title: Clinical diagnosis and typing of systemic amyloidosis in subcutaneous fat aspirates by mass spectrometry-based proteomics.
abstract: Examination of abdominal subcutaneous fat aspirates is a practical, sensitive and specific method for the diagnosis of systemic amyloidosis. Here we describe the development and implementation of a clinical assay using mass spectrometry-based proteomics to type amyloidosis in subcutaneous fat aspirates. First, we validated the assay comparing amyloid-positive (n=43) and -negative (n=26) subcutaneous fat aspirates. The assay classified amyloidosis with 88% sensitivity and 96% specificity. We then implemented the assay as a clinical test, and analyzed 366 amyloid-positive subcutaneous fat aspirates in a 4-year period as part of routine clinical care. The assay had a sensitivity of 90%, and diverse amyloid types, including immunoglobulin light chain (74%), transthyretin (13%), serum amyloid A (%1), gelsolin (1%), and lysozyme (1%), were identified. Using bioinformatics, we identified a universal amyloid proteome signature, which has high sensitivity and specificity for amyloidosis similar to that of Congo red staining. We curated proteome databases which included variant proteins associated with systemic amyloidosis, and identified clonotypic immunoglobulin variable gene usage in immunoglobulin light chain amyloidosis, and the variant peptides in hereditary transthyretin amyloidosis. In conclusion, mass spectrometry-based proteomic analysis of subcutaneous fat aspirates offers a powerful tool for the diagnosis and typing of systemic amyloidosis. The assay reveals the underlying pathogenesis by identifying variable gene usage in immunoglobulin light chains and the variant peptides in hereditary amyloidosis.
authors.affiliation: Department of Laboratory Medicine and Pathology.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Vrana
authors.affiliation: Department of Laboratory Medicine and Pathology.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Theis
authors.affiliation: Department of Health Sciences Research.
authors.forename: Surendra
authors.initials: S
authors.lastname: Dasari
authors.affiliation: Department of Laboratory Medicine and Pathology University of Turin, Italy.
authors.forename: Oana M
authors.initials: OM
authors.lastname: Mereuta
authors.affiliation: Department of Hematology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Dispenzieri
authors.affiliation: Department of Hematology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Zeldenrust
authors.affiliation: Department of Hematology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Morie A
authors.initials: MA
authors.lastname: Gertz
authors.affiliation: Department of Laboratory Medicine and Pathology.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kurtin
authors.affiliation: Department of Laboratory Medicine and Pathology.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Grogg
authors.affiliation: Department of Laboratory Medicine and Pathology Memorial Sloan-Kettering Cancer Center, New York, NY, USA (current affiliation) dogana@mskcc.org.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
mesh_terms: D000328:Adult; D000368:Aged; D000682:Amyloid / Q000378:metabolism; D028227:Amyloid Neuropathies, Familial / Q000175:diagnosis; D000686:Amyloidosis / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001054:Apolipoproteins A / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D001707:Biopsy, Needle; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000097:blood / Q000378:metabolism; D000075363:Immunoglobulin Light-chain Amyloidosis; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009154:Mutation; D040901:Proteomics; D012680:Sensitivity and Specificity; D000683:Serum Amyloid P-Component; D050151:Subcutaneous Fat / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000682:Amyloid; D001054:Apolipoproteins A; D001057:Apolipoproteins E; D007147:Immunoglobulin Light Chains; D000683:Serum Amyloid P-Component; C022205:apolipoprotein A-IV
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