Altered telomeres in tumors with ATRX and DAXX mutations - PubMed (original) (raw)
. 2011 Jul 22;333(6041):425.
doi: 10.1126/science.1207313. Epub 2011 Jun 30.
Roeland F de Wilde, Yuchen Jiao, Alison P Klein, Barish H Edil, Chanjuan Shi, Chetan Bettegowda, Fausto J Rodriguez, Charles G Eberhart, Sachidanand Hebbar, G Johan Offerhaus, Roger McLendon, B Ahmed Rasheed, Yiping He, Hai Yan, Darell D Bigner, Sueli Mieko Oba-Shinjo, Suely Kazue Nagahashi Marie, Gregory J Riggins, Kenneth W Kinzler, Bert Vogelstein, Ralph H Hruban, Anirban Maitra, Nickolas Papadopoulos, Alan K Meeker
Affiliations
- PMID: 21719641
- PMCID: PMC3174141
- DOI: 10.1126/science.1207313
Altered telomeres in tumors with ATRX and DAXX mutations
Christopher M Heaphy et al. Science. 2011.
Abstract
The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.
Figures
Fig. 1
Representative images of ALT-positive tumors with ATRX or DAXX mutations. (A) Example of ALT-positive PanNET. Large, ultrabright telomere FISH signals (red) indicative of ALT are marked (arrows). (B)Immunolabeling of the same PanNET shows loss of nuclear DAXX protein in tumor cells. (C) Example of ALT-positive GBM. Large, ultrabright telomere FISH signals (red) indicative of ALT are marked (arrows). (D) Immunolabeling of the same GBM shows loss of nuclear ATRX protein in tumor cells. In (B) and (D), benign endothelial cells (arrowheads) served as positive immunostaining controls. Scale bars, 30 mm.
Similar articles
- Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors.
de Wilde RF, Heaphy CM, Maitra A, Meeker AK, Edil BH, Wolfgang CL, Ellison TA, Schulick RD, Molenaar IQ, Valk GD, Vriens MR, Borel Rinkes IH, Offerhaus GJ, Hruban RH, Matsukuma KE. de Wilde RF, et al. Mod Pathol. 2012 Jul;25(7):1033-9. doi: 10.1038/modpathol.2012.53. Epub 2012 May 11. Mod Pathol. 2012. PMID: 22575867 Free PMC article. - Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors.
Singhi AD, Liu TC, Roncaioli JL, Cao D, Zeh HJ, Zureikat AH, Tsung A, Marsh JW, Lee KK, Hogg ME, Bahary N, Brand RE, McGrath KM, Slivka A, Cressman KL, Fuhrer K, O'Sullivan RJ. Singhi AD, et al. Clin Cancer Res. 2017 Jan 15;23(2):600-609. doi: 10.1158/1078-0432.CCR-16-1113. Epub 2016 Jul 12. Clin Cancer Res. 2017. PMID: 27407094 Free PMC article. - Alternative lengthening of telomeres and ATRX/DAXX loss can be reliably detected in FNAs of pancreatic neuroendocrine tumors.
VandenBussche CJ, Allison DB, Graham MK, Charu V, Lennon AM, Wolfgang CL, Hruban RH, Heaphy CM. VandenBussche CJ, et al. Cancer Cytopathol. 2017 Jul;125(7):544-551. doi: 10.1002/cncy.21857. Epub 2017 Apr 3. Cancer Cytopathol. 2017. PMID: 28371511 Free PMC article. - The diagnostic and prognostic utility of incorporating DAXX, ATRX, and alternative lengthening of telomeres to the evaluation of pancreatic neuroendocrine tumors.
Heaphy CM, Singhi AD. Heaphy CM, et al. Hum Pathol. 2022 Nov;129:11-20. doi: 10.1016/j.humpath.2022.07.015. Epub 2022 Jul 21. Hum Pathol. 2022. PMID: 35872157 Review.
Cited by
- Gastroenteropancreatic neuroendocrine neoplasms: epidemiology, genetics, and treatment.
Tan B, Zhang B, Chen H. Tan B, et al. Front Endocrinol (Lausanne). 2024 Sep 30;15:1424839. doi: 10.3389/fendo.2024.1424839. eCollection 2024. Front Endocrinol (Lausanne). 2024. PMID: 39411312 Free PMC article. Review. - Telomere Reprogramming and Cellular Metabolism: Is There a Link?
Rubtsova MP, Nikishin DA, Vyssokikh MY, Koriagina MS, Vasiliev AV, Dontsova OA. Rubtsova MP, et al. Int J Mol Sci. 2024 Sep 29;25(19):10500. doi: 10.3390/ijms251910500. Int J Mol Sci. 2024. PMID: 39408829 Free PMC article. Review. - A First-in-Class High-Throughput Screen to Discover Modulators of the Alternative Lengthening of Telomeres (ALT) Pathway.
Froney MM, Cook CR, Cadiz AM, Flinter KA, Ledeboer ST, Chan B, Burris LE, Hardy BP, Pearce KH, Wardell AC, Golitz BT, Jarstfer MB, Pattenden SG. Froney MM, et al. ACS Pharmacol Transl Sci. 2024 Aug 13;7(9):2799-2819. doi: 10.1021/acsptsci.4c00251. eCollection 2024 Sep 13. ACS Pharmacol Transl Sci. 2024. PMID: 39296266 - Prevalence of alternative lengthening of telomeres in pediatric sarcomas determined by the telomeric DNA C-circle assay.
Burrow TA, Koneru B, Macha SJ, Sun W, Barr FG, Triche TJ, Reynolds CP. Burrow TA, et al. Front Oncol. 2024 Aug 19;14:1399442. doi: 10.3389/fonc.2024.1399442. eCollection 2024. Front Oncol. 2024. PMID: 39224814 Free PMC article. - Neotelomeres and telomere-spanning chromosomal arm fusions in cancer genomes revealed by long-read sequencing.
Tan KT, Slevin MK, Leibowitz ML, Garrity-Janger M, Shan J, Li H, Meyerson M. Tan KT, et al. Cell Genom. 2024 Jul 10;4(7):100588. doi: 10.1016/j.xgen.2024.100588. Epub 2024 Jun 24. Cell Genom. 2024. PMID: 38917803 Free PMC article.
References
- Xue Y, et al. Proc. Natl. Acad. Sci. U.S.A. 2003;100:10635. - PubMed
- Elsaesser SJ, Allis CD. Cold Spring Harb. Symp. Quant. Biol. 2010;75:27. - PubMed
- Law MJ, et al. Cell. 2010;143:367. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- P50 NS020023/NS/NINDS NIH HHS/United States
- R01 CA113669-06/CA/NCI NIH HHS/United States
- R01 CA121113-01/CA/NCI NIH HHS/United States
- R01 CA140316-01A1/CA/NCI NIH HHS/United States
- R01 CA140316/CA/NCI NIH HHS/United States
- P50 NS020023-28/NS/NINDS NIH HHS/United States
- R01 NS055089-01A2/NS/NINDS NIH HHS/United States
- P01 CA134292-01A1/CA/NCI NIH HHS/United States
- R37 CA011898/CA/NCI NIH HHS/United States
- R01 NS055089/NS/NINDS NIH HHS/United States
- P50 CA062924/CA/NCI NIH HHS/United States
- R37 CA011898-41/CA/NCI NIH HHS/United States
- R01 CA121113/CA/NCI NIH HHS/United States
- P01 CA134292/CA/NCI NIH HHS/United States
- R01 CA113669/CA/NCI NIH HHS/United States
- P50 CA062924-06/CA/NCI NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical