coxa Hospital for Joint Replacement, Tampere, Finland.
authors.forename: Aleksi
authors.initials: A
authors.lastname: Reito
authors.affiliation: Coxa Hospital for Joint Replacement, Tampere, Finland.
authors.forename: Jyrki
authors.initials: J
authors.lastname: Nieminen
authors.affiliation: University of Helsinki, Faculty of Medicine, Department of Pathology, Helsinki, Finland.
authors.forename: Noora
authors.initials: N
authors.lastname: Porkka
authors.affiliation: University of Helsinki, Faculty of Medicine, Department of Pathology, Helsinki, Finland; HUSLAB, Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Wirtanen
authors.affiliation: Coxa Hospital for Joint Replacement, Tampere, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Laitinen
authors.affiliation: Coxa Hospital for Joint Replacement, Tampere, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Eskelinen
authors.affiliation: University of Helsinki, Faculty of Medicine, Department of Pathology, Helsinki, Finland. Electronic address: sakari.knuutila@helsinki.fi.
authors.forename: Sakari
authors.initials: S
authors.lastname: Knuutila
mesh_terms: D000368:Aged; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects*; D002857:Chromium / Q000009:adverse effects / Q000097:blood; D003035:Cobalt / Q000009:adverse effects / Q000097:blood; D055028:Comparative Genomic Hybridization; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D056915:DNA Copy Number Variations / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D013058:Mass Spectrometry; D061825:Metal-on-Metal Joint Prostheses / Q000009:adverse effects*; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects*; D051881:Receptor, Notch1 / Q000235:genetics; D017695:Soft Tissue Injuries / Q000139:chemically induced / Q000235:genetics*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C512663:INSL6 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C497761:NOTCH1 protein, human; C493709:RUNX2 protein, human; D051881:Receptor, Notch1; D002857:Chromium; D003035:Cobalt; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: Hip replacement; Metal-on-metal implant; Mutations; Periprosthetic tissue; Pseudotumor; aCGH