Biospecimens: Advancing Epidemiologic Research

Although the concept of biospecimen repositories, or biobanks, has been known for some time, recent advances in genomics, proteomics, and other technologies have underscored the growing importance of using biospecimens to advance biomedical research.

The availability of biospecimens is critical to epidemiologic research for identifying, developing, and validating biomarkers for cancer susceptibility, precursor states, carcinogenic exposures, and cancer progression and recurrence. "The advent of molecular epidemiologic research, including genome-wide association studies (GWAS), has highlighted the importance of incorporating biospecimens into epidemiologic strategies designed to identify the causes of cancers and the means of their prevention," stated Joseph F. Fraumeni, Jr., M.D., Division Director. Biomarkers hold the key to studies of molecular pathways that lead to cancer development and progression; surrogate markers for drug efficacy and toxicity; and targets for cancer prevention, diagnosis, and treatment. Emerging new fields, such as metabolomics and microbiomics, also benefit from these discoveries.

As Robert N. Hoover, M.D., Sc.D., Director of the Epidemiology and Biostatistics Program, explained, "Biospecimens are an important resource for studies of both cancer etiology and early detection by providing insights into the actual mechanisms of human carcinogenesis. They allow us to avoid some of the traditional challenges of 'conventional' epidemiology, which relies entirely on questionnaire data to measure variables of exposure and susceptibility." For example, beta-carotene intake can be directly measured from blood samples, rather than estimated based on a person’s recollection of his or her usual dietary practices. The same holds true for measuring chemical exposures that may occur without an individual's knowledge, such as polychlorinated biphenyls, which have been implicated in liver cancer and lymphoma.

The Wedgewood Biorepository in Frederick, Maryland. (Photo Credit: Fisher BioServices)

The availability of biospecimens has also allowed the discovery of biologic changes that precede cancer development. For example, an increased level of DNA damage in circulating lymphocytes may be a marker for an increased risk of lymphoid malignancies. "Studying biomarkers of disease allows us to better identify the causes of cancer," Dr. Hoover said. "Investigating events that occur closer to the time of an exposure can provide important etiologic clues long before the cancer itself develops."

Molecular epidemiology represents a strategy to probe into the nature of an epidemiologic association–such as the relation of obesity to breast cancer risk–by helping to elucidate the mechanisms involved. "Analysis of biospecimens has allowed us to implicate circulating estrogen levels in obese post-menopausal women as a likely mechanism for the increased breast cancer risk," Dr. Hoover said.

Studies differ in the types of specimens and the timing of sample collection. Most studies collect specimens at only one point in time. Others, such as the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which contains about 2.9 million specimens in its repository, have multiple specimens collected at different points during the follow-up period. These serial specimens allow researchers to correlate changes in the activity of certain molecules with the onset of different types of disease. "Most studies have only one blood sample, and a few have two or possibly three samples," Dr. Hoover explained. "The availability of multiple blood specimens in PLCO provides a rare and an extremely valuable resource for studies of cancer etiology as well as early detection."

Traditionally, the search for early markers of cancer development has involved comparing people with cancer to those without it and examining the differences. Once a possible marker is found, it is then applied to a test population to see how well it identifies people with early-stage disease compared with those who remain disease-free. "PLCO is an ideal resource for these tests," Dr. Hoover said. "It's extremely advantageous when a researcher wants samples from people at least a year prior to a clinical cancer diagnosis, for example. If the biomarker predicts disease in that group, then you know you have a robust marker for early-stage disease. This greatly improves the outcomes of therapy."

DCEG's extensive biospecimen collection now includes nearly 12 million specimens, triple the number from just 10 years ago. The collection—stored in freezers at NCI-Frederick—includes a wide variety of specimens, such as blood, urine, and tissue, as well as DNA, RNA, and proteins extracted from many of those samples. Investigators may gain access to many of these biospecimens through a peer-reviewed application process.

Karen E. Pitt, Ph.D., DCEG special assistant for biological resources, oversees the Division’s biospecimen collection and actively looks for ways to improve the way DCEG processes, stores, and tracks its biospecimens. Steps are taken to ensure that DCEG's biorepositories meet all standards and guidelines for collecting, handling, and storing biospecimens as established by the International Society for Biological and Environmental Repositories and the NCI Office of Biorepositories and Biospecimen Research. The Division's biospecimens are tracked using the Biospecimen Inventory Processing System (BSI-II), which stores information on each specimen as well as any modifications made to it over time. Many large projects have web portals that describe study specimens and the application procedures required for gaining access to them.

Robert Hoover and Karen Pitt

For the past two years, Dr. Pitt has been working with DCEG investigators, repository contract staff, and others to evaluate state-of-the-art equipment for specimen storage and handling, including increased use of robotics and automation to minimize contamination, enhance quality, and accelerate specimen handling. She and her colleagues have identified new equipment that will process samples more rapidly, improve the characterization of specimens, reduce labor and overall storage costs, and increase energy efficiency. To conserve valuable specimens, she has explored new techniques that permit biomarker assays requiring only minute quantities of samples. She also led efforts to establish a new DNA staging laboratory dedicated to preparing biological samples for genomic analysis.

Recently, Congress requested that NIH describe the methods used by the Intramural Research Program to track and store human biospecimens. Shelia Hoar Zahm, Sc.D., DCEG Deputy Director, served as cochair of the NIH Scientific Directors Subcommittee on Biorepository Practices and Guidelines. She played an integral role in developing the "Guidelines for Human Biospecimen Storage and Tracking within the NIH Intramural Research Program" and led efforts to develop a legislative implementation action plan to address the new congressional reporting requirements related to human biospecimen storage. "Congress has asked NIH how it tracks its samples," Dr. Zahm said. "We greatly value the details of a good inventory system and the agreements that document how biospecimens can be used when they are transported to or from NIH."

Careful handling and documentation of specimens have greatly accelerated DCEG's research program in molecular epidemiology. These efforts are augmented by NCI's Applied Molecular Pathology Laboratory, which carries out high-throughput studies of gene expression and somatic mutations in tumor specimens collected as part of GWAS. The high-throughput construction of tissue microarrays enables the molecular subclassification of cancers and allows differential evaluation of risk factors for a variety of tumor subtypes. The approach also serves to link genomic and molecular alterations within tumors with the germline variants uncovered by GWAS and more fully illuminates the carcinogenic process in tumor induction and progression. These efforts are designed to catalyze downstream biological research and speed the translation of genomic discoveries into clinical practice while strengthening NCI's multidisciplinary research and training programs in cancer genetics and biology.

—Catherine B. McClave, M.S.

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