Why Genomics Research Is Critical to Progress against Cancer
The study of cancer genomes has revealed abnormalities in genes that drive the development and growth of many types of cancer. This knowledge has improved our understanding of the biology of cancer and led to new methods of diagnosing and treating the disease.
For example, the discovery of cancer-causing genetic and epigenetic changes in tumors has enabled the development of therapies that target these changes as well as diagnostic tests that identify patients who may benefit from these therapies. One such targeted drug is vemurafenib (Zelboraf®), which was approved by the Food and Drug Administration (FDA) in 2011 for the treatment of some patients with melanoma who have a specific mutation in the BRAF gene as detected by an FDA-approved test.
Over the past decade, large-scale research projects have begun to survey and catalog the genomic changes associated with a number of types of cancer. These efforts have revealed unexpected genetic similarities across different types of tumors. For instance, mutations in the HER2 gene (distinct from amplifications of this gene, for which therapies have been developed for breast, esophageal, and gastric cancers) have been found in a number of cancers, including breast, bladder, pancreatic, and ovarian.
Researchers have also shown that a given type of cancer, such as breast, lung, and stomach, may have several molecular subtypes. For some types of cancer, the existence of certain subtypes had not been known until researchers began to profile the genomes of tumor cells.
The results of these projects illustrate the diverse landscape of genetic alterations in cancer and provide a foundation for understanding the molecular basis of this group of diseases.
Opportunities in Cancer Genomics Research
Although a large number of genetic alterations that drive the development and progression of many types of cancer have been identified through large-scale research studies, some tumor types have not been deeply characterized. New technologies and the knowledge gained from previous genomic studies could be used to define the full set of driver mutations and other alterations to DNA and RNA in many cancers. Studies that compare genomic information from tumors and normal tissue from the same patient allow researchers to discover genomic changes that may drive cancer.
Another opportunity is to expand the current use of genomic methods to investigate the molecular basis of clinical phenotypes. This approach could help researchers identify genetic changes that may distinguish aggressive cancers from indolent ones, for example. Similar approaches could be used to study the molecular basis of response to a given therapy, as well as mechanisms of resistance to treatment.
The wealth of data emerging from cancer genome studies increasingly will be integrated with patients’ medical histories and clinical data. These integrated results could be used to develop more tailored approaches to cancer diagnosis and treatment, as well as to improve methods of predicting cancer risk, prognosis, and response to treatment.
Genomic tools will also be essential for analyzing results from precision medicine clinical trials, such as those being conducted by NCI's National Clinical Trials Network.
Challenges in Cancer Genomics Research
Comprehensive analysis of cancer genomes has revealed a great deal of diversity in the genetic abnormalities found within cancers of a single type. Moreover, recurrent genetic alterations within these cancers are often involved in only a small percentage of cases. Identifying which genetic changes initiate cancer development and discovering rare genetic alterations that drive cancers are therefore challenges for the field.
Another challenge is acquiring high-quality biological samples needed for genomic studies, particularly for tumor types that are uncommon or rare, or those not treated primarily by surgery.
Developing cell lines and animal models that capture the diversity of human cancer is also an unmet need. Models of rare cancer subtypes may be nonexistent or underrepresented, and there are no models for many recurrent genetic lesions in human cancer.
Managing and analyzing the vast amounts of data involved in genomic studies are additional challenges for the field. This area of research requires an efficient bioinformatics infrastructure and increasingly involves contributions of data and expertise from cross-disciplinary teams.
NCI’s Role in Cancer Genomics Research
Pursuing the genetic foundations of cancer is a vital part of NCI’s current research. In its established programs in genomics research, NCI is using high-throughput techniques to identify and study mutations, large rearrangements of the genome, increases and decreases in DNA copy number, and chemical modifications of DNA, as well as changes in the expression of RNA and proteins. Several NCI programs support research and related efforts to translate these findings into clinical advances for patients.
Recognizing the importance of genomics for improving our understanding of cancer and how to treat it, NCI established the Center for Cancer Genomics (CCG) to develop genomic tools and apply them to the goal of improving the diagnosis and treatment of patients with cancer. For example, through CCG, NCI is supporting research to identify the genetic drivers of cancer, to advance the translation of genomic insights to clinical care, and to protect privacy without hindering treatment or research.
This program aims to characterize driver genetic events that occur in 2% or more cases of lung adenocarcinoma, colorectal cancer, and ovarian cancer. These cases are drawn from completed clinical trials and a biobank with thorough clinical information, allowing the program to determine if molecular features of the tumors influenced the response to treatment. By sequencing larger numbers of cases, the CDDP will have the statistical power to discover recurrently mutated genes in cancer that may drive the oncogenic process.
This initiative develops and applies DNA sequencing and other methods to characterize genomic changes in tumors. The project aims to identify physiologic pathways that are disrupted in certain cancers by uncovering the full spectrum of alterations in tumors, which could lead to improvements in diagnosis and treatment. CGCI completed work on medulloblastoma and non-Hodgkin lymphoma and is currently focusing on Burkitt Lymphoma and HIV-associated cancers.
CTD2 supports research that uses information from cancer genome projects to identify potential targets for developing new cancer diagnostics and treatments. The network aims to bridge the gap between the volumes of data generated by genomic characterization studies and the ability to use these data to develop cancer therapies.
Through robust cross-network collaborations, CTD2 uses innovative bioinformatics and functional biology to mine data to find alterations that potentially influence tumor biology, characterize the functional roles of candidate alterations in cancers, and identify novel approaches that target causative alterations either directly or indirectly. A list of all the projects can be found on the CTD2 Data Portal.
The GDC is an expandable cancer genomic data-sharing platform established by CCG to store and integrate the diverse datasets from NCI programs and external contributors. The GDC removes barriers to genomics discoveries by bringing together data, making contributed datasets compatible with each other, and providing a searchable data portal with analysis tools. Users can mine the data from the GDC and combine them with data from their own research or that of third parties, increasing the statistical power of their studies.
Investigators with the TCGA Research Network have conducted large-scale genomic studies of more than 30 types of cancer, including 10 rare cancers. This effort has been instrumental in identifying genomic drivers and discovering molecular subtypes in many different cancers. More than 1,000 papers have been published that have used this robust data set. TCGA is a joint effort by NCI and the National Human Genome Research Institute.
TCGA investigators published a cross-tumor analysis of 12 types of cancer, called the Pan-Cancer Analysis, which brought together more than 250 collaborators from 30 institutions to analyze the same dataset. Some of the results point to new uses for existing drugs based on shared molecular targets across cancer types.Having helped to set the standards for characterizing the genomic underpinnings of dozens of cancers on a large scale, TCGA is moving into its next phase. A press release includes a brief description of the history of the program and a summary of the future of cancer genomics within CCG.
Investigators with the TARGET program have conducted genomic analyses of several childhood cancers, including acute lymphoblastic leukemia, acute myeloid leukemia, kidney tumors, neuroblastoma, and osteosarcoma. Results from TARGET studies have pointed to new uses for existing targeted therapies, identified potential targets for new therapies, and influenced the design of Children’s Oncology Group (COG) clinical trials.
The information developed by TARGET and TCGA is stored in the GDC and can be accessed and analyzed by the entire cancer research community, even before reports related to the data have been published.
Other NCI Projects in Cancer Genomics Research
DCEG researchers investigate the biological basis of inherited and acquired genetic variants associated with cancer susceptibility using genome-wide association studies, exome sequencing, and candidate gene studies. Their goal is to identify the genetic cause of a specific cancer, understand how genes contribute to the disease, and use that understanding to help develop better prevention and treatment strategies.
The Exceptional Responders Initiative seeks to explore the genetic basis for the dramatic positive responses in a small fraction of patients treated with a therapy that normally does not benefit most patients treated with it. Clinicians propose cases to the Exceptional Responder Initiative of patients who have been treated with any systemic therapy, whether the patient was on a clinical trial or received standard care. Tumor tissue—and normal tissue, if available—are subjected to whole exome and targeted DNA sequencing, as well as to messenger RNA sequencing, and these results are analyzed in light of the treatment the patient received. The project is a joint initiative by NCI’s Division of Cancer Treatment and Diagnosis and CCG.
ICGC researchers are generating a catalog of genomic abnormalities in tumors from 50 different cancer types or subtypes of clinical and societal importance across the globe. TCGA, TARGET, and CGCI are all members of ICGC.
CTSP applies genomic science to NCI-sponsored clinical trials of the National Clinical Trials Network (NCTN). By studying the genomes of patients who have undergone treatment as part of an NCTN trial, this initiative seeks to understand why some patients respond well to a particular treatment while others with the same type of cancer experience disease progression. Investigators will ask, what is different about the genomic features of this tumor that may have led to a poor response, or to the development of drug resistance? With this information, scientists and clinicians can begin to better predict responses and develop strategies for tailoring treatment. CTSP is a collaboration between CCG and the Division of Cancer Treatment and Diagnosis (DCTD).