Somatic intronic microsatellite loci differentiate glioblastoma from lower-grade gliomas

Enusha Karunasena, Lauren J. McIver, Brian R. Rood, Xiaowei Wu, Hongxiao Zhu, Jasmin H. Bavarva, Harold R. Garner

Research output: Contribution to journalArticle

Abstract

Genomic studies of glioma sub-types have amassed new disease specific mutations, yet these only partially explain how mutations are linked to predisposition or progression. We hypothesized that microsatellite variation could expand the understanding of glioma etiology. Furthermore, germline markers for gliomas are typically undetectable; therefore we also hypothesize that the predictability of cancerassociated microsatellite loci in germline DNA may support the current hypothesis of a glioma cell of origin. In this study, "normal" germline exome sequenced DNA from the 1000 Genomes Project (n=390) were compared with exome sequences from germlines of subjects with WHO grade II and III lower-grade glioma (LGG, n=136) and WHO grade IV glioblastoma (GBM, n=252) from The Cancer Genome Atlas to identify microsatellite loci non-randomly associated with glioma. From germline data, we identified 48 GBM-specific loci, 42 Lower-grade glioma specific loci and 29 loci that distinguish GBM from LGG (p≤0.01). We then attempted to distinguish WHO grade II glioma (n=67) from GBM resulting in 8 informative loci. Significantly, in all glioma grades, comparisons between tumor and matched germline sequences demonstrated no significant differences in these variants (p≥0.01). Therefore, these microsatellite loci are considered to be components of grade-specific signatures for glioma which distinguish germline sequences of individuals with cancer from those of individuals that are "normal". In order to better understand the significance of these loci, we identified biological processes enriched in genes with these variants. Most strikingly, six helicase genes were enriched in the GBM cohort (p≤1.0 x10-3). The preservation of these glioma-specific loci could therefore serve as valuable diagnostic and therapeutic markers; especially since the heterogeneity of tumor cell populations can obscure the identification of mutations preceding a metastatic phenotype.

Original languageEnglish (US)
Pages (from-to)6003-6014
Number of pages12
JournalOncotarget
Volume5
Issue number15
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Glioblastoma
Glioma
Microsatellite Repeats
Exome
Mutation
Neoplasms
Genome
Biological Phenomena
Atlases
DNA
Genes
Phenotype

Keywords

  • Brain
  • GBM
  • Glioma
  • Helicase
  • Microsatellite
  • Ubiquitin proteasome system

ASJC Scopus subject areas

  • Oncology

Cite this

Karunasena, E., McIver, L. J., Rood, B. R., Wu, X., Zhu, H., Bavarva, J. H., & Garner, H. R. (2014). Somatic intronic microsatellite loci differentiate glioblastoma from lower-grade gliomas. Oncotarget, 5(15), 6003-6014. https://doi.org/10.18632/oncotarget.2076

Somatic intronic microsatellite loci differentiate glioblastoma from lower-grade gliomas. / Karunasena, Enusha; McIver, Lauren J.; Rood, Brian R.; Wu, Xiaowei; Zhu, Hongxiao; Bavarva, Jasmin H.; Garner, Harold R.

In: Oncotarget, Vol. 5, No. 15, 01.01.2014, p. 6003-6014.

Research output: Contribution to journalArticle

Karunasena, E, McIver, LJ, Rood, BR, Wu, X, Zhu, H, Bavarva, JH & Garner, HR 2014, 'Somatic intronic microsatellite loci differentiate glioblastoma from lower-grade gliomas', Oncotarget, vol. 5, no. 15, pp. 6003-6014. https://doi.org/10.18632/oncotarget.2076
Karunasena E, McIver LJ, Rood BR, Wu X, Zhu H, Bavarva JH et al. Somatic intronic microsatellite loci differentiate glioblastoma from lower-grade gliomas. Oncotarget. 2014 Jan 1;5(15):6003-6014. https://doi.org/10.18632/oncotarget.2076
Karunasena, Enusha ; McIver, Lauren J. ; Rood, Brian R. ; Wu, Xiaowei ; Zhu, Hongxiao ; Bavarva, Jasmin H. ; Garner, Harold R. / Somatic intronic microsatellite loci differentiate glioblastoma from lower-grade gliomas. In: Oncotarget. 2014 ; Vol. 5, No. 15. pp. 6003-6014.
@article{69747190fea8453293669df73f01652e,
title = "Somatic intronic microsatellite loci differentiate glioblastoma from lower-grade gliomas",
abstract = "Genomic studies of glioma sub-types have amassed new disease specific mutations, yet these only partially explain how mutations are linked to predisposition or progression. We hypothesized that microsatellite variation could expand the understanding of glioma etiology. Furthermore, germline markers for gliomas are typically undetectable; therefore we also hypothesize that the predictability of cancerassociated microsatellite loci in germline DNA may support the current hypothesis of a glioma cell of origin. In this study, {"}normal{"} germline exome sequenced DNA from the 1000 Genomes Project (n=390) were compared with exome sequences from germlines of subjects with WHO grade II and III lower-grade glioma (LGG, n=136) and WHO grade IV glioblastoma (GBM, n=252) from The Cancer Genome Atlas to identify microsatellite loci non-randomly associated with glioma. From germline data, we identified 48 GBM-specific loci, 42 Lower-grade glioma specific loci and 29 loci that distinguish GBM from LGG (p≤0.01). We then attempted to distinguish WHO grade II glioma (n=67) from GBM resulting in 8 informative loci. Significantly, in all glioma grades, comparisons between tumor and matched germline sequences demonstrated no significant differences in these variants (p≥0.01). Therefore, these microsatellite loci are considered to be components of grade-specific signatures for glioma which distinguish germline sequences of individuals with cancer from those of individuals that are {"}normal{"}. In order to better understand the significance of these loci, we identified biological processes enriched in genes with these variants. Most strikingly, six helicase genes were enriched in the GBM cohort (p≤1.0 x10-3). The preservation of these glioma-specific loci could therefore serve as valuable diagnostic and therapeutic markers; especially since the heterogeneity of tumor cell populations can obscure the identification of mutations preceding a metastatic phenotype.",
keywords = "Brain, GBM, Glioma, Helicase, Microsatellite, Ubiquitin proteasome system",
author = "Enusha Karunasena and McIver, {Lauren J.} and Rood, {Brian R.} and Xiaowei Wu and Hongxiao Zhu and Bavarva, {Jasmin H.} and Garner, {Harold R.}",
year = "2014",
month = "1",
day = "1",
doi = "10.18632/oncotarget.2076",
language = "English (US)",
volume = "5",
pages = "6003--6014",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "15",

}

TY - JOUR

T1 - Somatic intronic microsatellite loci differentiate glioblastoma from lower-grade gliomas

AU - Karunasena, Enusha

AU - McIver, Lauren J.

AU - Rood, Brian R.

AU - Wu, Xiaowei

AU - Zhu, Hongxiao

AU - Bavarva, Jasmin H.

AU - Garner, Harold R.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Genomic studies of glioma sub-types have amassed new disease specific mutations, yet these only partially explain how mutations are linked to predisposition or progression. We hypothesized that microsatellite variation could expand the understanding of glioma etiology. Furthermore, germline markers for gliomas are typically undetectable; therefore we also hypothesize that the predictability of cancerassociated microsatellite loci in germline DNA may support the current hypothesis of a glioma cell of origin. In this study, "normal" germline exome sequenced DNA from the 1000 Genomes Project (n=390) were compared with exome sequences from germlines of subjects with WHO grade II and III lower-grade glioma (LGG, n=136) and WHO grade IV glioblastoma (GBM, n=252) from The Cancer Genome Atlas to identify microsatellite loci non-randomly associated with glioma. From germline data, we identified 48 GBM-specific loci, 42 Lower-grade glioma specific loci and 29 loci that distinguish GBM from LGG (p≤0.01). We then attempted to distinguish WHO grade II glioma (n=67) from GBM resulting in 8 informative loci. Significantly, in all glioma grades, comparisons between tumor and matched germline sequences demonstrated no significant differences in these variants (p≥0.01). Therefore, these microsatellite loci are considered to be components of grade-specific signatures for glioma which distinguish germline sequences of individuals with cancer from those of individuals that are "normal". In order to better understand the significance of these loci, we identified biological processes enriched in genes with these variants. Most strikingly, six helicase genes were enriched in the GBM cohort (p≤1.0 x10-3). The preservation of these glioma-specific loci could therefore serve as valuable diagnostic and therapeutic markers; especially since the heterogeneity of tumor cell populations can obscure the identification of mutations preceding a metastatic phenotype.

AB - Genomic studies of glioma sub-types have amassed new disease specific mutations, yet these only partially explain how mutations are linked to predisposition or progression. We hypothesized that microsatellite variation could expand the understanding of glioma etiology. Furthermore, germline markers for gliomas are typically undetectable; therefore we also hypothesize that the predictability of cancerassociated microsatellite loci in germline DNA may support the current hypothesis of a glioma cell of origin. In this study, "normal" germline exome sequenced DNA from the 1000 Genomes Project (n=390) were compared with exome sequences from germlines of subjects with WHO grade II and III lower-grade glioma (LGG, n=136) and WHO grade IV glioblastoma (GBM, n=252) from The Cancer Genome Atlas to identify microsatellite loci non-randomly associated with glioma. From germline data, we identified 48 GBM-specific loci, 42 Lower-grade glioma specific loci and 29 loci that distinguish GBM from LGG (p≤0.01). We then attempted to distinguish WHO grade II glioma (n=67) from GBM resulting in 8 informative loci. Significantly, in all glioma grades, comparisons between tumor and matched germline sequences demonstrated no significant differences in these variants (p≥0.01). Therefore, these microsatellite loci are considered to be components of grade-specific signatures for glioma which distinguish germline sequences of individuals with cancer from those of individuals that are "normal". In order to better understand the significance of these loci, we identified biological processes enriched in genes with these variants. Most strikingly, six helicase genes were enriched in the GBM cohort (p≤1.0 x10-3). The preservation of these glioma-specific loci could therefore serve as valuable diagnostic and therapeutic markers; especially since the heterogeneity of tumor cell populations can obscure the identification of mutations preceding a metastatic phenotype.

KW - Brain

KW - GBM

KW - Glioma

KW - Helicase

KW - Microsatellite

KW - Ubiquitin proteasome system

UR - http://www.scopus.com/inward/record.url?scp=84906217018&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906217018&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.2076

DO - 10.18632/oncotarget.2076

M3 - Article

C2 - 25153720

AN - SCOPUS:84906217018

VL - 5

SP - 6003

EP - 6014

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 15

ER -