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首页 » BIOON报道 » Sci Transl Med:全基因组测序技术揭示马兜铃酸引发的上泌尿道癌症的遗传突变特性

Sci Transl Med:全基因组测序技术揭示马兜铃酸引发的上泌尿道癌症的遗传突变特性

来源:生物谷 2013-08-10 13:05

马兜铃属植物,图片来自www.sciencedaily.com

2013年8月10日 讯 /生物谷BIOON/ --近日,刊登在国际杂志Science Translational Medicine上的一篇研究报告中,来自约翰霍普金斯大学和石溪大学的研究者通过研究,揭示了一种由马兜铃酸引发的上泌尿道癌的显著疾病突变特性。马兜铃酸是一种存在于草药中的植物化合物,其被用于治疗关节炎、痛风以及炎症已经数千年了。

马兜铃酸是在马兜铃属植物中发现的一种化合物,2001年时美国FDA已经首次发出警告指出马兜铃酸具有促癌可能;这些年来科学家通过研究发现,暴露于植物性毒素中会引发上泌尿道癌症患者出现一些突变,但是与马兜铃酸相关的全基因组图谱突变分析却研究甚少。

在这项研究中,研究者使用全外显子组测序技术对暴露于马兜铃酸的19位台湾的上泌尿道癌患者进行测序研究,同时对7位无暴露的患癌个体也进行测序研究;研究者Kenneth Kinzler表示,全基因组测序技术可以帮助我们将马兜铃酸暴露直接与个体患癌联系起来,而且也可以帮助我们识别突变特性,来判断哪种毒性可以引发特殊癌症的发生。我们希望使用更多的靶向性全外显子组测序技术来获取更多的数据从而来指导公众进行健康的癌症预防措施。

研究者表示,在马兜铃酸暴露组的每个肿瘤中他们发现了753个突变,而在非暴露组群体的仅有91个突变;突变的水平要远高于由紫外辐射引发的黑色素瘤和吸烟引发的肺癌。在毒性暴露组中个体中也存在大量的DNA碱基ATCG化学编码的错误,毒性暴露肿瘤中,大约有72%其占主要优势的突变为碱基A替换T。

这项研究中,研究者阐述了遗传测序如何被用于鉴别引发癌症聚集发生的致癌物,癌症聚集发生被认为是在一定地理区域、一段时间以及在一类人群中引发的显著大量相似癌症的发生。(生物谷Bioon.com)

Genome-Wide Mutational Signatures of Aristolochic Acid and Its Application as a Screening Tool

Song Ling Poon1,2,*, See-Tong Pang3,*,†, John R. McPherson2,*, Willie Yu1,2,4, Kie Kyon Huang2,5, Peiyong Guan6, Wen-Hui Weng7, Ee Yan Siew1,2, Yujing Liu2,8, Hong Lee Heng1,2, Soo Ching Chong1,2, Anna Gan1,2, Su Ting Tay9, Weng Khong Lim1,2, Ioana Cutcutache2, Dachuan Huang1,2, Lian Dee Ler1,2,4, Maarja-Liisa Nairismägi1,2, Ming Hui Lee9, Ying-Hsu Chang3, Kai-Jie Yu3, Waraporn Chan-on1,2, Bin-Kui Li10, Yun-Fei Yuan11, Chao-Nan Qian11, Kwai-Fong Ng12, Ching-Fang Wu13, Cheng-Lung Hsu14, Ralph M. Bunte15, Michael R. Stratton16, P. Andrew Futreal17, Wing-Kin Sung6,18, Cheng-Keng Chuang3, Choon Kiat Ong1,2, Steven G. Rozen2,19,†, Patrick Tan2,5,9,18,† and Bin Tean Teh1,2,5,†

Aristolochic acid (AA), a natural product of Aristolochia plants found in herbal remedies and health supplements, is a group 1 carcinogen that can cause nephrotoxicity and upper urinary tract urothelial cell carcinoma (UTUC). Whole-genome and exome analysis of nine AA-associated UTUCs revealed a strikingly high somatic mutation rate (150 mutations/Mb), exceeding smoking-associated lung cancer (8 mutations/Mb) and ultraviolet radiation–associated melanoma (111 mutations/Mb). The AA-UTUC mutational signature was characterized by A:T to T:A transversions at the sequence motif A[C|T]AGG, located primarily on nontranscribed strands. AA-induced mutations were also significantly enriched at splice sites, suggesting a role for splice-site mutations in UTUC pathogenesis. RNA sequencing of AA-UTUC confirmed a general up-regulation of nonsense-mediated decay machinery components and aberrant splicing events associated with splice-site mutations. We observed a high frequency of somatic mutations in chromatin modifiers, particularly KDM6A, in AA-UTUC, demonstrated the sufficiency of AA to induce renal dysplasia in mice, and reproduced the AA mutational signature in experimentally treated human renal tubular cells. Finally, exploring other malignancies that were not known to be associated with AA, we screened 93 hepatocellular carcinoma genomes/exomes and identified AA-like mutational signatures in 11. Our study highlights an unusual genome-wide AA mutational signature and the potential use of mutation signatures as “molecular fingerprints” for interrogating high-throughput cancer genome data to infer previous carcinogen exposures.

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