Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma.
Retinoblastoma clinical observations revealed the role of tumor suppressor genes in human cancer, Knudson's 'two-hit' model of cancer induction. We now demonstrate that loss of both RB1 tumor suppressor gene alleles initiates quiescent RB1(-/-) retinomas with low level genomic instability and high expression of the senescence-associated proteins p16(INK4a) and p130. Although retinomas can remain unchanged throughout life, highly proliferative, clonal and aneuploid retinoblastomas commonly emerge, exhibiting altered gene copy number and expression of oncogenes (MYCN, E2F3, DEK, KIF14 and MDM4) and tumor suppressor genes (CDH11, p75(NTR)) and reduced expression of p16(INK4a) and p130. We suggest that RB1 inactivation in developing retina induces genomic instability, but senescence can block transformation at the stage of retinoma. However, stable retinoma is rarely clinically observed because progressive genomic instability commonly leads to highly proliferative retinoblastoma.
Dimaras
Helen
H
Department of Molecular and Medical Genetics, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada.
Khetan
Vikas
V
Halliday
William
W
Orlic
Marija
M
Prigoda
Nadia L
NL
Piovesan
Beata
B
Marrano
Paula
P
Corson
Timothy W
TW
Eagle
Ralph C
RC
Squire
Jeremy A
JA
Gallie
Brenda L
BL
D000328:Adult; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D018450:Disease Progression; D005784:Gene Amplification; D018628:Gene Dosage; D020868:Gene Silencing; D042822:Genomic Instability; D006720:Homozygote; D006801:Humans; D007223:Infant; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D015513:Oncogene Proteins / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012175:Retinoblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D015513:Oncogene Proteins; D018809:Proliferating Cell Nuclear Antigen; D016160:Retinoblastoma Protein; D050717:Retinoblastoma-Like Protein p130; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins