2015
DOI: 10.1158/1055-9965.epi-15-0553
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Low-Coverage Exome Sequencing Screen in Formalin-Fixed Paraffin-Embedded Tumors Reveals Evidence of Exposure to Carcinogenic Aristolochic Acid

Abstract: Background Dietary exposure to cytotoxic and carcinogenic aristolochic acid (AA) causes severe nephropathy typically associated with urological cancers. Monitoring of AA exposure uses biomarkers such as aristolactam-DNA adducts, detected by mass spectrometry in the kidney cortex, or the somatic A>T transversion pattern characteristic of exposure to AA, as revealed by previous DNA sequencing studies using fresh frozen tumors. Methods Here we report a low-coverage whole-exome sequencing method (LC-WES) optimiz… Show more

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Cited by 24 publications
(45 citation statements)
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“…22,40,51 Moreover, mutational signature analyses using whole exome and whole genome sequencing from a large panel of cancers identified aristolochic acid signature in bladder transitional cell carcinoma, clear renal cell carcinoma, and HCC. 22,51,52 A typical mutational fingerprint of exposure to aristolochic acid has been described with a high number of mutations (median of 233 nonsynonymous mutations per tumor in urothelial carcinoma due to aristolochic acid vs. 70 per tumor in urothelial carcinoma not related to aristolochic acid) with frequent T ! A transversions (also described as A:T to T:A taking into account the two strands of DNA) in a CTG trinucleotide context (mutational signature 22).…”
Section: The Story Of Aristolochic Acid: From Kidney To the Livermentioning
confidence: 99%
“…22,40,51 Moreover, mutational signature analyses using whole exome and whole genome sequencing from a large panel of cancers identified aristolochic acid signature in bladder transitional cell carcinoma, clear renal cell carcinoma, and HCC. 22,51,52 A typical mutational fingerprint of exposure to aristolochic acid has been described with a high number of mutations (median of 233 nonsynonymous mutations per tumor in urothelial carcinoma due to aristolochic acid vs. 70 per tumor in urothelial carcinoma not related to aristolochic acid) with frequent T ! A transversions (also described as A:T to T:A taking into account the two strands of DNA) in a CTG trinucleotide context (mutational signature 22).…”
Section: The Story Of Aristolochic Acid: From Kidney To the Livermentioning
confidence: 99%
“…Genomic DNA was extracted from macro-dissected paraffin sections, and 250 nanograms of each DNA sample were sheared by Covaris (Covaris, Inc.) to ~300 bp fragments, as previously described (Castells et al 2015). We prepared libraries with the Kapa LTP Library Preparation Kit (Kapa Biosystems) according to the manufacturer's recommendations.…”
Section: Whole-exome Sequencing Of Human Ffpe Samplesmentioning
confidence: 99%
“…( a ) Upper panels: spectra in upper urinary tract urothelial carcinomas (UTUC) of patients from Taiwan, China and from Balkan Endemic nephropathy (BEN) regions of Europe, two populations known to be exposed to AA. 75, 76, 97 The lower panel shows that exposure of Hupki MEF to AA 92 induces a similar mutational profile. Pooled data from multiple samples are shown for each data set.…”
Section: Figurementioning
confidence: 98%
“…95, 96 Another source of experimentally induced genome-wide mutation patterns is potentially available from past in vivo toxicology projects. There is an untapped reservoir of archived tumour samples from animal carcinogen tests that can be mined using robust protocols for extraction and NGS of DNA derived from formalin-fixed, paraffin-embedded tumours already developed for human studies, 77, 97, 98 allowing immediate access to information from this valuable source.…”
Section: Orphan Signatures and The Call For More Mutagenesis Studies mentioning
confidence: 99%
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