RB1 gene inactivation by chromothripsis in human retinoblastoma

Justina McEvoy, Panduka Nagahawatte, David Finkelstein, Jennifer Richards-Yutz, Marcus Valentine, Jing Ma, Charles Mullighan, Guangchun Song, Xiang Chen, Matthew Wilson, Rachel Brennan, Stanley Pounds, Jared Becksfort, Robert Huether, Charles Lu, Robert S. Fulton, Lucinda L. Fulton, Xin Hong, David J. Dooling, Kerri OchoaElaine R. Mardis, Richard K. Wilson, John Easton, Jinghui Zhang, James R. Downing, Arupa Ganguly, Michael A. Dyer

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Retinoblastoma is a rare childhood cancer of the developing retina. Most retinoblastomas initiate with biallelic inactivation of the RB1 gene through diverse mechanisms including point mutations, nucleotide insertions, deletions, loss of heterozygosity and promoter hypermethylation. Recently, a novel mechanism of retinoblastoma initiation was proposed. Gallie and colleagues discovered that a small proportion of retinoblastomas lack RB1 mutations and had MYCN amplification [1]. In this study, we identified recurrent chromosomal, regional and focal genomic lesions in 94 primary retinoblastomas with their matched normal DNA using SNP 6.0 chips. We also analyzed the RB1 gene mutations and compared the mechanism of RB1 inactivation to the recurrent copy number variations in the retinoblastoma genome. In addition to the previously described focal amplification of MYCN and deletions in RB1 and BCOR, we also identified recurrent focal amplification of OTX2, a transcription factor required for retinal photoreceptor development. We identified 10 retinoblastomas in our cohort that lacked RB1 point mutations or indels. We performed whole genome sequencing on those 10 tumors and their corresponding germline DNA.In one of the tumors, the RB1 gene was unaltered, the MYCN gene was amplified and RB1 protein was expressed in the nuclei of the tumor cells. In addition, several tumors had complex patterns of structural variations and we identified 3 tumors with chromothripsis at the RB1 locus. This is the first report of chromothripsis as a mechanism for RB1 gene inactivation in cancer.

Original languageEnglish (US)
Pages (from-to)438-450
Number of pages13
JournalOncotarget
Volume5
Issue number2
DOIs
StatePublished - Jan 1 2014

Fingerprint

Retinoblastoma
Gene Silencing
Neoplasms
Point Mutation
Retinal Neoplasms
Genome
Genes
Mutation
Vertebrate Photoreceptor Cells
Loss of Heterozygosity
DNA
Chromothripsis
Cell Nucleus
Single Nucleotide Polymorphism
Transcription Factors
Nucleotides

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

McEvoy, J., Nagahawatte, P., Finkelstein, D., Richards-Yutz, J., Valentine, M., Ma, J., ... Dyer, M. A. (2014). RB1 gene inactivation by chromothripsis in human retinoblastoma. Oncotarget, 5(2), 438-450. https://doi.org/10.18632/oncotarget.1686

RB1 gene inactivation by chromothripsis in human retinoblastoma. / McEvoy, Justina; Nagahawatte, Panduka; Finkelstein, David; Richards-Yutz, Jennifer; Valentine, Marcus; Ma, Jing; Mullighan, Charles; Song, Guangchun; Chen, Xiang; Wilson, Matthew; Brennan, Rachel; Pounds, Stanley; Becksfort, Jared; Huether, Robert; Lu, Charles; Fulton, Robert S.; Fulton, Lucinda L.; Hong, Xin; Dooling, David J.; Ochoa, Kerri; Mardis, Elaine R.; Wilson, Richard K.; Easton, John; Zhang, Jinghui; Downing, James R.; Ganguly, Arupa; Dyer, Michael A.

In: Oncotarget, Vol. 5, No. 2, 01.01.2014, p. 438-450.

Research output: Contribution to journalArticle

McEvoy, J, Nagahawatte, P, Finkelstein, D, Richards-Yutz, J, Valentine, M, Ma, J, Mullighan, C, Song, G, Chen, X, Wilson, M, Brennan, R, Pounds, S, Becksfort, J, Huether, R, Lu, C, Fulton, RS, Fulton, LL, Hong, X, Dooling, DJ, Ochoa, K, Mardis, ER, Wilson, RK, Easton, J, Zhang, J, Downing, JR, Ganguly, A & Dyer, MA 2014, 'RB1 gene inactivation by chromothripsis in human retinoblastoma', Oncotarget, vol. 5, no. 2, pp. 438-450. https://doi.org/10.18632/oncotarget.1686
McEvoy J, Nagahawatte P, Finkelstein D, Richards-Yutz J, Valentine M, Ma J et al. RB1 gene inactivation by chromothripsis in human retinoblastoma. Oncotarget. 2014 Jan 1;5(2):438-450. https://doi.org/10.18632/oncotarget.1686
McEvoy, Justina ; Nagahawatte, Panduka ; Finkelstein, David ; Richards-Yutz, Jennifer ; Valentine, Marcus ; Ma, Jing ; Mullighan, Charles ; Song, Guangchun ; Chen, Xiang ; Wilson, Matthew ; Brennan, Rachel ; Pounds, Stanley ; Becksfort, Jared ; Huether, Robert ; Lu, Charles ; Fulton, Robert S. ; Fulton, Lucinda L. ; Hong, Xin ; Dooling, David J. ; Ochoa, Kerri ; Mardis, Elaine R. ; Wilson, Richard K. ; Easton, John ; Zhang, Jinghui ; Downing, James R. ; Ganguly, Arupa ; Dyer, Michael A. / RB1 gene inactivation by chromothripsis in human retinoblastoma. In: Oncotarget. 2014 ; Vol. 5, No. 2. pp. 438-450.
@article{b737f99980a84a7b8d88d022281885b5,
title = "RB1 gene inactivation by chromothripsis in human retinoblastoma",
abstract = "Retinoblastoma is a rare childhood cancer of the developing retina. Most retinoblastomas initiate with biallelic inactivation of the RB1 gene through diverse mechanisms including point mutations, nucleotide insertions, deletions, loss of heterozygosity and promoter hypermethylation. Recently, a novel mechanism of retinoblastoma initiation was proposed. Gallie and colleagues discovered that a small proportion of retinoblastomas lack RB1 mutations and had MYCN amplification [1]. In this study, we identified recurrent chromosomal, regional and focal genomic lesions in 94 primary retinoblastomas with their matched normal DNA using SNP 6.0 chips. We also analyzed the RB1 gene mutations and compared the mechanism of RB1 inactivation to the recurrent copy number variations in the retinoblastoma genome. In addition to the previously described focal amplification of MYCN and deletions in RB1 and BCOR, we also identified recurrent focal amplification of OTX2, a transcription factor required for retinal photoreceptor development. We identified 10 retinoblastomas in our cohort that lacked RB1 point mutations or indels. We performed whole genome sequencing on those 10 tumors and their corresponding germline DNA.In one of the tumors, the RB1 gene was unaltered, the MYCN gene was amplified and RB1 protein was expressed in the nuclei of the tumor cells. In addition, several tumors had complex patterns of structural variations and we identified 3 tumors with chromothripsis at the RB1 locus. This is the first report of chromothripsis as a mechanism for RB1 gene inactivation in cancer.",
author = "Justina McEvoy and Panduka Nagahawatte and David Finkelstein and Jennifer Richards-Yutz and Marcus Valentine and Jing Ma and Charles Mullighan and Guangchun Song and Xiang Chen and Matthew Wilson and Rachel Brennan and Stanley Pounds and Jared Becksfort and Robert Huether and Charles Lu and Fulton, {Robert S.} and Fulton, {Lucinda L.} and Xin Hong and Dooling, {David J.} and Kerri Ochoa and Mardis, {Elaine R.} and Wilson, {Richard K.} and John Easton and Jinghui Zhang and Downing, {James R.} and Arupa Ganguly and Dyer, {Michael A.}",
year = "2014",
month = "1",
day = "1",
doi = "10.18632/oncotarget.1686",
language = "English (US)",
volume = "5",
pages = "438--450",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "2",

}

TY - JOUR

T1 - RB1 gene inactivation by chromothripsis in human retinoblastoma

AU - McEvoy, Justina

AU - Nagahawatte, Panduka

AU - Finkelstein, David

AU - Richards-Yutz, Jennifer

AU - Valentine, Marcus

AU - Ma, Jing

AU - Mullighan, Charles

AU - Song, Guangchun

AU - Chen, Xiang

AU - Wilson, Matthew

AU - Brennan, Rachel

AU - Pounds, Stanley

AU - Becksfort, Jared

AU - Huether, Robert

AU - Lu, Charles

AU - Fulton, Robert S.

AU - Fulton, Lucinda L.

AU - Hong, Xin

AU - Dooling, David J.

AU - Ochoa, Kerri

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Easton, John

AU - Zhang, Jinghui

AU - Downing, James R.

AU - Ganguly, Arupa

AU - Dyer, Michael A.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Retinoblastoma is a rare childhood cancer of the developing retina. Most retinoblastomas initiate with biallelic inactivation of the RB1 gene through diverse mechanisms including point mutations, nucleotide insertions, deletions, loss of heterozygosity and promoter hypermethylation. Recently, a novel mechanism of retinoblastoma initiation was proposed. Gallie and colleagues discovered that a small proportion of retinoblastomas lack RB1 mutations and had MYCN amplification [1]. In this study, we identified recurrent chromosomal, regional and focal genomic lesions in 94 primary retinoblastomas with their matched normal DNA using SNP 6.0 chips. We also analyzed the RB1 gene mutations and compared the mechanism of RB1 inactivation to the recurrent copy number variations in the retinoblastoma genome. In addition to the previously described focal amplification of MYCN and deletions in RB1 and BCOR, we also identified recurrent focal amplification of OTX2, a transcription factor required for retinal photoreceptor development. We identified 10 retinoblastomas in our cohort that lacked RB1 point mutations or indels. We performed whole genome sequencing on those 10 tumors and their corresponding germline DNA.In one of the tumors, the RB1 gene was unaltered, the MYCN gene was amplified and RB1 protein was expressed in the nuclei of the tumor cells. In addition, several tumors had complex patterns of structural variations and we identified 3 tumors with chromothripsis at the RB1 locus. This is the first report of chromothripsis as a mechanism for RB1 gene inactivation in cancer.

AB - Retinoblastoma is a rare childhood cancer of the developing retina. Most retinoblastomas initiate with biallelic inactivation of the RB1 gene through diverse mechanisms including point mutations, nucleotide insertions, deletions, loss of heterozygosity and promoter hypermethylation. Recently, a novel mechanism of retinoblastoma initiation was proposed. Gallie and colleagues discovered that a small proportion of retinoblastomas lack RB1 mutations and had MYCN amplification [1]. In this study, we identified recurrent chromosomal, regional and focal genomic lesions in 94 primary retinoblastomas with their matched normal DNA using SNP 6.0 chips. We also analyzed the RB1 gene mutations and compared the mechanism of RB1 inactivation to the recurrent copy number variations in the retinoblastoma genome. In addition to the previously described focal amplification of MYCN and deletions in RB1 and BCOR, we also identified recurrent focal amplification of OTX2, a transcription factor required for retinal photoreceptor development. We identified 10 retinoblastomas in our cohort that lacked RB1 point mutations or indels. We performed whole genome sequencing on those 10 tumors and their corresponding germline DNA.In one of the tumors, the RB1 gene was unaltered, the MYCN gene was amplified and RB1 protein was expressed in the nuclei of the tumor cells. In addition, several tumors had complex patterns of structural variations and we identified 3 tumors with chromothripsis at the RB1 locus. This is the first report of chromothripsis as a mechanism for RB1 gene inactivation in cancer.

UR - http://www.scopus.com/inward/record.url?scp=84896726240&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896726240&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.1686

DO - 10.18632/oncotarget.1686

M3 - Article

C2 - 24509483

AN - SCOPUS:84896726240

VL - 5

SP - 438

EP - 450

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 2

ER -