Plenary lecture: The application of integrative sequencing for precision oncology – Arul Chinnaiyan, Michigan Center for Translational Pathology, University of Michigan, USA

09:05-09:45

Room: Hall 1A

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.