Telomere shortening may be early marker of cancer activity
Studies suggest chromosomal destabilization is linked to malignancies
Washington, DC – Telomere shortening may be one of the earliest and most prevalent changes on a cell's path to cancer, according to two studies presented at the 94th Annual Meeting of the American Association for Cancer Research (AACR).
Telomeres, the ubiquitous safety caps on the ends of chromosomes, help to maintain genomic integrity. As cells divide and age, telomere DNA is lost and telomeres get shorter and shorter. The new study suggests that telomere dysfunction from the shortening may play a causal role in human intraepithelial neoplasia (IEN) found in precancers.
"Normal human cells have systems that monitor telomere length, either halting cell division or causing the cell to commit suicide, should telomeres become too short," said Alan K. Meeker, postdoctoral fellow in urology at the Johns Hopkins School of Medicine in Baltimore, and lead author of the studies. "When the systems break down, critically short telomeres can lose function, destabilizing the chromosomes and, we are finding, lead to cancer."
Direct evidence of telomere shortening and telomere length heterogeneity in human intraepithelial neoplasia (IEN) The objective of this study was to build on research that Meeker and his team had conducted comparing telomere lengths in very early pre-cancerous lesions in both the prostate and pancreas to normal epithelium in the same tissue. Using a high-resolution, fluorescent in situ hybridization (FISH) method for direct telomere length assessment, they found that in greater than 90 percent of the cases, there was evidence of significantly shorter telomeres in precancerous lesions compared to normal tissue. The FISH test involves labeling telomere DNA with fluorescent molecules, which enables them genes to be measured under a microscope.
Looking to extend the earlier findings "to the overall process of epithelial carcinogenesis," they examined a variety of cancers, including biliary, breast, cervix, colon, esophagus, and oral cavity. Working with a group of pathology experts at Johns Hopkins Kimmel Cancer Center, the study compared telomeres within a given lesion to those of adjacent, normal-appearing epithelial counterparts. Short telomeres were found in the majority of precursor lesions including biliary (11/11 dysplasia), breast (18/23 ductal carcinoma in situ), cervix (3/3 HGSIL), colon (5/5 adenomatous or benign polyps, 2/2 dysplasia), esophageal (3/3 metaplasia, 2/2 low-grade dysplasia, 4/4 high-grade dysplasia) and oral cavity (4/4 dysplasia).
"I cannot think of any other specific somatic molecular alteration that occurs this early across such a large number of types of human intra-epithelial neoplasia," said Angelo M. De Marzo, M.D., Ph.D., Associate Professor at the Johns Hopkins University School of Medicine, and lead investigator of the studies. "The degree of telomere shortening in these precancerous lesions is roughly the same as we see in the cancer, meaning the shortening that has been seen for years in invasive tumors actually happens very early in the process. It's not the result of cell division during tumor expansion; it's more cumulative support for this playing a more causative role and being an initiating event to most human epithelial cancers."
Dramatic telomere shortening occurs in breast luminal epithelial cells in subsets of non-malignant, normal-appearing lobules and small ducts: a potential early molecular mechanism underlying breast tumorigenesis To further understand the disease process in breast cancer, Meeker, DeMarzo and colleagues attempted to identify the specific molecular mechanisms responsible for the genetic defects that cause malignancy. Looking at ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), they compared telomere lengths among luminal epithelial cells, myoepithelial cells, and adjacent stromal cells in normal-appearing lobules and ducts. In benign breast biopsies from women without a sign of cancer, evidence of telomere shortening was found in terminal duct lobular units (TDLU) in seven of 12 cases. The shortening was in the luminal epithelial cells only. In women with cancer elsewhere in the breast, telomere shortening was observed in nine of 12 cases.
"Menstrual, or hormone, cycling may be a key player since the cell division that occurs during that regular process causes normal ductal epithelial cells to lose telomeric DNA," said Pedram Argani, M.D., assistant professor, Department of Pathology at the Johns Hopkins University School of Medicine, and an investigator of the study. "That loss puts the cells at risk for chromosomal destabilization which may, in time, lead to eventual malignancy."
More than 212,600 new cases of breast cancer will be diagnosed and nearly 40,000 women will die in 2003, according to the American Cancer Society. Breast cancer is the second leading cause of cancer-related death in women.
Other investigators contributing to the findings in the new results discussed here from Johns Hopkins include: William Westra, Jessica Hicks, Anirban Maitra, Donna Hansel, Elizabeth Montgomery, Theresa Chan, Christine Iacobuzio-Donahue, Brigette Ronnett, Elizabeth Platz, and William Westra. Investigators contributing to the past studies on prostate and pancreas also include: Scott Kern, Ralph Hruban, Wesely Gage and N.T. van Heek.
Founded in 1907, the American Association for Cancer Research (AACR) is a professional society of more than 20,000 laboratory and clinical scientists engaged in cancer research in the United States and more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals (Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention). AACR's annual meeting attracts more than 12,000 participants who share new and significant discoveries in the cancer field, and the AACR's specialty meetings throughout the year focus on all the important areas of basic, translational and clinical cancer research.