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Diagnostic Utility of Telomere Length Testing in a Hospital-Based Setting

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Diagnostic Utility of Telomere Length Testing in a Hospital-Based Setting Correction MEDICAL SCIENCES Correction for “Diagnostic utility of telomere length testing in a nuclear cell” should have instead appeared as “peripheral hospital-based setting,” by Jonathan K. Alder, Vidya Sagar blood mononuclear cells.” Hanumanthu, Margaret A. Strong, Amy E. DeZern, Susan E. The authors also note that, in the same paragraph, line 8, Stanley, Clifford M. Takemoto, Ludmilla Danilova, Carolyn D. “Alexa 488” should have instead appeared as “Alexa Fluor 488.” Applegate, Stephen G. Bolton, David W. Mohr, Robert A. The authors also note that, on page E2361, right column, Brodsky, James F. Casella, Carol W. Greider, J. Brooks Jackson, second full paragraph, line 5, “short telomere syndrome” should “ ” and Mary Armanios, which was first published February 20, have instead appeared as Short telomere syndrome. 2018; 10.1073/pnas.1720427115 (Proc Natl Acad Sci USA 115: The authors also note that, on page E2362, left column, first – paragraph, line 2, “across entire age spectrum” should have in- E2358 E2365). “ ” The authors note that the author name Ludmilla Danilova stead appeared as across the entire age spectrum. should have instead appeared as Ludmila Danilova. The cor- The authors also note that, on page E2364, right column, first rected author line appears below. paragraph, line 12, the following sentence should have been added to follow the sentence ending in “given the known effect The authors also note that Fig. 2 appeared incorrectly. The ” “ text “TINF1” in the key for Fig. 2E should have instead appeared of freezing on TL (23), at the end of the paragraph: Quanti- tative PCR was performed as previously described (20).” as “TINF2.” The article has been updated online to reflect these changes. The authors also note that, in the Significance Statement, line 8, “short telomeres syndrome” should have instead appeared as Jonathan K. Alder, Vidya Sagar Hanumanthu, Margaret A. “short telomere syndrome.” The authors also note that, on page E2363, left column, first Strong, Amy E. DeZern, Susan E. Stanley, Clifford M. paragraph, line 1, “short telomeres syndrome” should have in- Takemoto, Ludmila Danilova, Carolyn D. Applegate, stead appeared as “short telomere syndrome.” Stephen G. Bolton, David W. Mohr, Robert A. Brodsky, The authors also note that, on page E2364, left column, James F. Casella, Carol W. Greider, J. Brooks Jackson, second full paragraph, lines 2–3, “peripheral blood mono- and Mary Armanios Published under the PNAS license. Published online April 23, 2018. www.pnas.org/cgi/doi/10.1073/pnas.1805407115 E4312 | PNAS | May 1, 2018 | vol. 115 | no. 18 www.pnas.org Downloaded by guest on September 30, 2021 Diagnostic utility of telomere length testing in a PNAS PLUS hospital-based setting Jonathan K. Aldera,b,1, Vidya Sagar Hanumanthua,b, Margaret A. Strongb,c, Amy E. DeZerna,d, Susan E. Stanleya,b, Clifford M. Takemotoe, Ludmilla Danilovaa, Carolyn D. Applegatea,b,f, Stephen G. Boltong, David W. Mohrf, Robert A. Brodskya,d, James F. Casellae, Carol W. Greidera,b,c,2, J. Brooks Jacksong, and Mary Armaniosa,b,c,f,g,2 aDepartment of Oncology and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; bTelomere Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; cDepartment of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; dDepartment of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; eDepartment of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; fMcKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and gDepartment of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287 Contributed by Carol W. Greider, January 9, 2018 (sent for review November 28, 2017; reviewed by Thomas R. Cech and Agata Smogorzewska) Telomere length (TL) predicts the onset of cellular senescence in thologies are idiopathic pulmonary fibrosis (IPF) and related vitro but the diagnostic utility of TL measurement in clinical interstitial lung disorders (10, 11). Severe emphysema, alone or settings is not fully known. We tested the value of TL measure- combined with fibrosis, may also manifest in short telomere pa- ment by flow cytometry and FISH (flowFISH) in patients with tients who are smokers (12). Mutations in the essential telomerase mutations in telomerase and telomere maintenance genes. TL had enzyme genes, TERT, the telomerase reverse transcriptase, and a discrete and reproducible normal range with definable upper TR, the telomerase RNA component (also known as TERC), are and lower boundaries. While TL above the 50th age-adjusted per- the most common cause of IPF, and the frequency of TERT mu- centile had a 100% negative predictive value for clinically relevant tations in severe, early-onset emphysema rivals the prevalence mutations, the lower threshold in mutation carriers was age- of α-1 antitrypsin deficiency (12). Theprevalenceoftelomerase dependent, and adult mutation carriers often overlapped with mutations in adult-onset lung disease makes the short telomere the lowest decile of controls. The extent of telomere shortening syndromes the most-common premature aging disorders, with correlated with the age at diagnosis as well as the short telomere an estimated 10,000 affected individuals in the United States MEDICAL SCIENCES syndrome phenotype. Extremely short TL caused bone marrow alone (13). Identifying these patients is critical for clinical man- failure and immunodeficiency in children and young adults, while agement, as they are susceptible to life-threatening toxicities from milder defects manifested as pulmonary fibrosis-emphysema in DNA damaging agents and other cytotoxic therapies (14–17). In adults. We prospectively examined whether TL altered treatment de- the hematopoietic stem cell transplant setting for bone marrow cisions for newly diagnosed idiopathic bone marrow failure patients failure in particular, reduced intensity regimens improve outcomes and found abnormally short TL enriched for patients with mutations of short telomere syndrome patients (14). However, the vast in some inherited bone marrow failure genes, such as RUNX1,in addition to telomerase and telomere maintenance genes. The result Significance was actionable, altering the choice of treatment regimen and/or he- matopoietic stem cell donor in one-fourth of the cases (9 of 38, 24%). This study defines clinical indications for using telomere length We conclude that TL measurement by flowFISH, when used for tar- (TL) measurement as a diagnostic tool in a hospital setting. It geted clinical indications and in limited settings, can influence treat- shows that, in contrast to other methods, TL measurement by ment decisions in ways that improve outcome. flow cytometry and FISH (flowFISH) can be standardized, and has reproducible and definable upper and lower normal bound- aplastic anemia | interstitial lung disease | primary immunodeficiency | aries. In telomerase mutation carriers and carriers of other mu- liver disease | precision medicine tant telomere maintenance genes, TL had prognostic value, correlating with the age of onset of short telomeres syndrome hen primary human fibroblasts are grown in culture, they phenotypes, as well as the predominant complication. In a pro- Whave a finite replicative potential; it is predictable based spective study, TL results were actionable in one-fourth of cases on the length of telomere repeat DNA (1). Telomeres define the with idiopathic bone marrow failure affecting the stem cell donor ends of chromosomes and function to preserve genome integrity; choice and/or treatment regimen. The data show that, for they are comprised of TTAGGG sequences that are bound by targeted clinical indications, and in a hospital setting, TL mea- specialized proteins (2). Telomere length (TL) shortens during surement by flowFISH informs patient care decisions. DNA replication and, at a critical threshold, the shortest telomere(s) activate a DNA damage response that signals cell death or a per- Author contributions: J.K.A., C.W.G., J.B.J., and M.A. conceived the idea; J.K.A. and M.A. manent cell cycle arrest, known as cellular senescence (3, 4). The designed research; J.K.A., V.S.H., M.A.S., S.E.S., L.D., D.W.M., J.B.J., and M.A. performed observations in cultured cells, and the fact that TL shortens with research; A.E.D., C.M.T., L.D., C.D.A., S.G.B., R.A.B., J.F.C., and C.W.G. contributed new reagents/analytic tools; J.K.A., S.E.S., C.W.G., and M.A. analyzed data; and M.A. wrote aging, have led to a hypothesized role for telomere shortening in the paper. human aging and age-related disease (1, 5); however, the short TL Reviewers: T.R.C., University of Colorado Boulder; and A.S., The Rockefeller University. threshold that is clinically relevant for disease risk is not known, The authors declare no conflict of interest. and whether TL measurement can influence treatment decisions This open access article is distributed under Creative Commons Attribution-NonCommercial- in clinical settings has not been determined. NoDerivatives License 4.0 (CC BY-NC-ND). The short telomere syndromes are a group of genetic disorders 1Present address: Division of Pulmonary and Critical Care Medicine, University of Pitts- that are caused by mutations in components of the telomerase en- burgh School of Medicine, Pittsburgh, PA 15213. zyme and other
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