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Stefan Ambs, Ph.D., M.P.H.

Portait Photo of Stefan Ambs
Laboratory of Human Carcinogenesis
Head, Molecular Epidemiology Section
Senior Investigator
Center for Cancer Research
National Cancer Institute
Building 37, Room 3050B
Bethesda, MD 20892-4258
Phone:  
301-496-4668
Fax:  
301-496-0497
E-Mail:  
ambss@mail.nih.gov

Biography

Dr. Stefan Ambs earned a Master's degree in Biochemistry from the University of Tuebingen (1988) and a Master of Public Health degree (Epidemiology) from the Johns Hopkins Bloomberg School of Public Health (2005). He completed his Ph.D. thesis (1992) at the Institute of Toxicology, University of Wuerzburg, Germany, and was trained as a Postdoctoral Fellow at the Laboratory of Human Carcinogenesis (1992-1997), National Cancer Institute, Bethesda, Maryland. He continued his research at a biotechnology company in California and at the Aventis Genomics Center in Cambridge, Massachusetts. Dr. Ambs joined the NCI as a tenure-track investigator in November of 2001. He became a tenured Senior Investigator in 2010.

Research

The Breast and Prostate Cancer Unit (BPU) conducts molecular epidemiology studies of breast and prostate cancer, and utilizes epidemiological and translational research strategies to identify risk factors for tumor development and progression. We combine traditional epidemiology with laboratory investigations for risk factor discovery and to establish biological plausibility and mechanisms of causality. Our research includes genome-wide analysis of gene expression, common genetic variations, serum and tissue markers of disease development and progression, smoking and prostate cancer, and cancer health disparity. BPU is supported by a resource contract that provides an infrastructure to conduct epidemiological studies in the greater Baltimore area and to collect biospecimens, including both tumor and non-tumor tissues, and blood samples. This resource has been used to establish a case-control study of breast cancer. It is currently being used to recruit African-American and European-American males into a case-control study of prostate cancer that addresses the need of more health disparity research.

Cancer risk is driven by carcinogen exposure and inherited or acquired host factors. Inherited susceptibility factors, e.g., common variations in the genetic code and inherited mutations within a family, will modulate the effects of carcinogen exposure on human cancer risk. Heritable factors can also influence a patient response to therapy and can become biomarkers for therapeutic outcome. Heritable effects of genes on cancer risk can range from low to high. Inherited mutations in tumor suppressor genes (e.g., BRCA1, BRCA2, TP53, PTEN) are associated with familial cancer syndromes and predispose individuals to a high risk of cancer, largely independent of any additional exposure. However, these mutations are rare, and these highly penetrant single gene mutations account for less than 10% of all cancers. In contrast, common genetic variations, such as single nucleotide polymorphisms, contribute to common cancer. It is thought that the majority of cancer cases are caused, at least in part, by the collective effect of multiple, low penetrant genetic variations in a large group of genes and their interactions with environmental exposures. Our group is studying common genetic variations in genes of cancer-related pathways, e.g., the inflammation pathway, and examines how these variations influence cancer risk in the context of ethnicity and/or exposure to environmental risk factors. We are also evaluating how common genetic variations influence the response of patients to therapy.

The Institute of Medicine concluded that not all segments of the U.S. population have equally benefited from the advances in our knowledge and treatment of cancer. As a result, African-Americans have the highest death rates from all cancer sites combined, and from malignancies of the lung, colon and rectum, breast, prostate, and the cervix of all racial groups in the United States. Recent research showed that racial disparities in prostate and breast cancer survival between African-American (AA) and European-American (EA) patients can persist in randomized clinical trials, indicating that intrinsic differences in tumor biology may contribute to the disparities in survival between these two patient cohorts. Our group seeks to identify the race/ethnic differences in tumor biology that may either influence the presentation of the disease (e.g., causing a more aggressive disease among AA patients), or influence the response to therapy (e.g., causing an inferior response among AA patients). Any of these differences, if they exist, are not likely to be generalizable, meaning that all AA patients are equally different from all EA patients. Rather we believe that certain biologically-derived poor outcome factors are more prevalent among AA patients than EA patients, and that future clinical interventions will have to target these factors across all patient groups.

African-American men have the highest risk of developing prostate cancer in the United States, and due to the manifestation of a more aggressive disease, they have over twice the mortality rate of European-American men. While socioeconomic factors contribute to this health disparity, they do not fully explain the differences in prostate cancer incidence, aggressiveness, and mortality amongst the various race/ethnic groups in this country. One of our research projects pursued the hypothesis that the gene expression profiles of prostate tumors from African-American and European-American patients may reveal biological differences between these patient groups that could explain the aggressiveness of prostate tumors in African-Americans. The study revealed prominent differences in the expression of genes that regulate tumor immunobiology. Additionally, several known metastasis-promoting genes were more highly expressed in tumors from African-Americans than European-Americans. The data indicate the existence of a distinct different tumor microenvironment in these two patient groups. We also identified a two-gene tumor signature that accurately differentiated between African-American and European-American patients. One of these two genes that were highly differently expressed was PSPHL. The function of this gene is unknown, but it resides in a susceptibility locus for prostate cancer progression. These findings are being further pursued and we are currently studying the function of PSPHL. Future health disparity research will also include the analysis of various exposures, e.g. blood and tumor markers of infections and inflammation, medical history and lifestyle (questionnaire-based), and gene-environment interactions (e.g., the effect of common genetic variations on prostate cancer in the context of infections, medical history), and how these exposures relate to tumor development and disease aggressiveness among African-American and European-American patients.

Acute and chronic inflammation is commonly observed in prostate biopsies and frequently occurs in close proximity to prostatic intraepithelial neoplasia, a precursor lesion for prostate tumors. It has been proposed that the inflammation-to-carcinoma sequence is common in the development of human prostate cancer. A pro-inflammatory tumor environment is also a trigger for disease progression and cancer metastasis. The causes of prostatic inflammation are poorly understood, but could be caused by chronic infections and other environmental exposures. Our research discovered a pro-inflammatory interferon gene signature in tumors of African-Americans patient suggesting the possible involvement of viral infections in disease pathology. We also observed a unique gene expression profile in prostate tumors associated with current smoking that indicates an altered immune environment in tumors of current smokers. The observation could be very significant because current smoking increases the risk of metastatic prostate cancer. These preliminary findings will be further pursued in the context of our ongoing case-control study in the greater Baltimore area (05-C-N021).

Recently, a new class of small RNAs has been described, termed microRNAs, which was found to regulate mRNA function by modulating both mRNA stability and the translation of mRNA into protein. MicroRNA genes are expressed as large precursor RNAs, called pri-mRNAs, which may encode multiple microRNAs in a polycistronic arrangement. These precursors are converted into a mature microRNA of 19 to 25 nucleotides. A crucial role of microRNAs in cancer has been demonstrated. Their expression is commonly altered in solid human tumors. MicroRNA expression profiles also classify tumors by developmental lineage and differentiation state. Multiple microRNAs have been shown to have oncogenic properties, or act like tumor suppressor genes. These microRNAs have been termed oncomiRs. An alteration in their expression is causatively linked to cancer development. Another class of non-coding RNAs has also been implicated in cancer. Ultraconserved RNAs (ucRNAs) are transcribed non-coding RNAs that share 100% identity between human, mouse and rat genomes. While the functions of ucRNAs are largely unknown, a recent study found that expression patterns of ucRNAs are altered in tumors and that inhibition of a specific ucRNA can induce apoptosis, supporting a role for ucRNAs in cancer. We are studying microRNAs and ucRNAs in prostate cancer and are interested in determining if these RNAs are useful biomarkers for human prostate cancer.

Our current research in breast cancer focuses on three research questions. We are examining breast tumors by gene expression profiling and immunohistochemistry and pursue the hypothesis that differences exist in tumor biology between African-American and European-American patients beyond the current knowledge. Secondly, we are investigating the influence of common genetic variations (also called genetic polymorphisms) on the response to therapy and breast cancer survival. In the past, relatively few studies have explored the association between common genetic variations and disease outcome although the concept of gene-environment interactions strongly suggests that some polymorphisms may influence disease outcome because of their modifying effects on tumor biology and therapeutic outcome. It is well known that large differences exist in patient response to treatment. Several recent studies have shown that polymorphisms influence therapy response and breast cancer survival, but more studies are needed to define the relative contribution of gene polymorphisms to poor outcome after therapy. Some of these polymorphisms could become biomarkers to guide cancer therapy. Lastly, we are exploring the role of the inducible nitric oxide synthase (NOS2) in breast cancer biology. NOS2 is a signature gene of the inflammation response and has key functions in host defense. A major physiological role of this enzyme is the release of nitric oxide (NO) to support the wound healing process. It has been hypothesized that the wound healing properties of NO could turn NOS2 into an oncogene that promotes the metastatic spread of human cancer. NO may also select for a mutant p53 tumor status and activate oncogenic pathways such the Akt and HIF1alpha pathways leading to increased cell survival and resistance to therapy. We hypothesize that NOS2 expression leads to poor survival in breast cancer by activating these pathways, and by inducing a poor outcome gene signature. Preliminary data from our research indicate that NOS2 expression is significantly associated with a basal-like gene expression signature in breast tumors and with poor outcome among estrogen receptor-negative breast cancer patients.

This page was last updated on 11/11/2013.