viernes, 28 de noviembre de 2014

Studies of Telomere Biology Disorders Shed Light on Mechanisms of Cancer - National Cancer Institute

Studies of Telomere Biology Disorders Shed Light on Mechanisms of Cancer - National Cancer Institute

National Cancer Institute at the National Institutes of Health

Studies of Telomere Biology Disorders Shed Light on Mechanisms of Cancer

by Shelia Hoar Zahm, Sc.D.
DCEG scientists are studying telomere biology disorders to shed light on the mechanisms of cancer. “By combining clinical expertise, family studies, genetics, epidemiology, and basic science, we are learning about the defects in telomere biology that cause inherited bone marrow failure and cancer predisposition syndromes,” explained Sharon A. Savage, M.D., Chief of the Clinical Genetics Branch (CGB). She and colleagues across the Division are also finding that less-pronounced differences in telomere length and function may contribute to cancer risk among members of the general population.
Telomeres are specialized structures at the ends of chromosomes that are essential for maintaining chromosomal integrity. With each cell division, the telomeres become shorter until cell death or senescence is triggered. If neither occurs, the cell can continue to divide despite having critically short telomeres, which can lead to genetic instability and chromosomal abnormalities that can lead to cancer.

DCEG scientists combine clinical, laboratory, and epidemiological expertise to learn about defects in telomere biology that cause inherited bone marrow failure and cancer predisposition syndromes, such as dyskeratosis congenita.

Dyskeratosis Congenita

Mutations in the genes responsible for telomere maintenance have been found in subsets of patients with myelodysplastic syndromes, acute myeloid leukemia, severe aplastic anemia, and some other conditions. Dr. Savage’s work has focused on dyskeratosis congenita (DC), a cancer-prone inherited bone marrow failure syndrome. Through family-based genetic linkage studies and recent exome sequencing studies, Dr. Savage and colleagues have identified three genes in which mutations cause DC: TINF2 (a gene in the shelterin telomere protection complex), WRAP53 (also known as TCAB1, a gene related to telomerase localization), and RTEL1 (a gene that regulates telomere length). Germline mutations in these genes plus six others associated with telomere maintenance (CTC1DKC1NOP10,NHP2TERC, and TERT) are present in approximately 70 percent of DC patients.
DCEG investigators are continuing their efforts to identify additional genes that might be responsible for DC in patients without mutations in any of the nine known genes. Moving from the clinic to the population genetics setting, the investigators also have evaluated the frequency of a particular mutation in RTEL1 that causes Hoyeraal-Hreidarsson syndrome, a clinically severe variant of DC among Ashkenazi Jews. The mutation has been found at a high-enough frequency to recommend its inclusion in the genetic screening panels for the Ashkenazi population.
Blanche P. Alter, M.D., M.P.H., initiated the cohort study of patients and family members with cancer-prone inherited bone marrow failure syndromes in which the DC research has been conducted. She led an effort to use the knowledge that DC patients have extremely short telomeres (below the first percentile for age) to develop a diagnostic test for DC using automated flow-FISH (fluorescent in-situhybridization) in collaboration with Dr. Peter M. Lansdorp of the British Columbia Cancer Agency. By analyzing telomere length in white blood cells, this test can confirm the diagnosis of DC, distinguish patients with DC from unaffected family members, identify clinically silent DC carriers, and discriminate between patients with DC and those with other bone marrow failure disorders.

Telomere Biology

Patients with DC are at high risk from complications after hematopoietic stem cell transplantation (HSCT), possibly because of their germline defects in telomere biology. Shahinaz Gadalla, M.D., Ph.D., is investigating the association between telomere length and HSCT outcomes in patients with acquired severe aplastic anemia (SAA). Patients with SAA and short telomeres (even if not as short as those in DC patients) may be at risk of HSCT-related complications due to short telomeres.
Telomere biology also appears to play a role in cancer among persons other than those affected by bone marrow failure syndromes. Maria Teresa Landi, M.D., Ph.D.Jianxin Shi, Ph.D., and Xiaohong Rose Yang, Ph.D., M.P.H., recently found that rare inherited variant alleles in POT1, a gene that helps maintain the integrity of telomeres, increase the risk of familial melanoma. POT1 variant carriers had increased telomere lengths and numbers of fragile telomeres, suggesting that the variants perturb telomere maintenance. Also, sporadic melanoma cases (cases occurring outside melanoma-prone families) had significant overall genetic burden due to rare variants in POT1 when compared with healthy controls. Together with the TERT promoter variant previously identified in familial melanoma, the investigators’ findings suggest that genes involved in telomere maintenance may serve important roles in melanoma development.
Researchers across DCEG have been evaluating telomere length in relation to the risk of other cancers among members of the general population (i.e., people not in cancer-prone families). The strongest evidence for an association with short telomeres is for bladder, esophageal, gastric, and renal cancers, types of cancer that are linked to smoking and inflammation. To date, the results for other cancers have been inconsistent or null.

Telomere Molecular Epidemiology

The studies of telomeres and cancer among the general population could be affected by methodological issues, including whether the samples were collected after cancer diagnosis or treatment instead of prior to development of the disease, the use of surrogate tissues instead of the actual cancer cells, the laboratory technique used to measure length, variability in other cancer risk factors, and other issues. DCEG researchers are trying to resolve some of these issues. For example,Clara Bodelon, Ph.D., M.P.H., is comparing telomere length in DNA derived from the blood, breast cancer cells, and normal breast cells from the same patient, and she also is conducting a study relating telomere length to breast features, such as mammographic density and the complexity of terminal duct lobular units. Lisa Mirabello, Ph.D., M.S., is conducting a follow-up study of ovarian cancer and telomere length and plans to evaluate whether the use of average telomere length across all chromosomes may blur associations in comparison to chromosome-specific telomere length.
DCEG researchers will continue to examine the impact of genetics and telomere length on cancer risk and survival in future epidemiologic studies of cancer-prone families and the general population and through large data-sharing efforts such as the Clinical Care Consortium of Telomere Associated Ailments, which was founded by Dr. Savage and Dr. Suneet Agarwal of Boston Children’s Hospital, and the Global Alliance for Genomics and Health Exit Disclaimer.

Savage Presents at Director’s Seminar

Watch Dr. Savage discuss her research at the 2013 NIH Director’s Seminar Series.

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