Abstract CN10-02: Rare disorders informing cancer biology: Lessons learned from dyskeratosis congenita
Authors: Savage Sharon A. 
Published: October 2015

Abstract
Dyskeratosis congenita (DC) is a cancer-prone inherited bone marrow failure syndrome (IBMFS) caused by germline defects in telomere biology. The classic triad of dysplastic nails, lacy reticular skin pigmentation, and oral leukoplakia is diagnostic but not always present. Individuals with DC are at very high risk of bone marrow failure, leukemia, myelodysplastic syndrome, and head/neck cancers. Esophageal or urethral stenosis, liver disease, pulmonary fibrosis, developmental delay, and other medical conditions may also be present. The clinical consequences manifest at variable ages and in different patterns, even within the same family.
Approximately 70% of patients with DC have a germline mutation(s) in a key telomere biology gene. The inheritance of DC is variable with X-linked (DKC1), autosomal dominant (TERC, TERT, TINF2, or RTEL1), and autosomal recessive (NOP10, NHP2, TERT, WRAP53, CTC1, or RTEL1) inheritance patterns. Telomeres, tandem nucleotide repeats and a protein complex at chromosome ends, are vital in maintaining genomic integrity and function by keeping the chromosomes intact upon replication, preventing end-to-end fusion, and atypical recombination. They shorten with each cell division, and thus are a marker of cellular replicative capacity. When telomeres become critically short, cellular senescence or apoptosis are triggered. Cancer cells upregulate telomerase (TERT) and other pathways to continue cell division in the setting of telomere abnormalities and chromosomal instability.
We previously demonstrated that telomere length &lt;1st percentile for age, measured in leukocyte subsets by flow cytometry and fluorescent in situ hybridization (flow-FISH), was highly sensitive and specific for diagnosing DC. Numerous epidemiology studies suggest that short telomeres in blood or buccal cells may be associated with several diseases, including certain cancers. It is important to note that the telomere lengths in cases and controls from epidemiology studies may be statistically significantly different but they are still within the normal range for age whereas the telomeres of patients with DC are significantly shorter than expected for their age (&lt;1st percentile) compared with controls. Genome-wide association studies have found single nucleotide polymorphisms in two DC-associated genes, TERT and RTEL1, associated with cancer risk, a finding that further connects DC and telomere biology with cancer etiology.
We are conducting an IRB-approved longitudinal cohort study of DC nested within the NCI's IBMFS study (ClinicalTrials.gov Identifier: NCT00027274). This study includes comprehensive family history and individual history questionnaires, detailed medical record review, biospecimen collection, and evaluation at the NIH Clinical Center. In addition to the development of the diagnostic test, detailed clinical characterization of patients with DC and their families has led to improved understanding of the clinical consequences and management of DC and the spectrum of related telomere biology disorders. Through the use of genetic approaches ranging from linkage scans to whole exome sequencing, we have discovered three of the genetic causes of DC (TINF2, WRAP53, and RTEL1). Additional gene discovery efforts are underway. These clinical and molecular studies have led to improved understanding of key telomere proteins and formed the foundation for epidemiology studies of telomere biology and cancer in the general population.
Citation Format: Sharon A. Savage. Rare disorders informing cancer biology: Lessons learned from dyskeratosis congenita. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN10-02.