This document discusses retinoblastoma, a cancer that develops in the retina. It describes the genetic and non-genetic forms of the disease. The genetic form is caused by a mutation in the RB1 gene on chromosome 13. For tumor development to occur, both copies of the RB1 gene must be inactivated. The RB protein normally acts to prevent excessive cell growth by inhibiting the cell cycle. Loss of RB function contributes to unregulated cell growth and cancer development. Nearly all cancers involve disruption of the RB pathway that controls the G1 to S phase cell cycle transition.

1. Fadel Muhammad Garishah et al
Faculty of Medicine Universitas Diponegoro
Dr. Kariadi Hospital Medical Education Area
Jalan Dr. Soetomo 18 Semarang Indonesia

2.  Retinoblastoma (Rb) is a rapidly
developing cancer that develops in the
cells of retina, the light detecting tissue
of the eye.
 Classification: There are two forms of
the disease; a genetic and non-genetic
/sporadic
 Sign of retinoblastoma is an abnormal
appearance of the pupil, leukocoria

3.  In children with the heritable genetic form of
retinoblastoma there is a mutation on
chromosome 13, called the Rb1 gene.
 One highly studied function of pRb is to prevent
excessive cell growth by inhibiting cell cycle
progression until a cell is ready to divide.
 Should an oncogenic protein, such as those
produced by cells infected by high-risk types of
human papilloma viruses, bind and inactivate
pRb, this can lead to cancer.

4. leukocoria
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5. Copyrights belong to owner

6.  Tumor suppressor genes encode proteins that
inhibit cellular proliferation by regulating the cell
cycle.
 Both copies of the gene must be lost for tumor
development, leading to loss of heterozygosity
at the gene locus.
 In cases with familial predisposition to develop
tumors, the affected individuals inherit one
defective (nonfunctional) copy of a tumor
suppressor gene and lose the second one
through somatic mutation. In sporadic cases
both copies are lost through somatic mutations.

7.  In this section we describe tumor suppressor
genes, their products, and possible
mechanisms by which loss of their function
contributes to unregulated cell growth.
 We begin our discussion with the
retinoblastoma (RB) gene, the first and
prototypic cancer suppressor gene to be
discovered.

8. (Alfred George Knudson, Jr. MD, PhD - 1971)
Knudson's hypothesis substantiated by
cytogenetic and molecular studies with other tumor
suppressor genes and can now be formulated in
more precise terms, using retinoblastoma as a
paradigm

9.  The mutations required to produce
retinoblastoma involve the RB gene, located
on chromosome 13q14. In some cases, the
genetic damage is large enough to be visible
in the form of a deletion of 13q14.

10.  Both normal alleles of the RB locus must be
inactivated (two hits) for the development of
retinoblastoma.

11. Figure 6-20 Pathogenesis of retinoblastoma. Two mutations of the RB locus on
chromosome 13q14 lead to neoplastic proliferation of the retinal cells. In the familial
form, all somatic cells inherit one mutant RB gene from a carrier parent. The second
mutation affects the RB locus in one of the retinal cells after birth. In the sporadic
form, both mutations at the RB locus are acquired by the retinal cells after birth.

12.  Patients with familial retinoblastoma are also
at greatly increased risk of developing
osteosarcoma and some other soft tissue
sarcomas. (if mutation happened,
inheredited)
 Furthermore, inactivation of the RB locus has
been noted in several other tumors, including
adenocarcinoma of the breast, small cell
carcinoma of the lung, and bladder
carcinoma.

13.  Most importantly, alterations in the "RB
pathway," involving INK4a proteins, cyclin D-
dependent kinases, and RB family proteins,
are almost always present in cancer cells

14. Figure 7-36 Role of RB as a cell-cycle regulator. Various growth factors promote the
formation of the cyclin D-CDK4 complex. This complex (and to some extent cyclin E-
CDK2) phosphorylates RB, changing it from an active (hypophosphorylated) to an
inactive state (hyperphosphorylation). RB inactivation allows the cell to pass the G1/S
restriction point. Growth inhibitors such as TGF-β and p53 and the Cip/Kip (e.g., p21, p57)
and INK4a (p161NK4a and p19ARF) cell-cycle inhibitors prevent RB activation.
Transforming proteins of oncogenic viruses bind hypophosphorylated RB and cause its
functional inactivation. Virtually all cancers show dysregulation of the cell cycle by
affecting the four genes marked by an asterisk.

15.  RB exerts antiproliferative effects by
controlling the G1-to-S transition of the cell
cycle.
 In its active form RB is hypophosphorylated
and binds to E2F transcription factor. This
interaction prevents transcription of genes
like cyclin E that are needed for DNA
replication, and so the cells are arrested in G1.

17. activation block

18.  Growth factor signaling leads to cyclin D
expression, activation of the cyclin D-CDK4/6
complexes, inactivation of RB by
phosphorylation, and thus release of
E2F.Loss of cell cycle control is fundamental
to malignant transformation.

19.  Almost all cancers will have disabled the G1
checkpoint, by mutation of either RB or
genes that affect RB function, like cyclin D,
CDK4, and CDKIs.
 Many oncogenic DNA viruses, like HPV,
encode proteins (e.g., E7) that bind to RB and
render it nonfunctional.

20.  American Cancer Society (2003).
"Chapter 85. Neoplasms of the Eye". Cancer Medicine.
Hamilton, Ontario: BC Decker Inc. ISBN 1-55009-213-8.
 Du W, Pogoriler J (August 2006).
"Retinoblastoma family genes". Oncogene 25 (38): 5190–200.
 Kumar V, Abbas AK, Fausto N. Robbins and Cotran
Pathologic Basis of Disease. 8th Edition. Philadelpia. Elsevier.
 RB Gene and Cell Cycle on Kumar V, Abbas AK, Fausto N.
Robbins and Cotran Basic Pathology 8th Edition. Philadelpia.
Elsevier