Cancer Cytogenetics

Cytogenetics Staff

Dr. Arthur's research has focused on the clinical and biological significance of acquired chromosome abnormalities in cancer, with an emphasis on hematologic malignancies. Dr. Arthur was one of the first to describe the clinical features and prognostic significance of the t(4;11)(q21;q23) in acute lymphoblastic leukemia, and she has continued to publish on rearrangements of chromosome band 11q23, an area of intense investigations in recent years, with her colleagues in clinical medicine, epidemiology, and molecular biology at the University of Minnesota and in the Children's Cancer Group and Cancer and Leukemia Group B. Dr. Arthur was the first investigator to report the association of abnormalities of chromosome 16 with a specific morphologic subtype of acute myelogenous leukemia, now termed M4Eo, and a good prognosis. She has also coauthored seven publications of one of the largest series of cytogenetic analyses of non-Hodgkin's lymphomas in the literature, and correlations of cytogenetics with clinical, morphologic, and immunophenotypic features of these lymphomas. Dr. Arthur has contributed cytogenetics data and insightful interpretation of their significance to numerous collaborative investigators at the University of Minnesota and in national and international study groups.

Dr. Arthur is currently setting up the new Clinical Cytogenetics Laboratory in the Laboratory of Pathology. This laboratory will serve DCS and all Institutes of the NIH. The section will have three missions: service, research, and teaching. The laboratory will provide highly complex and specialized testing for the detection of constitutional as well as acquired chromosomal abnormalities in patients admitted to the NIH Clinical Center, and will also provide consultative cytogenetics services to other U.S. Government and private hospitals. Cytogenetics testing can be done on blood, body fluids, skin fibroblasts, bone marrow, lymph nodes, and other nonhematologic solid tumors from patients with a variety of constitutional chromosomal disorders, premalignant and malignant hematologic disorders, and nonhematologic neoplasms. The results of these tests may be used for diagnosis, treatment, and monitoring the course of disease in these patients. The director and staff of this laboratory will not only provide what is currently considered state-of-the-art cytogenetics service; they will also be actively involved in transferring new methods and technology from basic science laboratories in the NCI, NCHGR, and other Institutes into the clinical laboratory. In the coming year, we anticipate the transfer of spectral karyotyping (SKY) and comparative genomic hybridization (CGH) technologies. The members of the Clinical Cytogenetics Laboratory will also be available and eager to participate in collaborative research projects with clinical and basic science investigators across the NIH and affiliated institutions. Finally, Dr. Arthur and her staff will be involved in teaching students, residents, and postdoctoral fellows the scientific background, available techniques, and clinical applications of cytogenetics testing. The laboratory began accepting specimens on a limited basis at the end of April, and is expected to be fully operational by September 1997.

Developmental Molecular Cytogenetics A developmental diagnostics research unit has been established to originate and validate pilot cytogenetics-based tests. These include tumor LOH analysis by microdissection, FISH, and Fiber-FISH. Dr. Zhengping Zhuang is a Special Expert assigned to oversee this translational research component. The four main areas of research interest are as follows:

• Identification of new genes associated with hereditary and sporadic tumors. The lab participated in discovery of MEN 1 and HPRCC genes. Ongoing projects (in collaboration with the NIH Epidemiology group) include linkage analysis of familial chordoma, and esophageal carcinoma.
• Study of specific genetic alterations associated with several types of solid tumors, such as endolymphatic sac tumor, microcystic pancreatic adenoma, islet cell tumor, and hemangioblastoma.
• Identification of genetic changes associated with early events during carcinogenesis. APC gene deletion was identified in metaplastic mucosa of Barrett's esophagus, VHL gene deletion in benign and atypical renal cysts, p16 and p53 deletion in dysplastic nevi, 8p deletion in prostatic intraepithelial neoplasia, and 11q13 deletion in in situ carcinoma of the breast.
• Identification of neoplastic components in complex tumors in regard to their histogenetic origin and progression. Dr. Zhuang identified the "stromal cell" as the neoplastic component of cerebellar hemangioblastoma, and the stromal component of Wilms' tumor as a neoplastic rather than reactive component. He selectively analyzed different histologic components within complex tumors such as carcinosarcoma of the breast and colorectal adenocarcinoma associated with poorly differentiated neuroendocrine carcinoma.