Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival.

Abstract

Background: Amyloid light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibres derived from immunoglobulin that can lead to irreversible organ damage. Information about genomic profiles of AL amyloidosis is lacking.Methods: In this study, we adopted a two-step strategy to investigate the mutational profile of AL amyloidosis bone marrow plasma cells (PCs) and their clinical implications. In step one, whole-exome sequencing was performed in bone marrow PCs and paired with normal tissue from 10 AL amyloidosis patients, by which we identified 10 significantly mutated genes (SMGs). In step two, we constituted a targeted gene sequencing (TGS) panel covering the frequently mutated genes identified in step one, genes reported in prior AL amyloidosis studies, and known cancer driver mutations. Then, we analysed an expanded cohort of AL amyloidosis patients (N = 48) with this panel comprising 98 genes.Results: Four recurrent mutations were identified by TGS and verified by Sanger sequencing: ASB15 (c. 844 C > T), ASCC3 (c. 1595 A > G), HIST1H1E (c. 311 C > T) and KRAS (c. 35 G > A), among which the first three mutations were associated with inferior overall survival (OS). Additionally, we found that the number of mutations identified by the TGS panel of 98 genes could be a prognostic predictor for OS.Conclusions: In summary, we revealed genomic profiling in AL amyloidosis and found mutation profiles associated with OS.

• Authors: Xu-Fei Huang, Sun Jian, Jun-Liang Lu, Kai-Ni Shen, Jun Feng, Cong-Li Zhang, Zhuang Tian, Jia-Li Wang, Wan-Jun Lei, Xin-Xin Cao, Dao-Bin Zhou, Zhi-Yong Liang, Jian Li
• Journal: Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis (Amyloid) Vol. 27 Issue 1 Pg. 36-44 (Mar 2020) ISSN: 1744-2818 [Electronic] England
• PMID: 31635489 (Publication Type: Clinical Trial, Journal Article, Video-Audio Media)

Chemical References

• ASB15 protein, human
• H1-4 protein, human
• Histones
• KRAS protein, human
• Proteins
• ASCC3 protein, human
• DNA Helicases
• Proto-Oncogene Proteins p21(ras)

Topics

• Adult
• Aged
• DNA Helicases (genetics)
• DNA Mutational Analysis
• Disease-Free Survival
• Female
• Follow-Up Studies
• Histones (genetics)
• Humans
• Immunoglobulin Light-chain Amyloidosis (drug therapy, genetics, mortality)
• Male
• Middle Aged
• Mutation
• Proteins (genetics)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Survival Rate