September 22, 2019  |  

Proteomic detection of immunoglobulin light chain variable region peptides from amyloidosis patient biopsies.

Authors: Dasari, Surendra and Theis, Jason D and Vrana, Julie A and Meureta, Oana M and Quint, Patrick S and Muppa, Prasuna and Zenka, Roman M and Tschumper, Renee C and Jelinek, Diane F and Davila, Jaime I and Sarangi, Vivekananda and Kurtin, Paul J and Dogan, Ahmet

Immunoglobulin light chain (LC) amyloidosis (AL) is caused by deposition of clonal LCs produced by an underlying plasma cell neoplasm. The clonotypic LC sequences are unique to each patient, and they cannot be reliably detected by either immunoassays or standard proteomic workflows that target the constant regions of LCs. We addressed this issue by developing a novel sequence template-based workflow to detect LC variable (LCV) region peptides directly from AL amyloid deposits. The workflow was implemented in a CAP/CLIA compliant clinical laboratory dedicated to proteomic subtyping of amyloid deposits extracted from either formalin-fixed paraffin-embedded tissues or subcutaneous fat aspirates. We evaluated the performance of the workflow on a validation cohort of 30 AL patients, whose amyloidogenic clone was identified using a novel proteogenomics method, and 30 controls. The recall and negative predictive values of the workflow, when identifying the gene family of the AL clone, were 93 and 98%, respectively. Application of the workflow on a clinical cohort of 500 AL amyloidosis samples highlighted a bias in the LCV gene families used by the AL clones. We also detected similarity between AL clones deposited in multiple organs of systemic AL patients. In summary, AL proteomic data sets are rich in LCV region peptides of potential clinical significance that are recoverable with advanced bioinformatics.

Journal: Journal of proteome research
DOI: 10.1021/acs.jproteome.5b00015
Year: 2015

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