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Telomerase, Autophagy and Acute Kidney Injury.
Harris RC, Cheng H
(2016) Nephron 134: 145-148
MeSH Terms: Acute Kidney Injury, Autophagy, Humans, Telomerase, Telomere
Show Abstract · Added April 26, 2017
In humans, aging is associated with telomere shortening and increased susceptibility to acute kidney injury. Telomerase is essential to maintain telomere length. The fourth generation mice with telomerase deletion have progressive shortening of telomeres. Those mice delayed recovery from ischemia-reperfusion injury, due to an increase in tubule cell senescence and impairment of autophagy, the latter of which may be mediated in part by increased mTOR signaling. © 2016 S. Karger AG, Basel.
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5 MeSH Terms
Endogenous Hot Spots of De Novo Telomere Addition in the Yeast Genome Contain Proximal Enhancers That Bind Cdc13.
Obodo UC, Epum EA, Platts MH, Seloff J, Dahlson NA, Velkovsky SM, Paul SR, Friedman KL
(2016) Mol Cell Biol 36: 1750-63
MeSH Terms: Binding Sites, DNA Breaks, Double-Stranded, DNA Repair, DNA, Fungal, Enhancer Elements, Genetic, Genome, Fungal, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Telomerase, Telomere, Telomere-Binding Proteins
Show Abstract · Added April 8, 2019
DNA double-strand breaks (DSBs) pose a threat to genome stability and are repaired through multiple mechanisms. Rarely, telomerase, the enzyme that maintains telomeres, acts upon a DSB in a mutagenic process termed telomere healing. The probability of telomere addition is increased at specific genomic sequences termed sites of repair-associated telomere addition (SiRTAs). By monitoring repair of an induced DSB, we show that SiRTAs on chromosomes V and IX share a bipartite structure in which a core sequence (Core) is directly targeted by telomerase, while a proximal sequence (Stim) enhances the probability of de novo telomere formation. The Stim and Core sequences are sufficient to confer a high frequency of telomere addition to an ectopic site. Cdc13, a single-stranded DNA binding protein that recruits telomerase to endogenous telomeres, is known to stimulate de novo telomere addition when artificially recruited to an induced DSB. Here we show that the ability of the Stim sequence to enhance de novo telomere addition correlates with its ability to bind Cdc13, indicating that natural sites at which telomere addition occurs at high frequency require binding by Cdc13 to a sequence 20 to 100 bp internal from the site at which telomerase acts to initiate de novo telomere addition.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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MeSH Terms
Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.
Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, Morozova O, Newton Y, Radenbaugh A, Pagnotta SM, Anjum S, Wang J, Manyam G, Zoppoli P, Ling S, Rao AA, Grifford M, Cherniack AD, Zhang H, Poisson L, Carlotti CG, Tirapelli DP, Rao A, Mikkelsen T, Lau CC, Yung WK, Rabadan R, Huse J, Brat DJ, Lehman NL, Barnholtz-Sloan JS, Zheng S, Hess K, Rao G, Meyerson M, Beroukhim R, Cooper L, Akbani R, Wrensch M, Haussler D, Aldape KD, Laird PW, Gutmann DH, TCGA Research Network, Noushmehr H, Iavarone A, Verhaak RG
(2016) Cell 164: 550-63
MeSH Terms: Adult, Brain Neoplasms, Cell Proliferation, Cluster Analysis, DNA Helicases, DNA Methylation, Epigenesis, Genetic, Glioma, Humans, Isocitrate Dehydrogenase, Middle Aged, Mutation, Nuclear Proteins, Promoter Regions, Genetic, Signal Transduction, Telomerase, Telomere, Transcriptome, X-linked Nuclear Protein
Show Abstract · Added August 8, 2016
Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.
Copyright © 2016 Elsevier Inc. All rights reserved.
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19 MeSH Terms
A Phenome-Wide Association Study Identifies a Novel Asthma Risk Locus Near TERC.
Claar DD, Larkin EK, Bastarache L, Blackwell TS, Loyd JE, Hartert TV, Denny JC, Kropski JA
(2016) Am J Respir Crit Care Med 193: 98-100
MeSH Terms: Asthma, Female, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, RNA, Risk Factors, Telomerase
Added February 22, 2016
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13 MeSH Terms
Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the population architecture using genomics and epidemiology (PAGE) study.
Kocarnik JM, Park SL, Han J, Dumitrescu L, Cheng I, Wilkens LR, Schumacher FR, Kolonel L, Carlson CS, Crawford DC, Goodloe RJ, Dilks HH, Baker P, Richardson D, Matise TC, Ambite JL, Song F, Qureshi AA, Zhang M, Duggan D, Hutter C, Hindorff L, Bush WS, Kooperberg C, Le Marchand L, Peters U
(2015) PLoS One 10: e0120491
MeSH Terms: Aged, Aged, 80 and over, Alleles, Case-Control Studies, Female, Genetic Pleiotropy, Genome-Wide Association Study, Genotype, Humans, Lung Neoplasms, Male, Melanoma, Membrane Proteins, Metagenomics, Middle Aged, Neoplasm Proteins, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk, Sex Factors, Skin Neoplasms, Telomerase
Show Abstract · Added May 5, 2017
BACKGROUND - Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk.
METHODS - We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies.
RESULTS - We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4).
CONCLUSIONS - We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.
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22 MeSH Terms
The somatic genomic landscape of chromophobe renal cell carcinoma.
Davis CF, Ricketts CJ, Wang M, Yang L, Cherniack AD, Shen H, Buhay C, Kang H, Kim SC, Fahey CC, Hacker KE, Bhanot G, Gordenin DA, Chu A, Gunaratne PH, Biehl M, Seth S, Kaipparettu BA, Bristow CA, Donehower LA, Wallen EM, Smith AB, Tickoo SK, Tamboli P, Reuter V, Schmidt LS, Hsieh JJ, Choueiri TK, Hakimi AA, The Cancer Genome Atlas Research Network, Chin L, Meyerson M, Kucherlapati R, Park WY, Robertson AG, Laird PW, Henske EP, Kwiatkowski DJ, Park PJ, Morgan M, Shuch B, Muzny D, Wheeler DA, Linehan WM, Gibbs RA, Rathmell WK, Creighton CJ
(2014) Cancer Cell 26: 319-330
MeSH Terms: Base Sequence, Carcinoma, Renal Cell, Chromosome Breakpoints, Chromosome Deletion, Chromosomes, Human, DNA Copy Number Variations, DNA Methylation, DNA Mutational Analysis, DNA, Mitochondrial, Exome, Genome, Human, Humans, Kidney Neoplasms, Molecular Sequence Data, Promoter Regions, Genetic, Telomerase, Transcriptome
Show Abstract · Added October 17, 2015
We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.
Copyright © 2014 Elsevier Inc. All rights reserved.
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17 MeSH Terms
Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.
Wang Z, Zhu B, Zhang M, Parikh H, Jia J, Chung CC, Sampson JN, Hoskins JW, Hutchinson A, Burdette L, Ibrahim A, Hautman C, Raj PS, Abnet CC, Adjei AA, Ahlbom A, Albanes D, Allen NE, Ambrosone CB, Aldrich M, Amiano P, Amos C, Andersson U, Andriole G, Andrulis IL, Arici C, Arslan AA, Austin MA, Baris D, Barkauskas DA, Bassig BA, Beane Freeman LE, Berg CD, Berndt SI, Bertazzi PA, Biritwum RB, Black A, Blot W, Boeing H, Boffetta P, Bolton K, Boutron-Ruault MC, Bracci PM, Brennan P, Brinton LA, Brotzman M, Bueno-de-Mesquita HB, Buring JE, Butler MA, Cai Q, Cancel-Tassin G, Canzian F, Cao G, Caporaso NE, Carrato A, Carreon T, Carta A, Chang GC, Chang IS, Chang-Claude J, Che X, Chen CJ, Chen CY, Chen CH, Chen C, Chen KY, Chen YM, Chokkalingam AP, Chu LW, Clavel-Chapelon F, Colditz GA, Colt JS, Conti D, Cook MB, Cortessis VK, Crawford ED, Cussenot O, Davis FG, De Vivo I, Deng X, Ding T, Dinney CP, Di Stefano AL, Diver WR, Duell EJ, Elena JW, Fan JH, Feigelson HS, Feychting M, Figueroa JD, Flanagan AM, Fraumeni JF, Freedman ND, Fridley BL, Fuchs CS, Gago-Dominguez M, Gallinger S, Gao YT, Gapstur SM, Garcia-Closas M, Garcia-Closas R, Gastier-Foster JM, Gaziano JM, Gerhard DS, Giffen CA, Giles GG, Gillanders EM, Giovannucci EL, Goggins M, Gokgoz N, Goldstein AM, Gonzalez C, Gorlick R, Greene MH, Gross M, Grossman HB, Grubb R, Gu J, Guan P, Haiman CA, Hallmans G, Hankinson SE, Harris CC, Hartge P, Hattinger C, Hayes RB, He Q, Helman L, Henderson BE, Henriksson R, Hoffman-Bolton J, Hohensee C, Holly EA, Hong YC, Hoover RN, Hosgood HD, Hsiao CF, Hsing AW, Hsiung CA, Hu N, Hu W, Hu Z, Huang MS, Hunter DJ, Inskip PD, Ito H, Jacobs EJ, Jacobs KB, Jenab M, Ji BT, Johansen C, Johansson M, Johnson A, Kaaks R, Kamat AM, Kamineni A, Karagas M, Khanna C, Khaw KT, Kim C, Kim IS, Kim JH, Kim YH, Kim YC, Kim YT, Kang CH, Jung YJ, Kitahara CM, Klein AP, Klein R, Kogevinas M, Koh WP, Kohno T, Kolonel LN, Kooperberg C, Kratz CP, Krogh V, Kunitoh H, Kurtz RC, Kurucu N, Lan Q, Lathrop M, Lau CC, Lecanda F, Lee KM, Lee MP, Le Marchand L, Lerner SP, Li D, Liao LM, Lim WY, Lin D, Lin J, Lindstrom S, Linet MS, Lissowska J, Liu J, Ljungberg B, Lloreta J, Lu D, Ma J, Malats N, Mannisto S, Marina N, Mastrangelo G, Matsuo K, McGlynn KA, McKean-Cowdin R, McNeill LH, McWilliams RR, Melin BS, Meltzer PS, Mensah JE, Miao X, Michaud DS, Mondul AM, Moore LE, Muir K, Niwa S, Olson SH, Orr N, Panico S, Park JY, Patel AV, Patino-Garcia A, Pavanello S, Peeters PH, Peplonska B, Peters U, Petersen GM, Picci P, Pike MC, Porru S, Prescott J, Pu X, Purdue MP, Qiao YL, Rajaraman P, Riboli E, Risch HA, Rodabough RJ, Rothman N, Ruder AM, Ryu JS, Sanson M, Schned A, Schumacher FR, Schwartz AG, Schwartz KL, Schwenn M, Scotlandi K, Seow A, Serra C, Serra M, Sesso HD, Severi G, Shen H, Shen M, Shete S, Shiraishi K, Shu XO, Siddiq A, Sierrasesumaga L, Sierri S, Loon Sihoe AD, Silverman DT, Simon M, Southey MC, Spector L, Spitz M, Stampfer M, Stattin P, Stern MC, Stevens VL, Stolzenberg-Solomon RZ, Stram DO, Strom SS, Su WC, Sund M, Sung SW, Swerdlow A, Tan W, Tanaka H, Tang W, Tang ZZ, Tardon A, Tay E, Taylor PR, Tettey Y, Thomas DM, Tirabosco R, Tjonneland A, Tobias GS, Toro JR, Travis RC, Trichopoulos D, Troisi R, Truelove A, Tsai YH, Tucker MA, Tumino R, Van Den Berg D, Van Den Eeden SK, Vermeulen R, Vineis P, Visvanathan K, Vogel U, Wang C, Wang C, Wang J, Wang SS, Weiderpass E, Weinstein SJ, Wentzensen N, Wheeler W, White E, Wiencke JK, Wolk A, Wolpin BM, Wong MP, Wrensch M, Wu C, Wu T, Wu X, Wu YL, Wunder JS, Xiang YB, Xu J, Yang HP, Yang PC, Yatabe Y, Ye Y, Yeboah ED, Yin Z, Ying C, Yu CJ, Yu K, Yuan JM, Zanetti KA, Zeleniuch-Jacquotte A, Zheng W, Zhou B, Mirabello L, Savage SA, Kraft P, Chanock SJ, Yeager M, Landi MT, Shi J, Chatterjee N, Amundadottir LT
(2014) Hum Mol Genet 23: 6616-33
MeSH Terms: Alleles, Chromosomes, Human, Pair 5, Computational Biology, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Membrane Proteins, Neoplasm Proteins, Neoplasms, Odds Ratio, Polymorphism, Single Nucleotide, Risk, Telomerase
Show Abstract · Added April 3, 2018
Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
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MeSH Terms
Normal telomere length maintenance in Saccharomyces cerevisiae requires nuclear import of the ever shorter telomeres 1 (Est1) protein via the importin alpha pathway.
Hawkins C, Friedman KL
(2014) Eukaryot Cell 13: 1036-50
MeSH Terms: Active Transport, Cell Nucleus, Amino Acid Sequence, Cell Nucleus, Molecular Sequence Data, Nuclear Localization Signals, Nucleocytoplasmic Transport Proteins, RNA-Binding Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Telomerase, Telomere Homeostasis, beta Karyopherins
Show Abstract · Added January 20, 2015
The Est1 (ever shorter telomeres 1) protein is an essential component of yeast telomerase, a ribonucleoprotein complex that restores the repetitive sequences at chromosome ends (telomeres) that would otherwise be lost during DNA replication. Previous work has shown that the telomerase RNA component (TLC1) transits through the cytoplasm during telomerase biogenesis, but mechanisms of protein import have not been addressed. Here we identify three nuclear localization sequences (NLSs) in Est1p. Mutation of the most N-terminal NLS in the context of full-length Est1p reduces Est1p nuclear localization and causes telomere shortening-phenotypes that are rescued by fusion with the NLS from the simian virus 40 (SV40) large-T antigen. In contrast to that of the TLC1 RNA, Est1p nuclear import is facilitated by Srp1p, the yeast homolog of importin α. The reduction in telomere length observed at the semipermissive temperature in a srp1 mutant strain is rescued by increased Est1p expression, consistent with a defect in Est1p nuclear import. These studies suggest that at least two nuclear import pathways are required to achieve normal telomere length homeostasis in yeast.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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12 MeSH Terms
Pleiotropic associations of risk variants identified for other cancers with lung cancer risk: the PAGE and TRICL consortia.
Park SL, Fesinmeyer MD, Timofeeva M, Caberto CP, Kocarnik JM, Han Y, Love SA, Young A, Dumitrescu L, Lin Y, Goodloe R, Wilkens LR, Hindorff L, Fowke JH, Carty C, Buyske S, Schumacher FR, Butler A, Dilks H, Deelman E, Cote ML, Chen W, Pande M, Christiani DC, Field JK, Bickebller H, Risch A, Heinrich J, Brennan P, Wang Y, Eisen T, Houlston RS, Thun M, Albanes D, Caporaso N, Peters U, North KE, Heiss G, Crawford DC, Bush WS, Haiman CA, Landi MT, Hung RJ, Kooperberg C, Amos CI, Le Marchand L, Cheng I
(2014) J Natl Cancer Inst 106: dju061
MeSH Terms: Adenocarcinoma, Adult, Aged, Breast Neoplasms, Cyclin-Dependent Kinase Inhibitor p15, Female, Genome-Wide Association Study, Humans, Interdisciplinary Communication, Logistic Models, Lung Neoplasms, Male, Microfilament Proteins, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins, Risk Factors, Sex Factors, Smoking, Telomerase
Show Abstract · Added May 23, 2014
BACKGROUND - Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed.
METHODS - We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non-lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10(-5) was used to assign statistical significance.
RESULTS - The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10(-6)). This association was strongest for women with adenocarcinoma (P = 1.2×10(-4)) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10(-8)) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10(-5)), respectively.
CONCLUSIONS - Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.
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21 MeSH Terms
TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma.
Remke M, Ramaswamy V, Peacock J, Shih DJ, Koelsche C, Northcott PA, Hill N, Cavalli FM, Kool M, Wang X, Mack SC, Barszczyk M, Morrissy AS, Wu X, Agnihotri S, Luu B, Jones DT, Garzia L, Dubuc AM, Zhukova N, Vanner R, Kros JM, French PJ, Van Meir EG, Vibhakar R, Zitterbart K, Chan JA, Bognár L, Klekner A, Lach B, Jung S, Saad AG, Liau LM, Albrecht S, Zollo M, Cooper MK, Thompson RC, Delattre OO, Bourdeaut F, Doz FF, Garami M, Hauser P, Carlotti CG, Van Meter TE, Massimi L, Fults D, Pomeroy SL, Kumabe T, Ra YS, Leonard JR, Elbabaa SK, Mora J, Rubin JB, Cho YJ, McLendon RE, Bigner DD, Eberhart CG, Fouladi M, Wechsler-Reya RJ, Faria CC, Croul SE, Huang A, Bouffet E, Hawkins CE, Dirks PB, Weiss WA, Schüller U, Pollack IF, Rutkowski S, Meyronet D, Jouvet A, Fèvre-Montange M, Jabado N, Perek-Polnik M, Grajkowska WA, Kim SK, Rutka JT, Malkin D, Tabori U, Pfister SM, Korshunov A, von Deimling A, Taylor MD
(2013) Acta Neuropathol 126: 917-29
MeSH Terms: Adolescent, Adult, Brain Neoplasms, Child, Child, Preschool, DNA Mutational Analysis, Female, Gene Expression Profiling, Genotype, Humans, Infant, Male, Medulloblastoma, Middle Aged, Mutation, Prognosis, Promoter Regions, Genetic, Telomerase
Show Abstract · Added March 7, 2014
Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.
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18 MeSH Terms