References Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986;323:643-6. PMID 2877398. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971;68:820-3. PMID 5279523. Retinoblastoma in a 26-year-old adult. Takahashi T, Tamura S, Inoue M, Isayama Y, Sashikata T. Citation
causes Ultrasound of a retinoblastoma tumor within the eye of a three year old boy.

Retinoblastoma may occur on the basis of a hereditary (genetically inherited) predisposition. Children with hereditary predisposition to retinoblastoma usually develop tumors in both eyes (bilateral retinoblastoma). Children with non-hereditary form of retinoblastoma, which is present in about half of all patients, develop tumors in one eye only (unilateral retinoblastoma). When the disease occurs in both eyes or if this tumor has also occurred in relatives (familial retinoblastoma), it is hereditary. About 15% of patients with unilateral retinoblastoma and no family history of this tumor also have a hereditary predisposition to retinoblstoma. Because of the hereditary factor, patients and their brothers and sisters have an increased risk of retinoblastoma and should have periodic examinations during early childhood. Patients and their relatives usually profit from genetic counseling molecular risk prediction.

A statistical study by Alfred G. Knudson in 1971 led to a hypothesis (later known as the Knudson hypothesis) about why some retinablastomas are hereditary and others occur by chance. This hypothesis led to the identification of the RB1 gene, the first tumor suppressor gene, by a team led by Thaddeus P. Dryja in 1986. Knudson won the 1998 Albert Lasker Medical Research Award for this work.

Hereditary retinoblastoma is caused by an inherited mutation in a single copy of the RB1-gene thus resulting in a heterozygous individual. The remaining functional copy prevents most retinal cells from becoming cancerous. However, one or more cells in the retina are likely to undergo a spontaneous loss of this functional copy, causing those cells to transform into cancer. This loss of the second copy of RB1 is frequently accompanied by loss of heterozygosity of intragenic and flanking polymorphic markers. This is a frequent event in cancer for which retinoblastoma is the canonical example.

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