Loss of photoreceptorness and gain of genomic alterations in retinoblastoma reveal tumor progression.
BACKGROUND
Retinoblastoma is a pediatric eye cancer associated with RB1 loss or MYCN amplification (RB1 (+/+) MYCN(A) ). There are controversies concerning the existence of molecular subtypes within RB1(-/-) retinoblastoma. To test whether these molecular subtypes exist, we performed molecular profiling.


METHODS
Genome-wide mRNA expression profiling was performed on 76 primary human retinoblastomas. Expression profiling was complemented by genome-wide DNA profiling and clinical, histopathological, and ex vivo drug sensitivity data.


RESULTS
RNA and DNA profiling identified major variability between retinoblastomas. While gene expression differences between RB1 (+/+) MYCN(A) and RB1(-/-) tumors seemed more dichotomous, differences within the RB1(-/-) tumors were gradual. Tumors with high expression of a photoreceptor gene signature were highly differentiated, smaller in volume and diagnosed at younger age compared with tumors with low photoreceptor signature expression. Tumors with lower photoreceptor expression showed increased expression of genes involved in M-phase and mRNA and ribosome synthesis and increased frequencies of somatic copy number alterations.


CONCLUSIONS
Molecular, clinical and histopathological differences between RB1(-/-) tumors are best explained by tumor progression, reflected by a gradual loss of differentiation and photoreceptor expression signature. Since copy number alterations were more frequent in tumors with less photoreceptorness, genomic alterations might be drivers of tumor progression.


BACKGROUND
Retinoblastoma is an ocular childhood cancer commonly caused by mutations in the RB1 gene. In order to determine optimal treatment, tumor subtyping is considered critically important. However, except for very rare retinoblastomas without an RB1 mutation, there are controversies as to whether subtypes of retinoblastoma do exist. Our study shows that retinoblastomas are highly diverse but rather than reflecting distinct tumor types with a different etiology, our data suggests that this diversity is a result of tumor progression driven by cumulative genetic alterations. Therefore, retinoblastomas should not be categorized in distinct subtypes, but be described according to their stage of progression.
Department of Clinical Genetics, VU University Medical Center, Room J-376, Van der Boechorststraat 7, 108 1BT Amsterdam, The Netherlands.
Irsan E
IE
Kooi
Department of Clinical Genetics, VU University Medical Center, Room J-376, Van der Boechorststraat 7, 108 1BT Amsterdam, The Netherlands.
Berber M
BM
Mol
Department of Ophthalmology, VU University Medical Center, Amsterdam, The Netherlands.
Annette C
AC
Moll
Department of Pathology, VU University Medical Center, 3E47, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Paul
P
van der Valk
Department of Radiology and Nuclear Medicine, VU University Medical Center, 4 F005, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Marcus C
MC
de Jong
Department of Radiology and Nuclear Medicine, VU University Medical Center, 4 F005, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Pim
P
de Graaf
Department of Clinical Genetics, VU University Medical Center, Room J-376, Van der Boechorststraat 7, 108 1BT Amsterdam, The Netherlands.
Saskia E
SE
van Mil
Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center (AMC), Postbus 22660, 1100 DD Amsterdam, The Netherlands.
Antoinette Y N
AY
Schouten-van Meeteren
Department of Clinical Genetics, VU University Medical Center, Room J-376, Van der Boechorststraat 7, 108 1BT Amsterdam, The Netherlands.
Hanne
H
Meijers-Heijboer
Department of Pediatric Oncology/Hematology, VU University Medical Center, 9D28, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Gertjan L
GL
Kaspers
Department of Clinical Genetics, VU University Medical Center, Room J-376, Van der Boechorststraat 7, 108 1BT Amsterdam, The Netherlands ; Division of Biological Stress Response, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Hein
H
Te Riele
Department of Pediatric Oncology/Hematology, VU University Medical Center, 9D28, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands ; Department of Hematology, VU University Medical Center, CCA 3.26, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Jacqueline
J
Cloos
Department of Clinical Genetics, VU University Medical Center, Room J-376, Van der Boechorststraat 7, 108 1BT Amsterdam, The Netherlands.
Josephine C
JC
Dorsman
D002675:Child, Preschool; D016000:Cluster Analysis; D056915:DNA Copy Number Variations / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D063990:Gene Ontology; D015894:Genome, Human; D006801:Humans; D007223:Infant; D007621:Karyotyping; D008297:Male; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012175:Retinoblastoma / Q000235:genetics* / Q000473:pathology
D012333:RNA, Messenger; D003609:Dactinomycin
Cancer; Expression profiling; Pediatric oncology; Progression; Retina; Retinoblastoma