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.

Keywords:

• Amyloid light-chain amyloidosis
• mutation profile
• whole-exome sequencing
• targeted gene sequencing
• prognosis

Acknowledgments

The authors thank the patients and their families.

Disclosure statement

The authors declare no competing financial interests.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant number 81570195; Beijing Natural Science Foundation under Grant number 7182128; the Peking Union Medical College New Star under Grant number 2011LJ; the CAMS Innovation Fund for Medical Sciences under Grant number 2016-12M-1–002 and 2017-I2M-2–001; The National Key Research and Development Programme of China under Grant number 2016YFC0901503; and Peking Union Medical College Youth Fund under Grant number 2017310003. Joint Funds for the innovation of science and Technology, Fujian province under Grant number 2018Y92030043.