Association between hepatic angiosarcoma and end-stage renal disease: nationwide population-based evidence and enriched mutational signature of aristolochic acid exposure

Shih-Chiang Huang; Ian Yi-Feng Chang; Chee-Jen Chang; Hsuan Liu; Kuang-Hua Chen; Ting-Ting Liu; Tsan-Yu Hsieh; Huei-Chieh Chuang; Chien-Cheng Chen; I-Chieh Lin; Kwai-Fong Ng; Hsuan-Ying Huang; Tse-Ching Chen

doi:10.1002/path.6072

Association between hepatic angiosarcoma and end-stage renal disease: nationwide population-based evidence and enriched mutational signature of aristolochic acid exposure

J Pathol. 2023 Jun;260(2):165-176. doi: 10.1002/path.6072. Epub 2023 Apr 11.

Authors

Shih-Chiang Huang^{1

2}, Ian Yi-Feng Chang^{3

4}, Chee-Jen Chang^{2

5

6

7

8}, Hsuan Liu^{3

9

10

11}, Kuang-Hua Chen¹, Ting-Ting Liu^{12

13}, Tsan-Yu Hsieh¹⁴, Huei-Chieh Chuang¹⁵, Chien-Cheng Chen¹⁶, I-Chieh Lin¹, Kwai-Fong Ng¹, Hsuan-Ying Huang¹², Tse-Ching Chen¹

Affiliations

¹ Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan.
² Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
³ Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
⁴ Department of Neurosurgery, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan.
⁵ Research Services Center for Health Information, Chang Gung University, Taoyuan, Taiwan.
⁶ Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan.
⁷ Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
⁸ Department of Cardiology, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan.
⁹ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
¹⁰ Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
¹¹ Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
¹² Department of Anatomical Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
¹³ Department of Medical Laboratory Science, I-Shou University, Kaohsiung, Taiwan.
¹⁴ Department of Anatomic Pathology, Keelung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Keelung, Taiwan.
¹⁵ Department of Anatomic Pathology, Chiayi Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Chiayi, Taiwan.
¹⁶ Department of Radiology, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan.

PMID: 36815532
DOI: 10.1002/path.6072

Abstract

Hepatic angiosarcoma (HAS) is an aggressive mesenchymal malignancy that remains underexplored with respect to its etiology and mutational landscapes. To clarify the association between HAS and end-stage renal disease (ESRD), we used nationwide data of the National Health Insurance Research Database (NHIRD) in Taiwan, covering ~99% of the population, from 2001 to 2016. To investigate molecular signatures, we performed whole-exome sequencing (WES) in 27 surgical specimens, including nine ESRD-associated cases. The NHIRD analysis demonstrated that HAS ranked second among all angiosarcomas in Taiwan, with the incidence rates of HAS being 0.08, 2.49, and 5.71 per 100,000 person-years in the general population, chronic kidney disease (CKD), and ESRD patients, respectively. The standardized incidence ratios of HAS in CKD and ESRD patients were 29.99 and 68.77, respectively. In comparison with nonhepatic angiosarcoma, the multivariate regression analysis of our institutional cohort confirmed CKD/ESRD as an independent risk factor for HAS (odds ratio: 9.521, 95% confidence interval: 2.995-30.261, p < 0.001). WES identified a high tumor mutation burden (TMB; median: 8.66 variants per megabase) and dominant A:T-to-T:A transversion in HAS with frequent TP53 (81%) and ATRX (41%) mutations, KDR amplifications/gains (56%), and CDKN2A/B deletions (48%). Notably, ESRD-associated HAS had a significantly higher TMB (17.62 variants per megabase, p = 0.01) and enriched mutational signatures of aristolochic acid exposure (COSMIC SBS22, p < 0.001). In summary, a significant proportion of HAS in Taiwan is associated with ESRD and harbors a distinctive mutational signature, which concomitantly links nephrotoxicity and mutagenesis resulting from exposure to aristolochic acid or related compounds. A high TMB may support the eligibility for immunotherapy in treating ESRD-associated HAS. © 2023 The Pathological Society of Great Britain and Ireland.

Keywords: angiosarcoma; aristolochic acid; chronic kidney disease; end-stage renal disease; liver; next-generation sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Hemangiosarcoma* / epidemiology
Hemangiosarcoma* / genetics
Humans
Incidence
Kidney Failure, Chronic* / epidemiology
Kidney Failure, Chronic* / genetics
Liver Neoplasms* / epidemiology
Liver Neoplasms* / genetics
Mutation
Renal Insufficiency, Chronic* / complications
Risk Factors

Substances

aristolochic acid I