Fadel Muhammad Garishah et al

Faculty of Medicine Universitas DiponegoroDr. Kariadi Hospital Medical Education AreaJalan Dr. Soetomo 18 Semarang Indonesia

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

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.

Copyrights belong to owner

leukocoria

Copyrights belong to owner

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.

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.

(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

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.

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

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.

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.

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

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.

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.

activation block

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.

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.

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