Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes

Akash Kumar; Evan A Boyle; Mari Tokita; Andrei M Mikheev; Michelle C Sanger; Emily Girard; John R Silber; Luis F Gonzalez-Cuyar; Joseph B Hiatt; Andrew Adey; Choli Lee; Jacob O Kitzman; Donald E Born; Daniel L Silbergeld; James M Olson; Robert C Rostomily; Jay Shendure

doi:10.1186/s13059-014-0530-z

Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes

Akash Kumar, Evan A Boyle, Mari Tokita, Andrei M Mikheev, Michelle C Sanger, Emily Girard, John R Silber, Luis F Gonzalez-Cuyar, Joseph B Hiatt, Andrew Adey, Choli Lee, Jacob O Kitzman, Donald E Born, Daniel L Silbergeld, James M Olson, Robert C Rostomily, Jay Shendure

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

BACKGROUND: The extent of intratumoral mutational heterogeneity remains unclear in gliomas, the most common primary brain tumors, especially with respect to point mutation. To address this, we applied single molecule molecular inversion probes targeting 33 cancer genes to assay both point mutations and gene amplifications within spatially distinct regions of 14 glial tumors.

RESULTS: We find evidence of regional mutational heterogeneity in multiple tumors, including mutations in TP53 and RB1 in an anaplastic oligodendroglioma and amplifications in PDGFRA and KIT in two glioblastomas (GBMs). Immunohistochemistry confirms heterogeneity of TP53 mutation and PDGFRA amplification. In all, 3 out of 14 glial tumors surveyed have evidence for heterogeneity for clinically relevant mutations.

CONCLUSIONS: Our results underscore the need to sample multiple regions in GBM and other glial tumors when devising personalized treatments based on genomic information, and furthermore demonstrate the importance of measuring both point mutation and copy number alteration while investigating genetic heterogeneity within cancer samples.

Original language	English (US)
Pages (from-to)	530
Journal	Genome Biology
Volume	15
Issue number	12
DOIs	https://doi.org/10.1186/s13059-014-0530-z
State	Published - Dec 3 2014

Keywords

Brain Neoplasms
Gene Amplification
Genetic Heterogeneity
Glioblastoma
High-Throughput Nucleotide Sequencing
Humans
Molecular Sequence Data
Oligodendroglioma
Point Mutation
Proto-Oncogene Proteins c-kit
Receptor, Platelet-Derived Growth Factor alpha
Salivary Proline-Rich Proteins
Sequence Analysis, DNA
Tumor Suppressor Protein p53
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Access to Document

10.1186/s13059-014-0530-z

Cite this

Kumar, A., Boyle, E. A., Tokita, M., Mikheev, A. M., Sanger, M. C., Girard, E., Silber, J. R., Gonzalez-Cuyar, L. F., Hiatt, J. B., Adey, A., Lee, C., Kitzman, J. O., Born, D. E., Silbergeld, D. L., Olson, J. M., Rostomily, R. C., & Shendure, J. (2014). Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes. Genome Biology, 15(12), 530. https://doi.org/10.1186/s13059-014-0530-z

Kumar, A, Boyle, EA, Tokita, M, Mikheev, AM, Sanger, MC, Girard, E, Silber, JR, Gonzalez-Cuyar, LF, Hiatt, JB, Adey, A, Lee, C, Kitzman, JO, Born, DE, Silbergeld, DL, Olson, JM, Rostomily, RC & Shendure, J 2014, 'Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes', Genome Biology, vol. 15, no. 12, pp. 530. https://doi.org/10.1186/s13059-014-0530-z

@article{8c2f5c903aa9408caa57d6709bb89ed1,

title = "Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes",

abstract = "BACKGROUND: The extent of intratumoral mutational heterogeneity remains unclear in gliomas, the most common primary brain tumors, especially with respect to point mutation. To address this, we applied single molecule molecular inversion probes targeting 33 cancer genes to assay both point mutations and gene amplifications within spatially distinct regions of 14 glial tumors.RESULTS: We find evidence of regional mutational heterogeneity in multiple tumors, including mutations in TP53 and RB1 in an anaplastic oligodendroglioma and amplifications in PDGFRA and KIT in two glioblastomas (GBMs). Immunohistochemistry confirms heterogeneity of TP53 mutation and PDGFRA amplification. In all, 3 out of 14 glial tumors surveyed have evidence for heterogeneity for clinically relevant mutations.CONCLUSIONS: Our results underscore the need to sample multiple regions in GBM and other glial tumors when devising personalized treatments based on genomic information, and furthermore demonstrate the importance of measuring both point mutation and copy number alteration while investigating genetic heterogeneity within cancer samples.",

keywords = "Brain Neoplasms, Gene Amplification, Genetic Heterogeneity, Glioblastoma, High-Throughput Nucleotide Sequencing, Humans, Molecular Sequence Data, Oligodendroglioma, Point Mutation, Proto-Oncogene Proteins c-kit, Receptor, Platelet-Derived Growth Factor alpha, Salivary Proline-Rich Proteins, Sequence Analysis, DNA, Tumor Suppressor Protein p53, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

author = "Akash Kumar and Boyle, {Evan A} and Mari Tokita and Mikheev, {Andrei M} and Sanger, {Michelle C} and Emily Girard and Silber, {John R} and Gonzalez-Cuyar, {Luis F} and Hiatt, {Joseph B} and Andrew Adey and Choli Lee and Kitzman, {Jacob O} and Born, {Donald E} and Silbergeld, {Daniel L} and Olson, {James M} and Rostomily, {Robert C} and Jay Shendure",

year = "2014",

month = dec,

day = "3",

doi = "10.1186/s13059-014-0530-z",

language = "English (US)",

volume = "15",

pages = "530",

journal = "Genome Biology",

issn = "1474-7596",

publisher = "BioMed Central",

number = "12",

}

TY - JOUR

T1 - Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes

AU - Kumar, Akash

AU - Boyle, Evan A

AU - Tokita, Mari

AU - Mikheev, Andrei M

AU - Sanger, Michelle C

AU - Girard, Emily

AU - Silber, John R

AU - Gonzalez-Cuyar, Luis F

AU - Hiatt, Joseph B

AU - Adey, Andrew

AU - Lee, Choli

AU - Kitzman, Jacob O

AU - Born, Donald E

AU - Silbergeld, Daniel L

AU - Olson, James M

AU - Rostomily, Robert C

AU - Shendure, Jay

PY - 2014/12/3

Y1 - 2014/12/3

N2 - BACKGROUND: The extent of intratumoral mutational heterogeneity remains unclear in gliomas, the most common primary brain tumors, especially with respect to point mutation. To address this, we applied single molecule molecular inversion probes targeting 33 cancer genes to assay both point mutations and gene amplifications within spatially distinct regions of 14 glial tumors.RESULTS: We find evidence of regional mutational heterogeneity in multiple tumors, including mutations in TP53 and RB1 in an anaplastic oligodendroglioma and amplifications in PDGFRA and KIT in two glioblastomas (GBMs). Immunohistochemistry confirms heterogeneity of TP53 mutation and PDGFRA amplification. In all, 3 out of 14 glial tumors surveyed have evidence for heterogeneity for clinically relevant mutations.CONCLUSIONS: Our results underscore the need to sample multiple regions in GBM and other glial tumors when devising personalized treatments based on genomic information, and furthermore demonstrate the importance of measuring both point mutation and copy number alteration while investigating genetic heterogeneity within cancer samples.

AB - BACKGROUND: The extent of intratumoral mutational heterogeneity remains unclear in gliomas, the most common primary brain tumors, especially with respect to point mutation. To address this, we applied single molecule molecular inversion probes targeting 33 cancer genes to assay both point mutations and gene amplifications within spatially distinct regions of 14 glial tumors.RESULTS: We find evidence of regional mutational heterogeneity in multiple tumors, including mutations in TP53 and RB1 in an anaplastic oligodendroglioma and amplifications in PDGFRA and KIT in two glioblastomas (GBMs). Immunohistochemistry confirms heterogeneity of TP53 mutation and PDGFRA amplification. In all, 3 out of 14 glial tumors surveyed have evidence for heterogeneity for clinically relevant mutations.CONCLUSIONS: Our results underscore the need to sample multiple regions in GBM and other glial tumors when devising personalized treatments based on genomic information, and furthermore demonstrate the importance of measuring both point mutation and copy number alteration while investigating genetic heterogeneity within cancer samples.

KW - Brain Neoplasms

KW - Gene Amplification

KW - Genetic Heterogeneity

KW - Glioblastoma

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Molecular Sequence Data

KW - Oligodendroglioma

KW - Point Mutation

KW - Proto-Oncogene Proteins c-kit

KW - Receptor, Platelet-Derived Growth Factor alpha

KW - Salivary Proline-Rich Proteins

KW - Sequence Analysis, DNA

KW - Tumor Suppressor Protein p53

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1186/s13059-014-0530-z

DO - 10.1186/s13059-014-0530-z

M3 - Article

C2 - 25608559

SN - 1474-7596

VL - 15

SP - 530

JO - Genome Biology

JF - Genome Biology

IS - 12

ER -

Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes

Abstract

Keywords

Access to Document

Fingerprint

Cite this