The Clinical Impact of Proteomics in Amyloid Typing

Hill, Michelle M.; Dasari, Surendra; Mollee, Peter; Merlini, Giampaolo; Costello, Catherine E.; Hazenberg, Bouke P. C.; Grogan, Martha; Dispenzieri, Angela; Gertz, Morie A.; Kourelis, Taxiarchis; McPhail, Ellen D.

doi:10.1016/j.mayocp.2020.12.002

Cited by 11 publications

(14 citation statements)

References 35 publications

(39 reference statements)

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“…The field has been opened by pivotal studies that utilized a combination of chromatographic and MS techniques to obtain detailed sequence characterization and locate PTMs [13,15,59] in deposited LCs from single patients. More recently, also thanks to the use of laser-microdissection (LMD)-based methods to enrich amyloid deposits from biopsy specimens, MS analysis of LC fibrils has been performed on a patients-population scale [18,[60][61][62]. In LMD-MS, the Congo red-positive areas in a tissue section are dissected using a laser beam, collected and analyzed by mass spectrometry, allowing to enrich the signal from amyloid proteins over the tissue background [14].…”

Section: Amyloidogenic Light Chains: Biological Impact and Clinical Implications Of Proteomic Characterizationmentioning

confidence: 99%

“…The advent of proteomics has been a revolution in the field of amyloidosis typing, because it allows identifying the deposited proteins independently from the use of antibodies, through alignment of experimental tandem mass spectra against protein sequence databases. This type of analysis is routinely performed in major amyloid centers, and proteomic data from thousands of AL cases are now available [16,18,20,61,62,80,81]. Proteomic typing offers important advantages that have been extensively reviewed elsewhere [61,82]; however, AL amyloidosis also poses unique challenges to this approach.…”

Section: The Al Amyloid Proteome: Disease Typing Characterization Of Deposited Lc Proteoforms and The Amyloid Environmentmentioning

confidence: 99%

“…This type of analysis is routinely performed in major amyloid centers, and proteomic data from thousands of AL cases are now available [16,18,20,61,62,80,81]. Proteomic typing offers important advantages that have been extensively reviewed elsewhere [61,82]; however, AL amyloidosis also poses unique challenges to this approach. In fact, the above-discussed uniqueness of sequence in the V L translates in the fact that protein databases cannot contain the full sequence of each monoclonal LC, and therefore peptide ions from the variable domain, which forms the structured core of the fibrils, may not be matched [21,28,83].…”

Section: The Al Amyloid Proteome: Disease Typing Characterization Of Deposited Lc Proteoforms and The Amyloid Environmentmentioning

confidence: 99%

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Dissecting the Molecular Features of Systemic Light Chain (AL) Amyloidosis: Contributions from Proteomics

et al. 2021

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Amyloidoses are characterized by aggregation of proteins into highly ordered amyloid fibrils, which deposit in the extracellular space of tissues, leading to organ dysfunction. In AL (amyloid light chain) amyloidosis, the most common form in Western countries, the amyloidogenic precursor is a misfolding-prone immunoglobulin light chain (LC), which, in the systemic form, is produced in excess by a plasma cell clone and transported to target organs though blood. Due to the primary role that proteins play in the pathogenesis of amyloidoses, mass spectrometry (MS)-based proteomic studies have gained an established position in the clinical management and research of these diseases. In AL amyloidosis, in particular, proteomics has provided important contributions for characterizing the precursor light chain, the composition of the amyloid deposits and the mechanisms of proteotoxicity in target organ cells and experimental models of disease. This review will provide an overview of the major achievements of proteomic studies in AL amyloidosis, with a presentation of the most recent acquisitions and a critical discussion of open issues and ongoing trends.

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Section: Amyloidogenic Light Chains: Biological Impact and Clinical Implications Of Proteomic Characterizationmentioning

confidence: 99%

Section: The Al Amyloid Proteome: Disease Typing Characterization Of Deposited Lc Proteoforms and The Amyloid Environmentmentioning

confidence: 99%

Section: The Al Amyloid Proteome: Disease Typing Characterization Of Deposited Lc Proteoforms and The Amyloid Environmentmentioning

confidence: 99%

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Dissecting the Molecular Features of Systemic Light Chain (AL) Amyloidosis: Contributions from Proteomics

et al. 2021

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“…It is especially indicated when typing by routine techniques is equivocal, conflicting with clinical data or non-informative [8]. The Mayo Clinic and the UK National Amyloidosis Centre are currently the two major centers of amyloidosis typing by mass spectrometry, having reported hundreds to thousands of cases with high performances in amyloidosis typing [5,7,9]. For example, Rezk et al reported 80% of informative amyloidosis typing when the IHC technique was not [10] and a 100% rate of identification of an amyloid precursor has been reported by the Mayo Clinic [5,9].…”

Section: Introductionmentioning

confidence: 99%

“…The Mayo Clinic and the UK National Amyloidosis Centre are currently the two major centers of amyloidosis typing by mass spectrometry, having reported hundreds to thousands of cases with high performances in amyloidosis typing [5,7,9]. For example, Rezk et al reported 80% of informative amyloidosis typing when the IHC technique was not [10] and a 100% rate of identification of an amyloid precursor has been reported by the Mayo Clinic [5,9]. Both centers share a common bottom-up proteomics workflow: laser microdissection of amyloid deposits stained by Congo red, extraction and digestion of the proteins by trypsin before peptide analysis by liquid chromatography and tandem mass spectrometry (LC-MS/MS).…”

Section: Introductionmentioning

confidence: 99%

Quantification of amyloid protein enrichment by mass spectrometry improves amyloidosis typing

Di-Tommaso

Chauveau

Dourthe

et al. 2023

Preprint

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Introduction Amyloidosis typing is crucial to determine the best therapeutic strategy for patients. Since conventional histological techniques often fail, the identification of amyloid precursors by mass spectrometry became the new standard. However, without quantification, selecting the amyloid precursor from proteins that may be ubiquitous under non-pathological conditions may be equivocal. Therefore, we quantified protein enrichment in amyloid deposits to improve typing. Methods Protein enrichment was measured by extracted ion chromatogram based label free quantification by comparing a microdissected amyloid area with a non-amyloid area. We assessed the discrimination ability of candidate precursors with this approach compared to the two practiced identification methods. Results As proof of concept, we selected seven cases, 5 typical of the most common amyloidosis subtypes and typed by immunostainings, 2 inconclusive after immunohistochemistry. Proteins associated with amyloid deposits were identified in all samples confirming the pathology. When the routine clinical mass spectrometric identification techniques allowed unambiguous conclusions for 2/3 of 7 cases, quantification of the enrichment ratio in the amyloid deposit allowed unambiguous precursor selection in all cases. Conclusion Quantification of precursor enrichment in amyloid deposits is a promising optimization for amyloidosis typing. Incorporated into routine clinical processes, it will improve patient care in difficult diagnostic situations.

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Fine‐needle aspiration of amyloidoma: A critical analysis

Ramani,

Krishnan

2024

Cancer Cytopathology

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BackgroundAmyloid, presenting as a mass, is termed amyloidoma. Among the reported cases, fine‐needle aspiration (FNA) of amyloid is often misinterpreted as acellular nondiagnostic material.MethodsA computer search of all FNAs was performed and cases diagnosed as amyloidoma were identified.ResultsAmong 11,956 cases and 20,634 FNAs, there were six cases and 12 FNAs of amyloidoma. One case with mucin/myxoid matrix was misinterpreted as amyloid, which on our review was Congo red negative. All five other cases of amyloidoma were adequate for evaluation. The smears showed most of the aspirated contents in the middle of the slide and it did not spread when smeared. The amyloid was present as large chunks of waxy, smooth, orangophilic/cyanophilic fragments on Papanicolaou stain and as basophilic fragments on Diff‐Quik stain in a clean background. In cases with lymphoma/myeloma, there were admixed lymphocytes and/or plasma cells. Unlike fibrous tissue, amyloid aspirates well and provides adequate material for interpretation. The clean background distinguishes it from mucin/myxoid matrix. Congo red stain was positive with apple green birefringence in all five cases. Further subtyping by mass spectrometry showed AL (κ) type in three patients and AIns (insulin) type in one patient. In one patient with lymphoma, the subtyping was not done.ConclusionFNA of amyloidoma is rare (0.04%), but an optimal method for diagnosis and subtyping, avoiding unwanted surgical interventions. Although mistaken for fibrous tissue, which aspirates poorly, abundant acellular orangophilic/cyanophilic material on FNA should raise a suspicion for amyloid. Unlike mucin/myxoid matrix, amyloid does not smear the background.

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The Clinical Impact of Proteomics in Amyloid Typing

Cited by 11 publications

References 35 publications

Dissecting the Molecular Features of Systemic Light Chain (AL) Amyloidosis: Contributions from Proteomics

Dissecting the Molecular Features of Systemic Light Chain (AL) Amyloidosis: Contributions from Proteomics

Quantification of amyloid protein enrichment by mass spectrometry improves amyloidosis typing

Fine‐needle aspiration of amyloidoma: A critical analysis

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