Home LiteratureArticle Details
PMID: 25383969 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Systematic analysis of noncoding somatic mutations and gene expression alterations across 14 tumor types.

Nature genetics ·Vol. 46 ·No. 12 ·2014-12-00 ·Pages 1258-63

Fredriksson NJ, Ny L, Nilsson JA, Larsson E

Abstract

Somatic mutations in noncoding sequences are poorly explored in cancer, a rare exception being the recent identification of activating mutations in TERT regulatory DNA. Although this finding is suggestive of a general mechanism for oncogene activation, this hypothesis remains untested. Here we map somatic mutations in 505 tumor genomes across 14 cancer types and systematically screen for associations between mutations in regulatory regions and RNA-level changes. We identify recurrent promoter mutations in several genes but find that TERT mutations are exceptional in showing a strong and genome-wide significant association with increased expression. Detailed analysis of TERT across cancers shows that the strength of this association is highly variable and is strongest in copy number-stable cancers such as thyroid carcinoma. We additionally propose that TERT promoter mutations control expression of the nearby gene CLPTM1L. Our analysis provides a detailed pan-cancer view of TERT transcriptional activation but finds no clear evidence for frequent oncogenic promoter mutations beyond TERT.

MeSH Terms
Carrier Proteins/genetics Cell Transformation, Neoplastic DNA Mutational Analysis Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Intracellular Signaling Peptides and Proteins Mutation Neoplasms/genetics,metabolism Promoter Regions, Genetic Telomerase/genetics
Chemicals
Carrier Proteins DPH3 protein, human Intracellular Signaling Peptides and Proteins TERT protein, human Telomerase
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Fredriksson Nils J
Department of Medical Biochemisty and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Ny Lars
Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Nilsson Jonas A
Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Larsson Erik
Department of Medical Biochemisty and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
References (57)
57 references, click to expand
  1. Alternative lengthening of telomeres: models, mechanisms and implications.
    Nat Rev Genet. 2010 May;11(5):319-30 PMID: 20351727
  2. HTSeq--a Python framework to work with high-throughput sequencing data.
    Bioinformatics. 2015 Jan 15;31(2):166-9 PMID: 25260700
  3. Ovca1 regulates cell proliferation, embryonic development, and tumorigenesis.
    Genes Dev. 2004 Feb 1;18(3):320-32 PMID: 14744934
  4. Lessons from the cancer genome.
    Cell. 2013 Mar 28;153(1):17-37 PMID: 23540688
  5. Genome-wide analysis of noncoding regulatory mutations in cancer.
    Nat Genet. 2014 Nov;46(11):1160-5 PMID: 25261935
  6. Pathways and therapeutic targets in melanoma.
    Oncotarget. 2014 Apr 15;5(7):1701-52 PMID: 24743024
  7. Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins.
    Nat Rev Cancer. 2011 Mar;11(3):161-76 PMID: 21346783
  8. Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence.
    Nat Rev Genet. 2011 Dec 06;13(1):59-69 PMID: 22143240
  9. A general framework for detecting disease associations with rare variants in sequencing studies.
    Am J Hum Genet. 2011 Sep 9;89(3):354-67 PMID: 21885029
  10. Genome-wide association study identifies five susceptibility loci for glioma.
    Nat Genet. 2009 Aug;41(8):899-904 PMID: 19578367
  11. The phosphatidylinositol 3-Kinase AKT pathway in human cancer.
    Nat Rev Cancer. 2002 Jul;2(7):489-501 PMID: 12094235
  12. Integrative eQTL-based analyses reveal the biology of breast cancer risk loci.
    Cell. 2013 Jan 31;152(3):633-41 PMID: 23374354
  13. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing.
    Genome Res. 2012 Mar;22(3):568-76 PMID: 22300766
  14. The somatic genomic landscape of glioblastoma.
    Cell. 2013 Oct 10;155(2):462-77 PMID: 24120142
  15. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer.
    Nucleic Acids Res. 2011 Jan;39(Database issue):D945-50 PMID: 20952405
  16. Gene trap mutagenesis-based forward genetic approach reveals that the tumor suppressor OVCA1 is a component of the biosynthetic pathway of diphthamide on elongation factor 2.
    J Biol Chem. 2005 Mar 18;280(11):10572-7 PMID: 15637051
  17. CLPTM1L promotes growth and enhances aneuploidy in pancreatic cancer cells.
    Cancer Res. 2014 May 15;74(10):2785-95 PMID: 24648346
  18. A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia.
    Nat Genet. 2014 Jan;46(1):56-60 PMID: 24292274
  19. Identification of the proteins required for biosynthesis of diphthamide, the target of bacterial ADP-ribosylating toxins on translation elongation factor 2.
    Mol Cell Biol. 2004 Nov;24(21):9487-97 PMID: 15485916
  20. An integrated encyclopedia of DNA elements in the human genome.
    Nature. 2012 Sep 6;489(7414):57-74 PMID: 22955616
  21. TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism.
    Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17426-31 PMID: 24101484
  22. Mutational heterogeneity in cancer and the search for new cancer-associated genes.
    Nature. 2013 Jul 11;499(7457):214-8 PMID: 23770567
  23. OVCA1 inhibits the proliferation of epithelial ovarian cancer cells by decreasing cyclin D1 and increasing p16.
    Mol Cell Biochem. 2011 Aug;354(1-2):199-205 PMID: 21487939
  24. GENCODE: the reference human genome annotation for The ENCODE Project.
    Genome Res. 2012 Sep;22(9):1760-74 PMID: 22955987
  25. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.
    Sci Signal. 2013 Apr 02;6(269):pl1 PMID: 23550210
  26. Comprehensive mutation analysis of the TERT promoter in bladder cancer and detection of mutations in voided urine.
    Eur Urol. 2014 Feb;65(2):367-9 PMID: 24035680
  27. Melanoma genome sequencing reveals frequent PREX2 mutations.
    Nature. 2012 May 09;485(7399):502-6 PMID: 22622578
  28. A novel gene, CRR9, which was up-regulated in CDDP-resistant ovarian tumor cell line, was associated with apoptosis.
    Biochem Biophys Res Commun. 2001 Feb 2;280(4):1148-54 PMID: 11162647
  29. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
    Nat Genet. 2013 Apr;45(4):371-84, 384e1-2 PMID: 23535731
  30. Frequent somatic mutations of the telomerase reverse transcriptase promoter in ovarian clear cell carcinoma but not in other major types of gynaecological malignancy.
    J Pathol. 2014 Mar;232(4):473-81 PMID: 24338723
  31. Emerging patterns of somatic mutations in cancer.
    Nat Rev Genet. 2013 Oct;14(10):703-18 PMID: 24022702
  32. Silencing of diphthamide synthesis 3 (Dph3) reduces metastasis of murine melanoma.
    PLoS One. 2012;7(11):e49988 PMID: 23185508
  33. Frequency of TERT promoter mutations in human cancers.
    Nat Commun. 2013;4:2185 PMID: 23887589
  34. TERT promoter mutations in renal cell carcinomas and upper tract urothelial carcinomas.
    Oncotarget. 2014 Apr 15;5(7):1829-36 PMID: 24742867
  35. Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome.
    Eur Urol. 2014 Feb;65(2):360-6 PMID: 24018021
  36. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.
    Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6021-6 PMID: 23530248
  37. Expression of OVCA1, a candidate tumor suppressor, is reduced in tumors and inhibits growth of ovarian cancer cells.
    Cancer Res. 1999 Oct 1;59(19):4973-83 PMID: 10519411
  38. TERT promoter mutations in familial and sporadic melanoma.
    Science. 2013 Feb 22;339(6122):959-61 PMID: 23348503
  39. Signatures of mutational processes in human cancer.
    Nature. 2013 Aug 22;500(7463):415-21 PMID: 23945592
  40. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types.
    Nat Genet. 2009 Feb;41(2):221-7 PMID: 19151717
  41. Primer3--new capabilities and interfaces.
    Nucleic Acids Res. 2012 Aug;40(15):e115 PMID: 22730293
  42. Highly recurrent TERT promoter mutations in human melanoma.
    Science. 2013 Feb 22;339(6122):957-9 PMID: 23348506
  43. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.
    Cancer Discov. 2012 May;2(5):401-4 PMID: 22588877
  44. Ovca1, a candidate gene of the genetic modifier of Tp53, Mop2, affects mouse embryonic lethality.
    Genes Chromosomes Cancer. 2008 Apr;47(4):315-25 PMID: 18181179
  45. Integrated genomic characterization of endometrial carcinoma.
    Nature. 2013 May 2;497(7447):67-73 PMID: 23636398
  46. Rare-variant association testing for sequencing data with the sequence kernel association test.
    Am J Hum Genet. 2011 Jul 15;89(1):82-93 PMID: 21737059
  47. Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression.
    Hum Mol Genet. 2013 Jun 15;22(12):2520-8 PMID: 23535824
  48. Comprehensive analysis of long non-coding RNAs in ovarian cancer reveals global patterns and targeted DNA amplification.
    PLoS One. 2013 Nov 12;8(11):e80306 PMID: 24265805
  49. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.
    Nat Genet. 2014 May;46(5):444-50 PMID: 24705251
  50. Highly prevalent TERT promoter mutations in aggressive thyroid cancers.
    Endocr Relat Cancer. 2013 Jul 12;20(4):603-10 PMID: 23766237
  51. Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma.
    Oncogene. 2006 Jun 8;25(24):3357-64 PMID: 16462768
  52. Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor.
    Bioinformatics. 2010 Aug 15;26(16):2069-70 PMID: 20562413
  53. Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data.
    Am J Hum Genet. 2008 Sep;83(3):311-21 PMID: 18691683
  54. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.
    Nat Genet. 2011 Oct 30;43(12):1210-4 PMID: 22037553
  55. Telomerase reverse transcriptase promoter mutations in primary cutaneous melanoma.
    Nat Commun. 2014 Feb 26;5:3401 PMID: 24569790
  56. Telomerase reverse transcriptase gene promoter mutations help discern the origin of urogenital tumors: a genomic and molecular study.
    Eur Urol. 2014 Feb;65(2):274-7 PMID: 24215939
  57. Evolution of the cancer genome.
    Nat Rev Genet. 2012 Nov;13(11):795-806 PMID: 23044827
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.3141
Published
2014-12-00
Epub
2014-00-10
Pages
1258-63
Language
English
Region
United States
NLM ID
9216904
Subset
IM
External Links
PubMed source DOI: 10.1038/ng.3141 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2