Cancer Genomics Project
The Cancer Genomics and Personalized Medicine project under way at BGI involves building a cancer mutation map and determining the frequency of recurrent mutations and identifying cancer driver genes. Much progress has been made to date in surveying the landscape of somatic mutations and genomic variation in cancer and how they relate to tumor biology. Presenters at the meeting described work under way to identify biomarkers to support oncology drug development and drive the discovery of personalized cancer therapies and methods for predicting tumor response to treatment.
James Watters, Ph.D., head of applied genomics at Sanofi Oncology, suggested that it can hopefully help improve the field’s overall track record. About 1 in 20 oncology drugs in development succeed in becoming commercialized, with many failing in late-stage trails; approximately half of the compounds that make it to Phase III studies fail.
Describing next-generation sequencing (NGS) technology as “quite transformative” for translational medicine, Dr. Watters outlined four main approaches for how NGS is being applied to study human tumors: PCR amplicon sequencing, targeted gene panel hybrid capture, whole exome sequencing/hybrid capture, and RNA-Seq. Each strategy has advantages and disadvantages, and when a novel somatic mutation is identified, one of the main challenges is to determine whether it has functional consequences and to understand what the biological and phenotypic effects might be.
Assessing structural changes and complex rearrangements, detecting copy number variation (CNV) with high sensitivity, and performing NGS at the single-cell level represent additional ongoing challenges.
Funda Meric-Bernstam, M.D., medical director and professor, Institute for Personalized Cancer Therapy (IPCT), University of Texas, MD Anderson Cancer Center, described the evolution of genomic biomarker-selected clinical trials at her institution. When possible, patients are allocated to Phase II trials based on a molecular profile composed of somatic mutations linked to tumor types and predicted drug response.
Dr. Meric-Bernstam explained that nearly 600 patients are enrolled in the IPCT Clearinghouse Protocol, which is aimed at establishing a database of frequent somatic mutations in various patient populations and tumor types to assist in the delivery of personalized cancer therapy.
Mao Mao, Ph.D., research fellow at Pfizer and president of the Asian Cancer Research Group, jointly established by Eli Lilly, Merck, and Pfizer, emphasized the importance of identifying actionable mutations as the basis for developing targeted cancer therapeutics. To search for drivers of oncogenetic changes at the cellular and subcellular level, the group screens whole tumor genomes to identify potential drivers and their prevalence in well-annotated cohorts. The initial findings of NGS have shown that “30X whole genome sequencing is cost effective,” said Dr. Mao.
Dr. Mao explained that about half of all hepatocellular carcinomas were related to hepatitis B virus (HBV) infection. HBV is a double-stranded virus capable of integrating into the human genome. Dr. Mao’s group is taking a whole genome sequencing approach, using paired positive/negative tumor samples to study the hypothesis that HBV integration is associated with cancer.
The group has extracted the HBV integration breakpoints and found that tumor samples tend to have more HBV integrations than nontumor samples. Of 344 HBV integrations in tumor samples, 163 (47.4%) significantly affected the tumor, reported Dr. Mao. Integration breakpoints recurred in six particular genes in more than one sample, suggesting that HBV has preferred integration sites.