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Discovering the causes of cancer and the means of prevention

Mark H. Greene, M.D.

Senior Investigator
Division of Cancer Epidemiology & Genetics

NCI Shady Grove | Room 6E456



Dr. Greene received a B.A. (English) from Yale College, an M.D. from Tufts University, and completed his training in Internal Medicine at the Massachusetts General Hospital in Boston. He spent three years with the Epidemic Intelligence Service of the U.S. Centers for Disease Control and Prevention, and then came to the National Cancer Institute in 1975 as a Staff Fellow in the Environmental Epidemiology Branch. Dr. Greene completed his medical oncology fellowship at the Medicine Branch, NCI, and is board-certified in both Internal Medicine and Medical Oncology. In 1977, he became a Senior Investigator and, subsequently, Coordinator of Family Studies within the Environmental Epidemiology Branch (EEB). In 1984, Dr. Greene was appointed Deputy Branch Chief of EEB. In 1985, he left government service to enter the private practice of medical oncology and hematology in Sun City, Arizona. In 1991, he joined the faculty of Mayo Clinic Scottsdale as a Professor of Oncology in the Mayo Medical School. While at Mayo, he was a participating investigator with a variety of cooperative oncology groups, including NCCTG, ECOG and NSABP. Dr. Greene became the Principal Investigator for the Mayo Cancer Center’s Familial Cancer Program in 1994. In the fall of 1999, he returned to NCI as the Branch Chief of the newly-created Clinical Genetics Branch. Dr. Greene served as Branch Chief until 2013, and continues to direct studies as a senior investigator within the branch. His major research interests are familial/hereditary cancers, genetic determinants of outcomes following cancer treatment, as well as intervention studies (cancer screening, surgical risk reduction and chemoprevention) in genetically at-risk populations, genetic modifiers of cancer risk, and leveraging alert clinical observations into novel etiologic insights.

Research Interests

With the discovery of many of the genes underlying the hereditary components of the common adult malignancies (i.e., BRCA1/2 in hereditary breast/ovarian cancer, the mismatch repair genes in HNPCC, the CDKN2A gene in hereditary melanoma, etc.), the molecular biology of familial cancer has challenged our ability to manage germline mutation carriers in an effective, evidence-based fashion. Clinicians and patients alike are have worked together to take advantage of these molecular breakthroughs, and the past decade has witnessed major improvements in evidence-based approaches to the management of high-risk individuals, but important questions remain. The Clinical Genetics Branch focuses its resources on acquiring the data needed to address these issues, both for rare, highly-penetrant genes and common, lower penetrance genes, which contribute to the development of cancer in humans.

The National Ovarian Cancer Prevention and Early Detection Study (GOG-0199)

This is Dr. Greene’s major research initiative. GOG-0199 is a two-arm, prospective, nonrandomized natural history study of women at increased genetic risk of ovarian cancer. It is a unique collaborative undertaking between NCI’s Intramural Research Program (DCEG Clinical Genetics Branch), Extramural Research Program (DCP CCOP Program; DCTD CTEP Program), the Gynecologic Oncology Group (GOG), and the NCI-sponsored Cancer Genetics Network (CGN). He is comparing women who elect risk-reducing salpingo-oophorectomy (RRSO) to those who choose to participate in a pilot study of a novel ovarian cancer screening strategy (the “Risk of Ovarian Cancer Algorithm,” aka ‘ROCA’). The study closed to accrual in November 2007, after 5 years’ prospective follow-up, having enrolled 1000 women in the RRSO arm and 1600 women in the screening arm. Final data form retrieval, data QC and analytic database construction are underway, to permit analysis of Primary Study Endpoints, which include comparisons of the cancer incidence, medical decision-making, quality of life, and performance characteristics of the ROCA algorithm between the two study arms. The BRCA mutation status of all subjects has been defined (mutation-negative/family history-positive women were eligible for this study), and central review of the surgical specimens from all baseline risk-reducing salpingo-oophorectomies has been completed. We have also assembled a meticulously-annotated biospecimen repository to support diverse translational research endpoints.

The current translational research focus for GOG-0199 relates to our active membership in CIMBA (Consortium of Investigators of Modifiers of BRCA1/2), an international consortium of 30 research groups which has assembled a collection of 30,000 BRCA mutation carriers to conduct adequately-powered analyses of candidate genetic modifiers and related genomic research. He has co-authored 31 publications through this collaboration. Ongoing analyses include (1) performance characteristics of the ROCA screening algorithm (GOG + CGN); (2) histopathology of 1,000 RRSO surgical specimens (both ovaries and fallopian tubes); (3) factors influencing the choice between RRSO and screening among high-risk women; and (4) baseline quality-of-life profiles of women electing RRSO and screening.

Hereditary Breast/Ovarian Cancer (HBOC)

This syndrome has been under active investigation within the Division for the past 40 years. The long-term clinical follow-up of a cohort of 60 HBOC families, 33 of which have deleterious BRCA1/2 mutations, has provided a basis for ongoing CGB research targeting HBOC. Currently, enrollment of new subjects into active clinical research protocols has ended, with the exceptions of our behavioral studies targeting the needs of young (less than 30 years old) BRCA 1/2 mutation carriers (NCI Protocol 09-C-N074). Analysis of data collected under prior HBOC-related projects (Protocols 01-C-0009; 02-C-0212; 02-C-0268) continues. Combining DNA samples and clinical data from the various HBOC studies (Hereditary Breast/Ovarian Cancer protocol, HBOC Breast Imaging protocol, and GOG-0199), we have contributed > 1,100 subjects to the collaborative analyses being conducted by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Nearly 35 publications have resulted from this effort to date. This protocol has closed to new patient accrual, but translational analyses continue, utilizing the carefully-annotated biospecimens which have been collected from these study populations. 

Familial Testicular Cancer (FTC)

The mapping of a familial testicular cancer susceptibility gene to chromosome Xq27, and the initiation of a major new DCEG testicular cancer case-control study resulted in CGB re-activating DCEG's Familial Testicular Cancer Study. We joined the International Testicular Cancer Linkage Consortium (ITCLC), and contributed DNA and clinical data from our multiple-case families to the FTC cancer susceptibility gene mapping and positional cloning effort. Standard linkage analysis failed to corroborate the Xq27 locus finding, and further suggested that the genetic basis for FTC may represent the combined effects of multiple low-penetrance genes, rather than a classical, single highly-penetrant gene. We are bringing selected testicular cancer families to the NIH Clinical Center for more detailed etiologic studies [NCI Protocol 02-C-0178]. CGB is taking the lead in performing an expert, central pathology review comparing familial with sporadic testicular cancers, and quantitatively analyzing the occurrence of malignancies other than testicular cancer in the ITCLC family set [NCI Protocol 04-C-N076]. The relationship between testicular microlithiasis and FTC risk is the current clinical focus of this project. We are also leveraging the biospecimens collected from multiple-case family members and their relatives to pursue in greater depth the recent genomewide association study results, which have identified a number of genes involved in testicular embryogenesis and fertility as strong candidate risk factors. We have demonstrated that the same genes implicated as genetic modifiers of sporadic testicular cancer risk also contribute to the risk of familial testicular cancer, and have contributed our DNA samples to an international GWAS meta-analysis which has identified 5 new genomic regions as important modifiers of testicular cancer risk.

Myotonic Dystrophy (DM)

Based on the clinical impression developed by neurologists responsible for the management of DM that their patients were developing more cancer than expected, we have become involved in trying to answer the question “Is myotonic dystrophy a cancer susceptibility disorder?” Initial results of our first quantitative analysis – based upon data obtained from population-based diagnosis and cancer registries, in collaboration with investigators in Sweden and Denmark – the answer appears to be “yes.” We have identified a highly-significant, two-fold increase in the risk of all cancers combined – an excess accounted for by cancers of the colon, endometrium, ovary and brain – among DM patients. Subsequent reports have suggested that persons with Type 1 DM are twice as likely as those with Type 2 to report a personal history of cancer, that there is no clear correlation between trinucleotide repeat length in DM1, and that the cumulative burden of cancer among DM patients is substantial. Additional work is ongoing to refine and clarify this novel observation.

Genetic Polymorphisms as Determinants of Outcomes of Cancer Therapy

DCEG has a long and distinguished history of investigating the relationship between treatments administered to patients to control an initial cancer, and the risk of subsequently developing a second cancer. This represents a unique situation in which one can study the consequences of human exposure to well defined chemical carcinogens and ionizing radiation. The opportunity exists to move these studies into the genetic arena, by investigating the relationship between common polymorphisms in genes affecting the bioavailability of chemical carcinogens and various outcomes of clinical interest. Such studies could identify population sub-groups which are at particular risk of second cancers, thrombotic events, acute myelosuppression, response to treatment or even survival. Information of this kind could have a significant impact on clinical decision-making. CGB's first foray into this arena - a study of genetic polymorphisms in the genes related to tamoxifen and estrogen bioavailability and the risk of breast cancer as a result of tamoxifen exposure – and it provided interesting leads related to CYP2D6, a gene involved in the metabolism of tamoxifen, and breast cancer risk.

Our ongoing study of genetic polymorphisms in genes from the IGF signaling pathway represents another variation on the theme of common variants within less penetrant genes as modifiers of cancer risk is Elevated levels of IGF1, a cytokine with both mitogenic and anti-apoptotic effects, have been associated with increased risks of a variety of different cancers. In collaboration with NCI’s Core Genotyping Facility and investigators from DCEG’s Biostatistics and Occupational/Environmental Epidemiology Branches, genetic variations in 8 genes within this signaling pathway have been identified, and are now being analyzed as determinants of advanced colorectal adenoma risk among participants of the Prostate, Lung, Colon and Ovarian Cancer screening trial. Circulating levels of IGF1, IGF2 and IGF-BP3 are also being evaluated in this nested case-control study. The first report from this project documents an increased risk of advanced colorectal adenoma in persons with the highest circulating levels of IGF1. 

Behavioral, Counseling and Psychosocial Implications Related to Being at Increased Genetic Risk of Developing Cancer

Dr. Greene has implemented a strategy of actively seeking opportunities to investigate the genetic counseling, behavioral and psychosocial implications of being at increased genetic risk of cancer, since the Branch’s inception. This is accomplished through selective incorporation of such research into our new and ongoing clinical research projects. Many of our staff (medical and pediatric oncologists, clinical geneticist, oncology genetic counselor, cancer genetics research nurse, and a marriage and family therapist) have unique training, interests and perspectives relative to this research domain, which is further supplemented by collaborations with senior behavioral research colleagues from other NIH divisions, and post-doctoral fellows (including NCI Cancer Prevention Fellows), Division of Cancer Control and Population Studies (DCCPS) and the National Human Genome Research Institute (NHGRI). Since CGB began operations 12 years ago, this activity has yielded nearly 50 publications. Projects that currently fall within this domain include (1) the ongoing development of the CEGRM (Colored Ecogenetics Relationship Map), a novel counseling tool aimed at identifying sources of social support; (2) a series of analyses focused on the lives of young BRCA1/2 mutation carriers; (3) analyses of surgical decision-making and the influence of test ambiguity on screening behavior among BRCA mutation carriers; (4) a comprehensive set of psychosocial/behavioral analyses, both cross-sectional and longitudinal, among GOG-0199 study participants; and (5) initiation of data collection in our newest clinical research protocol, which targets the Li-Fraumeni syndrome.

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