Division of Extramural Activities Annual Report 2002 National Institutes of Health National Cancer Institute Molecular Diagnosis of Cancer Gene expression profiling using DNA microarrays is a technology that arose as a consequence of the Human Genome Project. With DNA microarrays, it is possible to determine the activity (“expression”) of tens of thousands of genes in parallel on microarray plates. The expression of genes influences the biological behavior of a cell because it dictates which proteins the cell can make and gives cells their unique characteristics. In the DNA microarray images shown at the bottom of the cover illustration, each spot represents a different human gene. Red, yellow, and green spots indicate that a gene is expressed at high, intermediate, and low levels, respectively. The pattern of expression of all of the genes in a cell constitutes its gene expression “profile.” Using DNA microarrays, different types of normal and malignant cells can be distinguished from one another because they have distinct gene expression profiles. Shown at the top of the cover illustration are photomicrographs of lymph node biopsies from two patients with diffuse large B cell lymphoma. The tumor at the right belongs to the germinal center B cell-like subgroup of diffuse large B cell lymphoma. Patients with this lymphoma type have a relatively favorable 5-year survival rate of 59% following multi-agent chemotherapy. The tumor at the left belongs to the activated B cell-like subgroup of diffuse large B cell lymphoma. Patients with this lymphoma type have a less favorable 5-year survival rate of 31%. Although the tumors from these patients were indistinguishable histologically, they had striking differences in their gene expression profiles, as exemplified by the microarray images shown below each lymphoma subgroup. Gene expression profiling has therefore revealed that the diagnostic category of diffuse large B cell lymphoma actually harbors more than one molecularly distinct disease. DNA microarray technology holds great promise for classifying different cancers, defining molecular subtypes of a tumor, optimizing treatment strategies, and monitoring clinical response to treatment. Cover Illustration: Courtesy of Louis M. Staudt, M.D., Ph.D., Chief, Lymphoid Malignancies Section, Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health. Reference: Staudt LM. Molecular diagnosis of the hematologic cancers. N Engl J Med 2003;348:1777-85. Foreword Since Congress passed the National Cancer Act in 1971, we have been experiencing exponential growth in our knowledge of cancer. That sci- entific knowledge base, which is a primary responsibility of the National Cancer Institute (NCI), is the first stage along a continuum of discovery, development, and delivery that will ultimately take us to the goal I have challenged myself and the entire cancer community to reach by the year 2015—the elimination of suffering and death from cancer. The know-ledge that we discover, whether at the level of the gene, molecule, cell, tissue, organ, individual, or population, feeds development—the process of creating tools and interventions to reduce the cancer burden—with the end result being delivery, the process of disseminating, facilitating, and promoting evidence- based prevention, detection, diagnosis, and treatment practices and policies. The NCI is committed to exploiting that discovery-development-delivery strategy to achieve the 2015 challenge goal. In large measure, this will be accomplished through the efforts of outstanding NCI extramural scientists who have and will continue to enhance the scientific knowledge base. The NCI Division of Extramural Activities (DEA), carries a major respon- sibility for strengthening the scientific knowledge base by conducting the scientific review of applications for support of extramural research; managing and coordinating the Institute’s advisory activities, including the Presidentially appointed National Cancer Advisory Board and the Board of Scientific Advisors; formulating, coordinating, and disseminating operating policies pertaining to extramural programs; and analyzing and reporting on all extramural research programs funded by the NCI. The DEA Annual Report provides a comprehensive look at each of the major areas of responsibility within the DEA, including referral, review, advisory activities, information resources, portfolio tracking and analysis, management, and extramural policy. I am pleased to present this annual report, which not only describes the DEA’s activities and accomplishments and its work in the context of achieving the NCI’s overall scientific goal of reducing the burden of cancer, but also gratefully acknowledges the hundreds of researchers who have contributed to the success of our peer-review and advisory activities. Andrew C. von Eschenbach, M.D. Director, National Cancer Institute Introduction The mission and responsibilities of the NCI Division of Extramural Activities (DEA) affect, in some way, all extramural scientists receiving research or training support from the NCI. The DEA is centrally involved in all aspects of grant development and tracking, from original conception of research and training programs for introduction in the extramural community, to issuance of announcements of such programs, to receipt and referral of incoming applications, to review and final approval of the applications, to coding and tracking after disbursement of funds. In brief, the DEA was established to: Provide advice and guidance to potential applicants Refer incoming grant applications to appropriate programs within the NCI Provide the highest quality and most effective scientific peer review and oversight of extramural research Coordinate and administer advisory activities, such as the National Cancer Advisory Board (NCAB) and Board of Scientific Advisors (BSA), related to the various aspects of the NCI mission Establish and disseminate extramural policies and procedures, such as requirements for inclusion of certain populations in research, actions for ensuring research integrity, budgetary limitations for grant applications, and policies to expedite funding Track the NCI research portfolio (more than 6,445 research and training awards) using consistent, budget-linked scientific information to provide a basis for budget projections and to serve as a resource for the dissemination of information about cancer. In essence, the DEA is the organizational component of the NCI that coordinates the scientific review of extramural research before funding and provides systematic surveillance of that research after awards are made. In this latter role, the DEA assists the NCI in its goal of achieving a balanced portfolio of research in biology, behavior, epidemiology, and cancer con- trol, prevention, detection, diagnosis, and treatment, as well as long-term survival/survivorship, rehabilitation, and end-of-life issues. In addition, the DEA serves as a focal point for information about the NCI’s peer-review and grants policies. DEA maintains a comprehensive Web site providing detailed information and links to application procedures and to announcements regarding funding opportunities—see http://deainfo.nci.nih.gov/funding.htm.*† * See Appendix A for a glossary of acronyms used in this report. † A directory of Cancer Information Sources on the Internet, including selected DEA and NCI Web sites, is included in Appendix G. Grant Referral: DEA as the First Point of Contact with the NCI In Fiscal Year (FY) 2002, the NCI received 9,346 grant applications for referral (see Table 1). These included applications for 43 different types of funding award mechanisms (see Appendix F), including Clinical Investigator Awards (K08), Research Program Projects (P01), Cancer Center Support Grants (CCSGs) (P30), Research Projects (R01), and Small Business Innovation Research (SBIR) Grants (R43). During FY2002, the Program Coordination and Referral Branch (PCRB) in the DEA was responsible for receipt, referral, and assignment of applications, as well as other program development functions. Upon receipt of a primary or secondary assignment to the NCI by the National Institutes of Health (NIH) Center for Scientific Review (CSR), the DEA Referral Officer (RO) assigns all incoming applications to one of the 45 NCI extramural research program areas. The RO also must track, in real time, the review status of all applications assigned to the NCI. The RO distributes all of the applications directly reviewed by the DEA for the NCI. These applications include P01 Program Projects, P30 Centers, P20 Planning Grants, P50 Specialized Centers, R13 Conference Grants, R03 Small Grants, T32 Training Grants, certain R01 Research Project Grants, and U series Cooperative Agreement applications. These applications are sent to one of the three DEA Review Branches for assignment to individual Scientific Review Administrators (SRAs) and to one of the seven subcommittees of the NCI Initial Review Group (IRG) or to a Special Emphasis Panel (SEP), as described later. The DEA is often the first point of contact for applicants and the recipient of Letters of Intent from potential applicants for multiproject Program Grants (P01) and Conference Grants (R13). It is also the only point of receipt for distribution to program staff of Research Supplements for Underrepresented Minorities, Supplements to Promote Reentry Into Biomedical and Behavioral Research Careers, Research Supplements for Individuals