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
Y1 - 2014
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.
KW - Chromothripsis
KW - MYCN
KW - RB1
KW - Retinoblastoma
UR - http://www.scopus.com/inward/record.url?scp=84896726240&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.1686
DO - 10.18632/oncotarget.1686
M3 - Article
C2 - 24509483
AN - SCOPUS:84896726240
SN - 1949-2553
VL - 5
SP - 438
EP - 450
JO - Oncotarget
JF - Oncotarget
IS - 2
ER -