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National Cancer Institute U.S. National Institutes of Health www.cancer.gov
About DCEG

Mark H. Greene, M.D.

Chief, Clinical Genetics Branch

Location: 6120 Executive Boulevard, EPS Room 7022
Phone: 301-594-7641
Fax: 301-496-1854
E-mail: greenem@mail.nih.gov

 Mark H. Greene, M.D.

Biography

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. 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.

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 outstripped our ability to manage germline mutation carriers in an effective, evidence-based fashion. Clinicians and patients alike are now struggling to take advantage of these molecular breakthroughs, but at present there are more questions than answers. The Clinical Genetics Branch focuses its resources on acquiring the data needed to address these issues, both for the rare, highly-penetrant genes and the common, lower penetrance genes which contribute to the development of cancer in humans.

Hereditary Breast/Ovarian Cancer (HBOC)

This syndrome has been under active investigation within the Division for the past 30 years. The long-term clinical follow-up of a cohort of 60 HBOC families, 32 of which have deleterious BRCA1/2 mutations, continues to provide a basis for ongoing CGB research targeting HBOC.  Projects now underway include: (a) "Clinical, Behavioral, Genetic & Laboratory Studies in HBOC Families" [NCI Protocol 02-C-0212]; (c) "National Ovarian Cancer Prevention and Early Detection Study" targeting women at increased genetic risk of ovarian cancer," [GOG 0199; NCI Protocol 02-C-0268]; (d) "Analysis of Family History of Cancer and Westernization as Risk Factors among Asian-American Women with Breast Cancer," [data from a large, population-based, case-control study of Chinese, Japanese and Filipino women with breast cancer]; (e) "Phase II Randomized Trial of Alendronate for Osteoporosis Prevention in Women Undergoing Surgical Menopause " [GOG 0215]; (f) "Genetic Modifiers of the Risk of BRCA1/2-Related Breast Cancer," and (g) a pilot Study to Develop an in vivo Method for Collecting Ovarian Surface Epithelium for Molecular Analysis.

Inherited Bone Marrow Failure Syndromes (IBMFS)

There exists a series of hereditary pediatric disorders which predispose to bone marrow failure, acute leukemia and solid tumors in adult survivors. Fanconi's Anemia is the prototype of these diseases, and it forms the cornerstone of an interdisciplinary project designed to shed light on mechanisms of carcinogenesis in humans [NCI Protocol 02-C-0052]. Dr. Blanche Alter, an internationally-recognized expert in Fanconi's anemia, leads this project. With the recent addition of tenure-track investigator Dr. Sharon Savage to the CGB staff, dyskeratosis congenita will receive special emphasis within the IBMFS project, as a consequence of Dr. Savage’s expertise in telomere biology.

Familial Testicular Cancer (FTC)

The mapping of a familial testicular cancer susceptibility gene to the X chromosome, 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 have joined the International Testicular Cancer Linkage Consortium (ITCLC), and are contributing DNA and clinical data from our multiple-case families to the FTC cancer susceptibility gene mapping and positional cloning effort that is now underway. 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].

Familial Cancer of the Urinary Bladder

Historically, DCEG is one of the very few centers that has had a research interest in familial urinary bladder cancer. More recently, the Division has focused its bladder cancer research in the arena of analytic epidemiology, in the form of several large case-control studies. Currently, planning has begun relative to implementing a new multidisciplinary, etiologic study of multiple-case bladder cancer families. This represents an under-studied familial cancer syndrome; as such, familial bladder cancer falls within CGB’s research mandate.

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 is now nearing completion: this is 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. This project represents a collaboration between CGB, DCP, CCR and NSABP, in which DNA collected from participants in the NSABP Tamoxifen Breast Cancer Prevention Trial are being studied.

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 the Office of the Director, Epidemiology & Biostatistics Program, 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.

A study of genetic variants in genes related to chemotherapy drug metabolism and DNA repair as modifiers of the risk of cancer treatment-related acute myelogenous leukemia and myelodysplastic syndrome has been approved in concept form, and is now in protocol development. This project is a joint collaboration between 3 DCEG branches (CGB, VEB and REB) and several of NCI’s clinical trials cooperative groups.

Other Intervention Studies in Persons at Increased Genetic Risk of Cancer

While the progress in identifying major cancer susceptibility genes has been gratifying, our ability to intervene at the molecular level in order to reduce the risk associated with mutations in these genes is embryonic. We are in urgent need of safe and effective strategies through which the risk of cancer in mutation carriers can be reduced now. We are collaborating with colleagues in CCR to support the breast cancer (NCI Protocol 04-C-0044) and colon cancer chemoprevention trials currently underway, by recruiting members of our cancer-prone families to participate in these important studies. One of CGB’s staff scientists is the lead investigator on a pilot study of physical activity as a breast cancer risk-reducing strategy (NCI Protocol 04-C-0276). The possibility of initiating a series of Phase II clinical trials (in collaboration with the University of Arizona Cancer Center) among patients with dysplastic nevi, a known melanoma precursor, to seek biologically active compounds which might hold promise as topical skin cancer chemoprevention agents is also under consideration.

Selected Publications