Variation in genomic landscape of clear cell renal cell carcinoma across Europe

Scélo, Ghislaine; Riazalhosseini, Yasser; Greger, Liliana; Létourneau, Louis; Gonzàlez-Porta, Mar; Wozniak, Magdalena B.; Bourgey, Mathieu; Harnden, Patricia; Egevad, Lars; Jackson, Sharon M.; Karimzadeh, Mehran; Arseneault, Madeleine; Lepage, Pierre; How‐Kit, Alexandre; Daunay, Antoine; Renault, Victor; Blanché, Hélène; Tubacher, Emmanuel; Sehmoun, Jeremy; Vīksna, Juris; Celms, Edgars; Opmanis, Mārtiņš; Zarins, Andris; Vasudev, Naveen S.; Seywright, Morag; Abedi-Ardekani, Behnoush; Carreira, Christine; Selby, Peter J.; Cartledge, Jon; Byrnes, Graham; Zavadil, Jiří; Su, Jing; Holcátová, Ivana; Brisuda, A.; Заридзе, Давид; Moukeria, Anush; Foretová, Lenka; Navrátilová, Marie; Mateș, Dana; Jinga, Viorel; Av, Artemov; Nedoluzhko, Artem; Mazur, Alexander; Расторгуев, С. М.; Boulygina, Eugenia S.; Heath, Simon; Gut, Marta; Bihoreau, Marie-Thérèse; Lechner, Doris; Foglio, Mario; Gut, Ivo; Skryabin, K. G.; Prokhortchouk, Egor; Cambon‐Thomsen, Anne; Rung, Johan; Bourque, Guillaume; Brennan, Paul; Tost, Jörg; Banks, Rosamonde E.; Brāzma, Alvis; Lathrop, G.M.

doi:10.1038/ncomms6135

Cited by 167 publications

(173 citation statements)

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“…25 The identification of AL-DNA adducts in renal tissue of populations in China, the United Kingdom, and the USA, 38,40 confirm that exposure to AA has occurred, most likely through usage of TCM containing Aristolochia sp . 20,70,71 Recent genome-wide sequence studies of tumors reveal the mutational signature associated with AA to be present in renal cell carcinomas from Romania 87 and Croatia 88 as well as hepatocellular carcinomas and intrahepatic cholangiocarcinomas from China. 46,89 These findings increase the scope of the potential public health risk associated with exposure to AA; however, these recent studies did not include confirmatory exposure to AA by measurement of AL-DNA adducts and the extent of AA exposure is unknown in these cohorts.…”

Section: Discussionmentioning

confidence: 99%

New approaches for biomonitoring exposure to the human carcinogen aristolochic acid

et al. 2015

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Aristolochic acids (AA) are found in all Aristolochia herbaceous plants, many of which have been used worldwide for medicinal purposes for centuries. AA are causal agents of the chronic kidney disease entity termed aristolochic acid nephropathy (AAN) and potent upper urinary tract carcinogens in humans. AAN and upper urinary tract cancers are endemic in rural areas of Croatia and other Balkan countries where exposure to AA occurs through the ingestion of home-baked bread contaminated with Aristolochia seeds. In Asia, exposure to AA occurs through usage of traditional Chinese medicinal herbs containing Aristolochia. Despite warnings from regulatory agencies, traditional Chinese herbs containing AA continue to be used world-wide. In this review, we highlight novel approaches to quantify exposure to AA, by analysis of aristolactam (AL) DNA adducts, employing ultraperformance liquid chromatography–electrospray ionization/multistage mass spectrometry (UPLC-ESI/MSn). DNA adducts are a measure of internal exposure to AA and serve as an important end point for cross-species extrapolation of toxicity data and human risk assessment. The level of sensitivity of UPLC-ESI/MSn surpasses the limits of detection of AL-DNA adducts obtained by 32P-postlabeling techniques, the most widely employed methods for detecting putative DNA adducts in humans. AL-DNA adducts can be measured by UPLC-ESI/MS3, not only in fresh frozen renal tissue, but also in formalin-fixed, paraffin-embedded (FFPE) samples, an underutilized biospecimen for assessing chemical exposures, and in exfoliated urinary cells, a non-invasive approach. The frequent detection of AL DNA adducts in renal tissues, combined with the characteristic mutational spectrum induced by AA in TP53 and other genes provides compelling data for a role of AA in upper urothelial tract cancer.

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Section: Discussionmentioning

confidence: 99%

New approaches for biomonitoring exposure to the human carcinogen aristolochic acid

et al. 2015

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“…AAN is a progressive tubulo-interstitial nephropathy with high risk of developing upper tract urothelial carcinoma (UTUC) (2–5). Additionally, recent studies proposed AA as a factor contributing to the development of hepatocellular (6–8), renal cell (9, 10) and urinary bladder carcinomas (11) and intrahepatic cholangiocarcinoma (12). Given this growing spectrum of AA-associated tumor types, AA exposure detection methods for screening of disease-risk populations are of key importance.…”

Section: Introductionmentioning

confidence: 99%

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

Castells

Karanović

Ardin

et al. 2015

Cancer Epidemiology, Biomarkers &Amp; Prevention

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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) optimized for multi-sample 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 aristolochic acid 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 ~10x. Analysis at 3–9x 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 non-synonymous 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. Conclusion 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.

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“…These data have made substantial contributions to our knowledge of the molecular biology of cancer, and have highlighted novel factors which had not been acknowledged previously. For example, emerging data indicate that the mutational makeup of tumors can significantly vary based on geographical variations among patients, 1 pointing to the contribution of potentially different mechanisms (e.g. environmental) to tumorigenesis in different populations.…”

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confidence: 99%