报告题目：The Application of Integrative Sequencing for Precision Oncology

报告时间：2018年10月30日（周二）14：00-16：00

报告地点：闵行校区李政道图书馆B1报告厅

报告人：Arul M.Chinnaiyan

美国医学科学院院士

美国艺术与科学院院士

密西根大学医学院S.P. Hicks冠名病理学教授

语言：英文

报告人简介：

Arul M. Chinnaiyan，美国医学科学院院士、美国艺术与科学院院士，密西根大学医学院S.P. Hicks冠名病理学教授、病理学和泌尿学教授。2007年起，他担任密歇根大学转化病理学中心（MCTP）主任，该中心的目标是探索并研究人类疾病（尤其是癌症），全新的分子标志物以及治疗策略。Chinnaiyan教授拥有临床病理医师执照，还担任病理学信息部主任以及癌症生物信息学部主任。他还当选为美国临床调查学会和美国医师协会成员。

Chinnaiyan教授拥有医学、哲学双博士学位，获得50多项国内、国际大奖，包括密歇根大学医学院院长办公室颁发的基础科学研究奖，AMGEN杰出研究者奖，皮尤生物医学学者奖，Burroughs欢迎基金会临床转化研究奖，2006年Benjamin Castleman奖，2007年Ramzi Cotran青年研究者奖，担任霍华德休斯医学研究所（Howard Hughes Medical Institute）研究员。2016年1月，他作为十五位世界顶尖癌症专家之一，与时任副总统拜登讨论“抗癌登月计划”，谋划行动方案。

Arul Chinnaiyan教授发表超过450篇研究论文。他重点利用功能性基因组、蛋白质组学、代谢组学和生物信息学等方法来研究人类恶性癌症，以了解肿瘤生物学的分子机理以及探索发现新的临床生物标志物。他发现了许多前列腺癌特异性的分子标志物，包括AMACR，EZH₂，hepsin，肌氨酸代谢物和TMPRSS₂-ETS融合基因等。AMACR和TMPRSS₂-ERG已经在美国全国各地临床推广，应用于诊断评估前列腺癌症的发生以及发展。2012年，通过分析检测尿液中TMPRSS₂-ERG用于前列腺癌的诊断以及预后也开始大规模临床应用。

迄今为止，Chinnaiyan教授最具有里程碑意义的研究是在大多数前列腺癌中发现TMPRSS₂-ETS基因融合。该研究首次指出，TMPRSS₂-ETS基因融合是导致前列腺癌的根本原因，从而成为了一个高度特异性的生物标志物，同时也是非常好的治疗靶标，就好像BCR-ABL基因融合既是慢性髓性白血病的生物标志物，也是其治疗靶标一样。前列腺癌中，该基因融合的发现具有划时代的意义，重新定义了该疾病以及其他常见上皮癌的分子基础。参与这些研究的团队由此获得了2007年AACR团队科学奖，该研究结果于2012年开始大面积于临床应用，转化为更有效的前列腺癌诊断和预后手段。

Chinnaiyan教授还开发了全球最普及的癌症分析生物信息学资源Oncomine（www.oncomine.org），免费为学术界提供服务（来自30多个国家的15,000多名注册用户）。2011年他在密歇根大学癌症研究中心发起了一项名为MI-ONCOSEQ的探索性临床测序计划，该研究计划旨在分析评估新一代高通量测序技术在个性化肿瘤学中的应用。

报告内容简介：

To exploit the rapid advances in high throughput DNA sequencing technologies to realize the goals of “precision cancer medicine” we established the Michigan Oncology Sequencing Center (MI-ONCOSEQ). An “integrative sequencing approach” carried out in a CLIA-certified laboratory is utilized to provide a comprehensive landscape of the genetic alterations in individual tumor specimens for the purpose of identifying informative and/or actionable mutations. This approach enables the detection of point mutations, insertions/deletions, gene fusions and rearrangements, amplifications/deletions, and outlier expressed genes. Furthermore, we can identify certain germline alterations that may also be relevant. We applied this to over 3000 adult and pediatric patients thus far and discovered informative and/or actionable mutation in nearly 60% of cases. Moreover, we identified germline mutations in ~10% of patients (high penetrance cancer risk genes in 4.4% of patients and mutations in moderate penetrance cancer risk genes in 4.7% of patients).

Concomitantly, significant research discoveries were made through our clinical sequencing efforts. We discovered a novel gene fusion, NAB2-STAT6 in a rare cancer, solitary fibrous tumor, in all cases we tested (Nat Genet, 45:180-5); this result will be very important in designing future therapies to treat this cancer. We also identified gene fusions involving the FGFR gene in diverse cancers, including breast and prostate cancer (Cancer Discov, 3:636-647). The exciting part of this discovery is that these FGFR fusions are targetable by available drugs. We identified activating mutations in the estrogen receptor (ESR1) gene in a cohort of breast cancer patients that are an important mechanism of acquired endocrine resistance in breast cancer therapy (Nat Genet. 45(12):1446-51). In collaboration with the Stand Up 2 Cancer-Prostate Cancer Foundation (SU2C-PCF) International Dream Team Consortium, we led the study to develop a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC) by obtaining a comprehensive landscape of cancer-related mutations in order to potentially incorporate this information for therapeutic strategies and/or enrolling subjects into appropriate clinical trials (Cell. 2015 May 21;161(5):1215-28). In collaboration with colleagues in Pediatrics, we published the results from the first 102 pediatric patients enrolled in the PEDS-ONCOSEQ clinical sequencing study (JAMA, Vol. 314, No. 9, Sept. 1, 2015). The study was the first to report on combined multiple genome sequencing approaches (tumor as well as normal DNA and tumor RNA) in real-time, in children and young adults with relapsed cancers. Most recently, we carried out a comprehensive molecular analysis of metastatic solid tumors of diverse lineage and biopsy site from 500 adult patients (MET500 cohort) by performing clinical-grade integrative whole exome (tumor/normal) and transcriptome sequencing (Nature. 2017 Aug 17;548(7667):297-303). Overall, our results demonstrated that integrative sequence analysis provides clinically relevant, multidimensional view of the complex molecular landscape and microenvironment of metastatic cancers.