Systematic analysis of telomere length and somatic alterations in 31 cancer types

Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. Telomeres were shorter in tumors than in normal tissues and longer in sarcomas and gliomas than in other cancers. Among 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications and transcript fusions and predictive of telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, characterized by undetectable TERT expression and alterations in ATRX or DAXX, demonstrated elongated telomeres and increased telomeric repeat–containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT nor harbored alterations in ATRX or DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations. Our analysis integrates TERT abnormalities, telomerase activity and genomic alterations with telomere length in cancer.

[1]  Steven A. Roberts,et al.  Mutational heterogeneity in cancer and the search for new cancer-associated genes , 2013 .

[2]  Manel Esteller,et al.  Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin , 2005, Nature Cell Biology.

[3]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[4]  Lynda Chin,et al.  Highly Recurrent TERT Promoter Mutations in Human Melanoma , 2013, Science.

[5]  J. Hackett,et al.  Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis , 2002, Oncogene.

[6]  R. DePinho,et al.  Connecting chromosomes, crisis, and cancer. , 2002, Science.

[7]  R. Weinberg,et al.  Telomeres: cancer to human aging. , 2006, Annual review of cell and developmental biology.

[8]  J. Shay,et al.  A role for both RB and p53 in the regulation of human cellular senescence. , 1991, Experimental cell research.

[9]  Simon C Watkins,et al.  Telomerase activation by genomic rearrangements in high-risk neuroblastoma , 2015, Nature.

[10]  R. Weinberg,et al.  Telomerase activity is restored in human cells by ectopic expression of hTERT (hEST2), the catalytic subunit of telomerase , 1998, Oncogene.

[11]  J. Lingner,et al.  Molecular Dissection of Telomeric Repeat-Containing RNA Biogenesis Unveils the Presence of Distinct and Multiple Regulatory Pathways , 2010, Molecular and Cellular Biology.

[12]  R. McLendon,et al.  Altered Telomeres in Tumors with ATRX and DAXX Mutations , 2011, Science.

[13]  R. Lloyd,et al.  Pheochromocytomas and Paragangliomas: An Update on Recent Molecular Genetic Advances and Criteria for Malignancy , 2015, Advances in anatomic pathology.

[14]  David T. W. Jones,et al.  Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma , 2012, Nature.

[15]  R. Hrdličková,et al.  Alternatively Spliced Telomerase Reverse Transcriptase Variants Lacking Telomerase Activity Stimulate Cell Proliferation , 2012, Molecular and Cellular Biology.

[16]  T. Cech,et al.  Inventory of telomerase components in human cells reveals multiple subpopulations of hTR and hTERT , 2014, Nucleic acids research.

[17]  Carol W. Greider,et al.  Identification of a specific telomere terminal transferase activity in tetrahymena extracts , 1985, Cell.

[18]  J. Wysocka,et al.  Modification of enhancer chromatin: what, how, and why? , 2013, Molecular cell.

[19]  D. Schadendorf,et al.  TERT Promoter Mutations in Familial and Sporadic Melanoma , 2013, Science.

[20]  Victor V Lobanenkov,et al.  Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene , 2007, Nucleic acids research.

[21]  M. Blasco.  Telomeres and human disease: ageing, cancer and beyond , 2005, Nature Reviews Genetics.

[22]  J. Shay,et al.  Alternative splicing regulation of telomerase: a new paradigm? , 2014, Trends in genetics : TIG.

[23]  H. Wakimoto,et al.  Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors , 2015, Science.

[24]  Miguel Melo,et al.  Frequency of TERT promoter mutations in human cancers , 2013, Nature Communications.

[25]  Heng Li.  Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM , 2013, 1303.3997.

[26]  Susan Smith,et al.  Loss of ATRX Suppresses Resolution of Telomere Cohesion to Control Recombination in ALT Cancer Cells. , 2015, Cancer cell.

[27]  D. Bowtell,et al.  Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types. , 1997, Human molecular genetics.

[28]  Victor Treviño,et al.  Comparison of gene expression patterns across twelve tumor types identifies a cancer supercluster characterized by TP53 mutations and cell cycle defects , 2014, Oncogene.

[29]  David T. W. Jones,et al.  Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study. , 2013, The Lancet. Oncology.

[30]  Sahil Seth,et al.  Flowr: Robust and efficient pipelines using a simple language-agnostic approach , 2015, bioRxiv.

[31]  V. Lánská,et al.  Comparison of the relative telomere length measured in leukocytes and eleven different human tissues. , 2014, Physiological research.

[32]  Gary L. Gallia,et al.  TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal , 2013, Proceedings of the National Academy of Sciences.

[33]  John N. Weinstein,et al.  PRADA: pipeline for RNA sequencing data analysis , 2014, Bioinform..

[34]  E. Montgomery,et al.  Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. , 2011, The American journal of pathology.

[35]  A. Regev,et al.  An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors , 2008, Nature Genetics.

[36]  Richard Durbin,et al.  Estimating telomere length from whole genome sequence data , 2014, Nucleic acids research.

[37]  M. White,et al.  Absence of cancer–associated changes in human fibroblasts immortalized with telomerase , 1999, Nature Genetics.

[38]  P. Russo,et al.  Chromophobe Renal Cell Carcinoma: A Clinicopathologic Study of 203 Tumors in 200 Patients With Primary Resection at a Single Institution , 2011, The American journal of surgical pathology.

[39]  Michael Q. Zhang,et al.  Integrative analysis of 111 reference human epigenomes , 2015, Nature.

[40]  James C. Costello,et al.  TERT promoter mutations and telomerase reactivation in urothelial cancer , 2015, Science.

[41]  Lawrence A. Donehower,et al.  The somatic genomic landscape of chromophobe renal cell carcinoma. , 2014, Cancer cell.

[42]  A. Zetterberg,et al.  Frequent amplification of the telomerase reverse transcriptase gene in human tumors. , 2000, Cancer research.

[43]  Frédérique Magdinier,et al.  Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances , 2014, Genes & development.

[44]  D. Zwijnenburg,et al.  Abstract PR06: TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors , 2016 .

[45]  R. Reddel,et al.  Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines , 1997, Nature Medicine.

[46]  Erika J. Thompson,et al.  Landscape of DNA Virus Associations across Human Malignant Cancers: Analysis of 3,775 Cases Using RNA-Seq , 2013, Journal of Virology.

[47]  A M Olovnikov,et al.  A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. , 1973, Journal of theoretical biology.

[48]  J. Lingner,et al.  TERRA biogenesis, turnover and implications for function , 2010, FEBS letters.

[49]  G. Getz,et al.  GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers , 2011, Genome Biology.

[50]  R. Reddel.  The role of senescence and immortalization in carcinogenesis. , 2000, Carcinogenesis.

[51]  Brian Craft,et al.  The Cancer Genomics Hub (CGHub): overcoming cancer through the power of torrential data , 2014, Database J. Biol. Databases Curation.

[52]  J. Shay,et al.  A survey of telomerase activity in human cancer. , 1997, European journal of cancer.

[53]  Aziz Khan,et al.  dbSUPER: a database of super-enhancers in mouse and human genome , 2015, bioRxiv.

[54]  T. de Lange.  How Telomeres Solve the End-Protection Problem , 2009, Science.

[55]  E. Sahin,et al.  Axis of ageing: telomeres, p53 and mitochondria , 2012, Nature Reviews Molecular Cell Biology.

[56]  R. Verhaak,et al.  The landscape and therapeutic relevance of cancer-associated transcript fusions , 2014, Oncogene.

[57]  Monika Engelhardt,et al.  Telomerase activity in germ cell cancers and mature teratomas. , 1999, Journal of the National Cancer Institute.

[58]  Louise Davies,et al.  Increasing incidence of thyroid cancer in the United States, 1973-2002. , 2006, JAMA.

[59]  T. Cech,et al.  Polyadenylation of telomerase RNA in budding yeast. , 1997, RNA.

[60]  M. Blasco,et al.  A role for the Rb family of proteins in controlling telomere length , 2002, Nature Genetics.

[61]  R. Greenberg,et al.  ALTernative Telomere Maintenance and Cancer. , 2015, Trends in cancer.

[62]  Daniel R. Zerbino,et al.  Ensembl 2016 , 2015, Nucleic Acids Res..

[63]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[64]  Michael A. Choti,et al.  DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors , 2011, Science.

[65]  Ryan M. Layer,et al.  SpeedSeq: Ultra-fast personal genome analysis and interpretation , 2014, Nature Methods.

[66]  E. Wang,et al.  Analysis and design of RNA sequencing experiments for identifying isoform regulation , 2010, Nature Methods.

[67]  B. Wullich,et al.  Expression of the human telomerase reverse transcriptase is not related to telomerase activity in normal and malignant renal tissue. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[68]  D. Higgs,et al.  Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX , 2015, Nature Communications.

[69]  R. O'Sullivan,et al.  Telomeres: protecting chromosomes against genome instability , 2010, Nature Reviews Molecular Cell Biology.