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Charis Eng , MD, PhD
Genomic Medicine Institute
Eng Lab Research Program

The optimal manner of achieving seamless translational cancer research is on a single platform of cancer research, clinical care and education. On such a platform, the broad thrust of the Eng laboratory can be characterized as clinical cancer genetics translational cancer research, which involves the utilization of nucleic acid-based technologies to identify, characterize and understand genes which cause susceptibility to traditional and complex heritable cancer syndromes, to determine their role in sporadic carcinogenesis and to perform molecular epidemiologic analyses as they might relate to future clinical applications.

Upon this cancer research framework, we are examining the genetics of two heritable cancer syndromes, Cowden syndrome, which has a high risk of breast, thyroid and endometrial cancers, and multiple endocrine neoplasia type 2 (MEN 2), characterized by medullary thyroid cancer and pheochromocytoma, and related sporadic cancers. Our work on the RET genotype-MEN 2 phenotype correlations is acknowledged as the paradigm for the practice of clinical cancer genetics.

Currently, in an on-going multi-national study, the Eng lab has found that approximately 25% of population-based apparently sporadic pheochromocytoma cases are due to germline mutations in one of 4 genes. This has led to changing the practice of clinical cancer genetics.

This multi-national study now seeks to meticulously phenotype this cohort to determine if clinical clues can help target which gene to begin testing in these individuals. The genetics of susceptibility gene PTEN, encoding a dual specificity phosphatase on 10q23.3, is being examined in Cowden syndrome and other heritable hamartoma syndromes as well as populations of sporadic cancers. Somatic genetics of PTEN and the precise diverse mechanisms of inactivation are being pursued in a range of sporadic cancers, including those of the breast, thyroid and endometrium. Gene-gene interactions and gene-environment interactions are being explored. Biochemical, cellular and functional studies are performed in the laboratory to understand the non-traditional mechanisms of somatic PTEN inactivation in breast cancer, including nuclear-cytoplasmic partitioning.

This fundamental cancer research is aimed at not only mechanism resolution but also hopes to identify novel targets for therapeutic and preventative drug development. Global expression analyses of one of the sporadic counterparts of a Cowden component neoplasia, follicular thyroid neoplasias, is on-going to search for etiology and for the diagnostic differentiation of benign versus malignant follicular neoplasias. The latter will address the current challenge in fine needle aspiration biopsy diagnosis of thyroid nodules where a significant proportion are non-diagnostic.

Recent efforts in the Eng laboratory have focused on the role of somatic genomic alterations in tumor stroma in sporadic breast and prostate carcinomas and head and neck cancers. So, our work in cancer research may have broad implications not only for examining the pathogenesis of common cancers but may reveal novel targets and novel compartments germane for diagnosis, prognosis, therapy and prevention.

I am particularly interested in systematically drawing out genomic and biological similarities and parallels amongst various disease processes. Thus, commonalities of processes and fundamental understanding from cancer research can be utilized and extended to other diseases. Similarly, commonalities from other disorders can be used to enhance and extend fundamental understanding of carcinogenesis. As one example, the Eng lab is studying the genomic and epigenomic alterations the intimal proliferative process of atherogenesis as a parallel to solid tumor stromal alterations.

Selected Original Peer Reviewed Publications (from total of 240 published/in press)

Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, Ploos van Amstel HK, Lips CJM, Nishisho I, Takai S-I, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjöld M, Komminoth P, Hendy GN, Gharib H, Thibodeau SN, Lacroix A, Frilling A, Ponder BAJ, Mulligan LM.

The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET Mutation Consortium analysis. JAMA 1996; 276:1575-9.

Liaw D, Marsh DJ, Li J, Dahia PLM, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C*, Parsons R*. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet 1997; 16:64-7. (*Joint Senior Authors)

Marsh DJ, Dahia PLM, Zheng Z, Liaw D, Parsons R, Gorlin RJ, Eng C. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nature Genet 1997; 16:333-4.

Zhou XP, Hampel H, Thiele H, Gorlin RJ, Hennekam RCM, Parisi M, Winter RM, Eng C. Association of germline mutation in the PTEN tumour suppressor gene and a subset of Proteus sand Proteus-like syndromes. Lancet 2001; 358:210-1.

Neumann HPH, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehöfer C, Zerres K, Januszewicz A, Eng C. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002; 346:1459-66.

Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou XP, Eng C. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nature Genet 2002; 32:355-7.

Neumann HPH, Pawlu C, Peçzkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley T, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C. Distinct clinical features characterize paraganglioma syndromes associated with SDHB and SDHD mutations. JAMA 2004; 292:943-51.

Fukino K, Shen L, Matsumoto S, Morrison CD, Mutter GL, Eng C. Combined total genome loss-of-heterozygosity scan of breast cancer stroma and epithelium reveals multiplicity of stromal targets. Cancer Res 2004; 64:7231-6.

Chung JH, Eng C. Nuclear-cytoplasmic partitioning of PTEN differentially regulates the cell cycle and apoptosis. Cancer Res 2005; 65:8096-8100.

Sweet K, Willis J, Zhou XP, Gallione C, Sawada T, Alhopuro P, Khoo SK, Patocs A, Martin C, Bridgeman S, Heinz J, Pilarski R, Lehtonen R, Prior TW, Frebourg T, Teh BT, Marchuk DA, Aaltonen LA, Eng C. Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 2005; 294:2465-73.

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