TY  - JOUR
AU  - Schmeiser, Heinz
AU  - Nortier, Jöelle L
AU  - Singh, Rajinder
AU  - Gamboa da Costa, Gonçalo
AU  - Sennesael, Jacques
AU  - Cassuto-Viguier, Elisabeth
AU  - Ambrosetti, Damien
AU  - Rorive, Sandrine
AU  - Pozdzik, Agnieszka
AU  - Phillips, David H
AU  - Stiborova, Marie
AU  - Arlt, Volker M
TI  - Exceptionally long-term persistence of DNA adducts formed by carcinogenic aristolochic acid I in renal tissue from patients with aristolochic acid nephropathy.
JO  - International journal of cancer
VL  - 135
IS  - 2
SN  - 0020-7136
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2017-04287
SP  - 502-507
PY  - 2014
AB  - Aristolochic acid (AA) causes aristolochic acid nephropathy (AAN), first described in women in Belgium accidently prescribed Aristolochia fangchi in a slimming treatment, and also Balkan endemic nephropathy (BEN), through probable dietary contamination with Aristolochia clematitis seeds. Both nephropathies have a high risk of urothelial cancer, with AA being the causative agent. In tissues of AAN and BEN patients, a distinct DNA adduct, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), has been detected. DNA adducts can be removed through DNA repair, they can result in mutations through erroneous DNA replication or they can cause cell death. The dA-AAI adduct induces AT to TA transversions in the tumor-suppressor TP53 gene in experimental systems, matching TP53 mutations observed in urothelial tumors from AAN cancer cases. Using thin-layer chromatography 32P-postlabeling and mass spectrometric analysis we report the detection of dA-AAI in renal DNA from 11 Belgian AAN patients over 20 years after exposure to AA had ceased. Our results showed that dA-AAI is an established biomarker of AA exposure, and that this biomarker can be demonstrated to be persistent decades after a distinct AA exposure. Further, the persistence of dA-AAI adducts appears to be a critical determinant for the AA mutational fingerprint frequently found in oncogenes and tumor suppressor genes recently identified by whole genome sequencing of AA-associated urothelial tumors. The potential for exposure to AA worldwide is high; the unprecedented long-term persistence of dA-AAI provides a useful long-term biomarker of exposure and attests to the role of AA in human urothelial malignancy.
KW  - Aristolochic Acids (NLM Chemicals)
KW  - Biomarkers (NLM Chemicals)
KW  - DNA Adducts (NLM Chemicals)
KW  - Mutagens (NLM Chemicals)
KW  - aristolochic acid I (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24921086
UR  - https://inrepo02.dkfz.de/record/128270
ER  -