Naslov
Low-coverage exome sequencing screen in formalin- Fixed Paraffin-Embedded Tumors Reveals Evidence of Exposure to Carcinogenic Aristolochic Acid

Autori
Xavier Castells, Xavier ; Karanović, Sandra ; Ardin, Maude ; Tomić, Karla ; Xylinas, Evanguelos ; Durand, Geoffroy ; Villar, Stephanie ; Forey, Nathalie ; Le Calvez-Kelm, Florence ; Voegele, Catherine ; Karlović, Krešimir ; Mišić, Maja ; Dittrich, Damir ; Dolgalev, Igor ; McKay, James ; Shariat, Shahrokh ; Sidorenko, Viktoria ; Fernandes, Andrea ; Heguy, Adriana ; Dickman, Kathleen ; Olivier, Magali ; Grollman, Arthur ; Jelaković, Bojan ; Zavadil, Jiri

Izvornik
Cancer epidemiology biomarkers & prevention (1055-9965) 24 (2015), 12; 1873-1881

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, pregledni rad, stručni

Ključne riječi
aristolochic acid ; urothelial carcinoma ; formalin-fixed paraffin-embedded tumors ; whole-exome sequencing ; mutational signature

Sažetak
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. 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. 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. 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.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti

POVEZANOST RADA