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Low-Coverage Exome Sequencing Screen in Formalin-Fixed Paraffin-Embedded Tumors Reveals Evidence of Exposure to Carcinogenic Aristolochic Acid

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Low-Coverage Exome Sequencing Screen in Formalin-Fixed Paraffin-Embedded Tumors Reveals Evidence of Exposure to Carcinogenic Aristolochic Acid Published OnlineFirst September 17, 2015; DOI: 10.1158/1055-9965.EPI-15-0553 Research Article Cancer Epidemiology, Biomarkers Low-Coverage Exome Sequencing Screen in & Prevention Formalin-Fixed Paraffin-Embedded Tumors Reveals Evidence of Exposure to Carcinogenic Aristolochic Acid Xavier Castells1, Sandra Karanovic2, Maude Ardin1, Karla Tomic3, Evanguelos Xylinas4, Geoffroy Durand5, Stephanie Villar1, Nathalie Forey5, Florence Le Calvez-Kelm5, Catherine Voegele5,Kresimir Karlovic3, Maja Misic3, Damir Dittrich3, Igor Dolgalev6, James McKay5, Shahrokh F. Shariat4, Viktoria S. Sidorenko7, Andrea Fernandes7, Adriana Heguy6, Kathleen G. Dickman7,8, Magali Olivier1, Arthur P. Grollman7,8, Bojan Jelakovic2, and Jiri Zavadil1 Abstract Background: Dietary exposure to cytotoxic and carcinogenic 10Â. Analysis at 3 to 9Â coverage revealed the signature in aristolochic acid (AA) causes severe nephropathy typically asso- 91% of the positive samples. The exome-wide distribution of the ciated with urologic cancers. Monitoring of AA exposure uses predominant A>T transversions exhibited a stochastic pattern, biomarkers such as aristolactam-DNA adducts, detected by mass whereas 83 cancer driver genes were enriched for recurrent non- spectrometry in the kidney cortex, or the somatic A>T transversion synonymous A>T mutations. In two patients, pairs of tumors pattern characteristic of exposure to AA, as revealed by previous from different parts of the urinary tract, including the bladder, DNA-sequencing studies using fresh-frozen tumors. harbored overlapping mutation patterns, suggesting tumor dis- Methods: Here, we report a low-coverage whole-exome semination via cell seeding. sequencing method (LC-WES) optimized for multisample detec- Conclusions: LC-WES analysis of archived tumor tissues is a tion of the AA mutational signature, and demonstrate its utility in reliable method applicable to investigations of both the exposure 17 formalin-fixed paraffin-embedded urothelial tumors obtained to AA and its biologic effects in human carcinomas. from 15 patients with endemic nephropathy, an environmental Impact: By detecting cancers associated with AA exposure in form of AA nephropathy. high-risk populations, LC-WES can support future molecular Results: LC-WES identified the AA signature, alongside signa- epidemiology studies and provide evidence-base for relevant tures of age and APOBEC enzyme activity, in 15 samples preventive measures. Cancer Epidemiol Biomarkers Prev; 24(12); 1873–81. sequenced at the average per-base coverage of approximately Ó2015 AACR. 1Molecular Mechanisms and Biomarkers Group, International Agency Introduction for Research on Cancer, Lyon, France. 2School of Medicine, University of Zagreb, Department of Nephrology, Hypertension, Dialysis, and The International Agency for Research on Cancer (IARC) clas- Transplantation, University Hospital Center Zagreb, Zagreb, Croatia. sified aristolochic acid (AA) as a group 1 carcinogen (1). Exposure 3General Hospital "Dr. Josip Bencevi c," Slavonski Brod, Croatia. to AA, following intake of Aristolochia herbaceous plants as tra- 4 Department of Urology, Weill Cornell Medical College, New York, ditional medicines or due to consumption of bread from flour New York. 5Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France. 6OCS Genome Technology contaminated by Aristolochia seeds, can lead to AA nephropathy Center, New York University Langone Medical Center, New York, New (AAN). AAN is a progressive tubulointerstitial nephropathy with York. 7Department of Pharmacological Sciences, Stony Brook Univer- 8 high risk of developing upper tract urothelial carcinoma (UTUC; sity, Stony Brook, New York. Department of Medicine, Stony Brook – University, Stony Brook, New York. refs. 2 5). In addition, recent studies proposed AA as a factor contributing to the development of hepatocellular (6–8), renal Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/). cell (9, 10) and urinary bladder carcinomas (11), and intrahepatic cholangiocarcinoma (12). Given this growing spectrum of AA- Current address for E. Xylinas: Department of Urology, Cochin Hospital, Paris Descartes University, Paris, France; and current address for S.F. Shariat; Department associated tumor types, AA exposure detection methods for of Urology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria. screening of disease-risk populations are of key importance. Following metabolic activation of AA, aristolactam (AL)-DNA X. Castells, S. Karanovic, and M. Ardin contributed equally to this article. adducts accumulate in the proximal tubules of the renal cortex and Corresponding Author: Jiri Zavadil, International Agency for Research on are used as biomarker of exposure (4, 13, 14). AL-DNA adducts Cancer, 150 cours Albert Thomas, Room 709, Lyon 69008, France. Phone: may persist for over 20 years after the exposure had ceased (15, 16) 33-4-7273-8362; Fax: 33-4-7273-8322; E-mail: [email protected] and can be measured by 32P-postlabeling (14, 17) or by ultra- doi: 10.1158/1055-9965.EPI-15-0553 performance-liquid chromatography-electrospray ionization- Ó2015 American Association for Cancer Research. multistage scan mass spectrometry (UPLC-ESI-MS/MSn), both www.aacrjournals.org 1873 Downloaded from cebp.aacrjournals.org on September 26, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst September 17, 2015; DOI: 10.1158/1055-9965.EPI-15-0553 Castells et al. applicable to formalin-fixed paraffin-embedded (FFPE) tissues DNA purity was evaluated by the NanoDrop 8000 spectropho- (16, 18, 19). However, the 32P-postlabeling method lacks spec- tometer (Thermo Fisher Scientific), and DNA integrity assessed by ificity, and access to the UPLC-ESI-MS/MSn methodology and its 0.8% agarose gel electrophoresis. optimization for biomaterial of low quantity are limiting factors. DNA sequencing established a characteristic AA mutational AL-DNA adduct analysis and TP53 resequencing signature marked by accumulation of A>T transversions within DNA was isolated from the renal cortex and tumor tissues by the 50-Pyr-A-Pur-30 sequence context (enriched for 50-CpApG-30), standard phenol-chloroform extraction techniques. The level of preferentially located on the nontranscribed strand (8–10, 20, AL-DNA adducts in the renal cortex DNA (10–20 mg) was deter- 21). In cancers not associated with AA, such A>T transversions are mined using 32P-postlabeling PAGE, as previously described (13). infrequent (22, 23). The TP53-specific mutations were identified using the AmpliChip We exploited the unique features of the AA mutational signa- p53 Research Test (Roche Molecular Diagnostics), sensitively ture to devise a sensitive method for AA exposure detection, based detecting all single base-pair substitutions and single-base dele- on low-coverage whole-exome sequencing (LC-WES, at approx- tions (13). imately 10Â in contrast with the conventional 100Â coverage), optimized for analysis of tumor-specific DNA of limited quantity WES library preparation, exome capture, and sequencing and integrity extracted from archived FFPE tissues. The studied Two hundred and fifty (250) ng of genomic DNA was sheared urothelial tumor samples originated from a well-characterized by the adaptive focused acoustics method (Covaris, Inc.) to obtain population residing in the endemic nephropathy (EN) regions of approximately 300 bp fragments, with water temperature of 4C, Croatia and Bosnia and Herzegovina (13), with EN being thus far one cycle at 175 Watt peak power, duty factor 10 and 200 cycles the only recognized environmental form of AAN (4, 24). For the per burst. Resulting fragment size was assessed using the 2100 first time, we report in the urothelial tumors of EN patients the Bioanalyzer and High Sensitivity DNA Kit (Agilent Technologies). genome-wide signatures of AA, age, and APOBEC cytidine deam- The sheared DNA was converted into libraries using the Kapa LTP inase activity, thereby extending previous mutational analyses of Library Preparation Kit (Kapa Biosystems). Briefly, the fragmented this population based solely on the mutations of the TP53 tumor- DNA was subjected to end repair reaction followed by poly-A- suppressor gene (4, 13, 25). In addition, we demonstrate the tailing and adapter ligation, excess adapters removed by Agen- ability of LC-WES to elucidate the impact of the AA mutation court AMPure XP beads (Beckman Coulter). Eight cycles of PCR spectra on key homeostatic biologic pathways and to reveal were performed to amplify the libraries with correct adapters on possible mechanisms of tumor dissemination along the urinary both ends. Four libraries (250 ng each) were pooled per exome tract. capture with the Nimblegen SeqCap EZ Exome reagent. Exome- enriched mixes were PCR-amplified in 10 cycles, post-enrichment m fi Materials and Methods libraries pooled in 420 L of water to a nal concentration of 6 pmol/L. This volume was divided and loaded in two lanes of the Patients and tumor samples rapid run mode flow cell for cluster generation and sequencing Exposure to AA was investigated in 15 patients with urothelial on the HiSeq2500, in a paired-end 50 bp cycle run. Multiplexing tumors, diagnosed with EN following established criteria 16 samples per run resulted in the target coverage of approxi- (13, 26). As controls, UTUC samples were obtained from 4 mately 10Â. patients from a metropolitan area of the United States, unlikely Four additional
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