A retrospective examination of mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study

Blackburn,Nicholas B.; Charlesworth,Jac C.; Marthick,James R.; Tegg,Elizabeth M.; Marsden,Katherine A.; Srikanth,Velandai; Blangero,John; Lowenthal,Ray M.; Foote,Simon J.; Dickinson,Joanne L.

doi:10.3892/or.2014.3568

A retrospective examination of mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study

Authors:
- Nicholas B. Blackburn
- Jac C. Charlesworth
- James R. Marthick
- Elizabeth M. Tegg
- Katherine A. Marsden
- Velandai Srikanth
- John Blangero
- Ray M. Lowenthal
- Simon J. Foote
- Joanne L. Dickinson
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Affiliations: Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS 7000, Australia, Royal Hobart Hospital, Hobart, TAS 7001, Australia, Department of Medicine, Monash Medical Centre, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3168, Australia, Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78245-0549, USA, John Curtain School of Medical Research, Australian National University, ACT 2601, Australia
Published online on: October 24, 2014 https://doi.org/10.3892/or.2014.3568
Pages: 25-32
Copyright: © Blackburn et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Telomere length has a biological link to cancer, with excessive telomere shortening leading to genetic instability and resultant malignant transformation. Telomere length is heritable and genetic variants determining telomere length have been identified. Telomere biology has been implicated in the development of hematological malignancies (HMs), therefore, closer examination of telomere length in HMs may provide further insight into genetic etiology of disease development and support for telomere length as a prognostic factor in HMs. We retrospectively examined mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study using a quantitative PCR method on genomic DNA from peripheral blood samples. Fifty-five familial HM cases, 191 unaffected relatives of familial HM cases and 75 non-familial HM cases were compared with 758 population controls. Variance components modeling was employed to identify factors influencing variation in telomere length. Overall, HM cases had shorter mean relative telomere length (p=2.9×10-6) and this was observed across both familial and non-familial HM cases (p=2.2x10-4 and 2.2x10-5, respectively) as well as additional subgroupings of HM cases according to broad subtypes. Mean relative telomere length was also significantly heritable (62.6%; p=4.7x10-5) in the HM families in the present study. We present new evidence of significantly shorter mean relative telomere length in both familial and non-familial HM cases from the same population adding further support to the potential use of telomere length as a prognostic factor in HMs. Whether telomere shortening is the cause of or the result of HMs is yet to be determined, but as telomere length was found to be highly heritable in our HM families this suggests that genetics driving the variation in telomere length is related to HM disease risk.

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1	Moyzis RK, Buckingham JM, Cram LS, et al: A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA. 85:6622–6626. 1988. View Article : Google Scholar : PubMed/NCBI
2	Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB and Bacchetti S: Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 11:1921–1929. 1992.PubMed/NCBI
3	Harley CB, Futcher AB and Greider CW: Telomeres shorten during ageing of human fibroblasts. Nature. 345:458–460. 1990. View Article : Google Scholar : PubMed/NCBI
4	Greider CW and Blackburn EH: Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 43:405–413. 1985. View Article : Google Scholar : PubMed/NCBI
5	Allsopp RC, Vaziri H, Patterson C, et al: Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA. 89:10114–10118. 1992. View Article : Google Scholar : PubMed/NCBI
6	Brouilette SW, Moore JS, McMahon AD, et al: Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. Lancet. 369:107–114. 2007. View Article : Google Scholar : PubMed/NCBI
7	McGrath M, Wong JYY, Michaud D, Hunter DJ and de Vivo I: Telomere length, cigarette smoking, and bladder cancer risk in men and women. Cancer Epidemiol Biomarkers Prev. 16:815–819. 2007. View Article : Google Scholar : PubMed/NCBI
8	Willeit P, Willeit J, Mayr A, et al: Telomere length and risk of incident cancer and cancer mortality. JAMA. 304:69–75. 2010. View Article : Google Scholar : PubMed/NCBI
9	Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L and DePinho RA: Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature. 406:641–645. 2000. View Article : Google Scholar : PubMed/NCBI
10	Slagboom PE, Droog S and Boomsma DI: Genetic determination of telomere size in humans: a twin study of three age groups. Am J Hum Genet. 55:876–882. 1994.PubMed/NCBI
11	Vasa-Nicotera M, Brouilette S, Mangino M, et al: Mapping of a major locus that determines telomere length in humans. Am J Hum Genet. 76:147–151. 2005. View Article : Google Scholar :
12	Njajou OT, Cawthon RM, Damcott CM, et al: Telomere length is paternally inherited and is associated with parental lifespan. Proc Natl Acad Sci USA. 104:12135–12139. 2007. View Article : Google Scholar : PubMed/NCBI
13	Huda N, Tanaka H, Herbert BS, Reed T and Gilley D: Shared environmental factors associated with telomere length maintenance in elderly male twins. Aging Cell. 6:709–713. 2007. View Article : Google Scholar : PubMed/NCBI
14	Graakjaer J, Bischoff C, Korsholm L, et al: The pattern of chromosome-specific variations in telomere length in humans is determined by inherited, telomere-near factors and is maintained throughout life. Mech Ageing Dev. 124:629–640. 2003. View Article : Google Scholar : PubMed/NCBI
15	Graakjaer J, Londoño-Vallejo JA, Christensen K and Kølvraa S: The pattern of chromosome-specific variations in telomere length in humans shows signs of heritability and is maintained through life. Ann NY Acad Sci. 1067:311–316. 2006. View Article : Google Scholar : PubMed/NCBI
16	Chiang YJ, Calado RT, Hathcock KS, Lansdorp PM, Young NS and Hodes RJ: Telomere length is inherited with resetting of the telomere set-point. Proc Natl Acad Sci USA. 107:10148–10153. 2010. View Article : Google Scholar : PubMed/NCBI
17	Wu X, Amos CI, Zhu Y, et al: Telomere dysfunction: a potential cancer predisposition factor. J Natl Cancer Inst. 95:1211–1218. 2003. View Article : Google Scholar : PubMed/NCBI
18	Kirwan MJ, Vulliamy T, Marrone A, et al: Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia. Hum Mutat. 30:1567–1573. 2009. View Article : Google Scholar : PubMed/NCBI
19	Swerdlow SH, Campo E, Harris NL, et al: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC; Lyon: 2008
20	Goldin LR, Björkholm M, Kristinsson SY, Turesson I and Landgren O: Elevated risk of chronic lymphocytic leukemia and other indolent non-Hodgkin’s lymphomas among relatives of patients with chronic lymphocytic leukemia. Haematologica. 94:647–653. 2009. View Article : Google Scholar : PubMed/NCBI
21	Wu K, Lund M, Bang K and Thestrup-Pedersen K: Telomerase activity and telomere length in lymphocytes from patients with cutaneous T-cell lymphoma. Cancer. 86:1056–1063. 1999. View Article : Google Scholar : PubMed/NCBI
22	Terasaki Y, Okumura H, Ohtake S and Nakao S: Accelerated telomere length shortening in granulocytes: a diagnostic marker for myeloproliferative diseases. Exp Hematol. 30:1399–1404. 2002. View Article : Google Scholar : PubMed/NCBI
23	Wu KD, Orme LM, Shaughnessy J, Jacobson J, Barlogie B and Moore MAS: Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status, and overall survival. Blood. 101:4982–4989. 2003. View Article : Google Scholar : PubMed/NCBI
24	Hartmann U, Brümmendorf TH, Balabanov S, Thiede C, Illme T and Schaich M: Telomere length and hTERT expression in patients with acute myeloid leukemia correlates with chromosomal abnormalities. Haematologica. 90:307–316. 2005.PubMed/NCBI
25	Ghaffari SH, Shayan-Asl N, Jamialahmadi AH, Alimoghaddam K and Ghavamzadeh A: Telomerase activity and telomere length in patients with acute promyelocytic leukemia: indicative of proliferative activity, disease progression, and overall survival. Ann Oncol. 19:1927–1934. 2008. View Article : Google Scholar : PubMed/NCBI
26	Capraro V, Zane L, Poncet D, et al: Telomere deregulations possess cytogenetic, phenotype, and prognostic specificities in acute leukemias. Exp Hematol. 39:195–202.e2. 2011. View Article : Google Scholar
27	Lan Q, Cawthon R, Shen M, et al: A prospective study of telomere length measured by monochrome multiplex quantitative PCR and risk of non-Hodgkin lymphoma. Clin Cancer Res. 15:7429–7433. 2009. View Article : Google Scholar : PubMed/NCBI
28	Mansouri L, Grabowski P, Degerman S, et al: Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients. Am J Hematol. 88:647–651. 2013. View Article : Google Scholar : PubMed/NCBI
29	Tegg EM, Thomson RJ, Stankovich J, et al: Evidence for a common genetic aetiology in high-risk families with multiple haematological malignancy subtypes. Br J Haematol. 150:456–462. 2010.PubMed/NCBI
30	Tegg EM, Thomson RJ, Stankovich JM, et al: Anticipation in familial hematologic malignancies. Blood. 117:1308–1310. 2011. View Article : Google Scholar
31	Lowenthal RM, Tegg EM and Dickinson JL: The Familial Tasmanian Haematological Malignancies Study (FaTHMS): its origins, its history and the phenomenon of anticipation. Transfus Apher Sci. 49:113–115. 2013. View Article : Google Scholar : PubMed/NCBI
32	FitzGerald LM, Patterson B, Thomson R, et al: Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease. Eur J Hum Genet. 17:368–377. 2009. View Article : Google Scholar
33	Callisaya ML, Blizzard L, Schmidt MD, Martin KL, McGinley JL, Sanders LM and Srikanth VK: Gait, gait variability and the risk of multiple incident falls in older people: a population-based study. Age Ageing. 40:481–487. 2011. View Article : Google Scholar : PubMed/NCBI
34	Giles GG, Lickiss JN, Baikie MJ, Lowenthal RM and Panton J: Myeloproliferative and lymphoproliferative disorders in Tasmania, 1972–80: occupational and familial aspects. J Natl Cancer Inst. 72:1233–1240. 1984.PubMed/NCBI
35	Lickiss JN, Giles GG, Baikie MJ, Lowenthal RM, Challis D and Panton J: Myeloproliferative and lymphoproliferative disorders in Tasmania, 1972–80: patterns in space and time. J Natl Cancer Inst. 72:1223–1231. 1984.PubMed/NCBI
36	Cawthon RM: Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Res. 37:e212009. View Article : Google Scholar : PubMed/NCBI
37	Ruijter JM, Ramakers C, Hoogaars WMH, Karlen Y, Bakker O, van den Hoff MJB and Moorman AFM: Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data. Nucleic Acids Res. 37:e452009. View Article : Google Scholar : PubMed/NCBI
38	Almasy L and Blangero J: Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet. 62:1198–1211. 1998. View Article : Google Scholar : PubMed/NCBI
39	Almasy L and Blangero J: Variance component methods for analysis of complex phenotypes. Cold Spring Harb Protoc. 2010.pdb.top77-pdb.top77. 2010. View Article : Google Scholar : PubMed/NCBI
40	Njajou OT, Blackburn EH, Pawlikowska L, et al: A common variant in the telomerase RNA component is associated with short telomere length. PLoS One. 5:e130482010. View Article : Google Scholar : PubMed/NCBI
41	Kampstra P: Beanplot: A boxplot alternative for visual comparison of distributions. J Statistical Software. 28:1–9. 2008.http://www.jstatsoft.org/v28/c01/.
42	Aubert G, Baerlocher GM, Vulto I, Poon SS and Lansdorp PM: Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes. PLoS Genet. 8:e10026962012. View Article : Google Scholar : PubMed/NCBI
43	Schröder CP, Wisman GB, de Jong S, et al: Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplantation. Br J Cancer. 84:1348–1353. 2001. View Article : Google Scholar : PubMed/NCBI
44	Mirabello L, Garcia-Closas M, Cawthon R, et al: Leukocyte telomere length in a population-based case-control study of ovarian cancer: a pilot study. Cancer Causes Control. 21:77–82. 2010. View Article : Google Scholar
45	Engelhardt M, Ozkaynak MF, Drullinsky P, Sandoval C, Tugal O, Jayabose S and Moore MA: Telomerase activity and telomere length in pediatric patients with malignancies undergoing chemotherapy. Leukemia. 12:13–24. 1998. View Article : Google Scholar : PubMed/NCBI
46	Franco S, Ozkaynak MF, Sandoval C, Tugal O, Jayabose S, Engelhardt M and Moore MAS: Telomere dynamics in childhood leukemia and solid tumors: a follow-up study. Leukemia. 17:401–410. 2003. View Article : Google Scholar : PubMed/NCBI
47	Diker-Cohen T, Uziel O, Szyper-Kravitz M, Shapira H, Natur A and Lahav M: The effect of chemotherapy on telomere dynamics: clinical results and possible mechanisms. Leuk Lymphoma. 54:2023–2029. 2013. View Article : Google Scholar