American Association for Cancer Research
10559965epi150553-sup-149673_1_fig_0_nsqbdj.xlsx (2.15 MB)

Supplemental Material (for review only) File - Supplementary Tables 1-5. from Low-Coverage Exome Sequencing Screen in Formalin-Fixed Paraffin-Embedded Tumors Reveals Evidence of Exposure to Carcinogenic Aristolochic Acid

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posted on 2023-03-31, 13:44 authored by Xavier Castells, Sandra Karanović, Maude Ardin, Karla Tomić, Evanguelos Xylinas, Geoffroy Durand, Stephanie Villar, Nathalie Forey, Florence Le Calvez-Kelm, Catherine Voegele, Krešimir Karlović, Maja Mišić, Damir Dittrich, Igor Dolgalev, James McKay, Shahrokh F. Shariat, Viktoria S. Sidorenko, Andrea Fernandes, Adriana Heguy, Kathleen G. Dickman, Magali Olivier, Arthur P. Grollman, Bojan Jelaković, Jiri Zavadil

Supplementary Table S1: Clinicopathological and epidemiological patient data and urothelial tumor sample description. Supplementary Table S2: Complete list of annotated SBS identified in all LC-WES analyzed urothelial tumors (HiSeq2500 data only). Supplementary Table S3: GO and KEGG Classification of genes mutated by non-synonymous A:T>T:A mutations. Supplementary Table S4: List of cancer driver genes found recurrently mutated in the EN and Taiwan UTUC sample sets. Supplementary Table S5: GO and KEGG classification of the recurrently mutated cancer driver genes (see Figure 3B).



Background: Dietary exposure to cytotoxic and carcinogenic aristolochic acid (AA) causes severe nephropathy typically associated with urologic 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) optimized for multisample detection of the AA mutational signature, and demonstrate its utility in 17 formalin-fixed paraffin-embedded urothelial tumors obtained from 15 patients with endemic nephropathy, an environmental form of AA nephropathy.Results: LC-WES identified the AA signature, alongside signatures of age and APOBEC enzyme activity, in 15 samples sequenced at the average per-base coverage of approximately 10×. Analysis at 3 to 9× coverage revealed the signature in 91% of the positive samples. The exome-wide distribution of the predominant A>T transversions exhibited a stochastic pattern, whereas 83 cancer driver genes were enriched for recurrent nonsynonymous A>T mutations. In two patients, pairs of tumors from different parts of the urinary tract, including the bladder, harbored overlapping mutation patterns, suggesting tumor dissemination via cell seeding.Conclusions: LC-WES analysis of archived tumor tissues is a reliable method applicable to investigations of both the exposure to AA and its biologic effects in human carcinomas.Impact: By detecting cancers associated with AA exposure in high-risk populations, LC-WES can support future molecular epidemiology studies and provide evidence-base for relevant preventive measures. Cancer Epidemiol Biomarkers Prev; 24(12); 1873–81. ©2015 AACR.