Knudson’s hypothesis and the genetics of retinoblastoma
Study of the occurrence of unilateral and bilateral retinoblastoma led to the 2-hit hypothesis, according to which some tumors arise from a single cell with de novo mutations in both copies of a key gene (RB1 in retinoblastoma or other oncogenes in other diseases). Conversely, in an individual who has a germline mutation (first “hit”) in every cell of their body, a second mutation (“hit”) occurring spontaneously in a somatic cell(s) can result in single or multiple tumors (Fig 6-7). Knudson’s hypothesis, now proven, is applicable to many cancers.
RB1 mutations occurring in a cone precursor cell result in retinoblastoma. In other cell lines, additional mutations in other genes (sometimes precipitated by radiation from radiotherapy or computed tomography [CT] scans) can lead to the development of other tumors, such as osteosarcoma, soft tissue sarcoma, and malignant melanoma. A cascade of mutations in other genes can also lead to increasing malignancy of a tumor.
With an autosomal dominant inheritance pattern, a germline mutation may be inherited from either parent. Alternatively, a child may inherit a germline mutation from an unaffected parent who has mutations in the cells producing eggs or, more often, in sperm. The risk of mutations in sperm increases with increasing age of the father. Guidelines for clinical screening and DNA testing of children at risk for retinoblastoma have recently been revised.
Skalet AH, Gombos DS, Gallie BL, et al. Screening children at risk for retinoblastoma: consensus report from the American Association of Ophthalmic Oncologists and Pathologists. Ophthalmology. 2018;125(3):453–458.
Genetics of the phakomatoses
As mentioned, Knudson’s 2-hit hypothesis is applicable to many tumors, including the phakomatoses. The phakomatoses are a group of hereditary disorders characterized by hamartomas of the skin, eye, CNS, and viscera. Three disorders have traditionally been designated as phakomatoses: NF1 and NF2, von Hippel–Lindau syndrome, and tuberous sclerosis.
NF1 (von Recklinghausen disease) occurs with a germline mutation in the NF1 gene, which produces neurofibromin. A second “hit,” or mutation, can result in the development of neurofibromas in nerves, gliomas in the optic nerve, Lisch nodules (iris hamartomas), café-au-lait spots in the skin, and other tumors. Genetic studies of isolated gliomas have found that these can arise from 2 hits in the NF1 gene.
Figure 6-7 Comparison of sporadic retinoblastoma (A), where 2 independent mutations (“hits”) in the RB1 gene occur in a somatic cell, with hereditary retinoblastoma (B), where a germline mutation is present in every cell and second mutations can arise in multiple cells, leading to multiple tumors.
(Illustration by Cyndie C.H. Wooley.)
NF2 occurs with mutations in the NF2 gene, which produces merlin (also called schwannomin). A second hit can result in acoustic neuromas, meningiomas, gliomas, ependymomas, and schwannomas.
Von Hippel–Lindau syndrome (also called familial cerebello retinal angiomatosis) occurs with germline mutations in the VHL tumor suppressor gene. Hypoxia inducible factor, a regulator of cell division and angiogenesis, is a target of the VHL protein. The syndrome is characterized by benign and malignant multisystem tumors, including retinal and CNS hemangioblastomas, clear cell renal carcinoma, pheochromocytoma, epidydimal cystadenoma, and pancreatic carcinoma.
Tuberous sclerosis is caused by mutation in either of 2 genes: TSC1, which produces the protein hamartin, and TSC2, which produces the protein tuberin. Each of these account for 50% of cases. The 2 proteins interact, forming a heterodimer in the cytoplasm. Tuberous sclerosis has many clinical features, including optic nerve or retinal tumors (astrocytic hamartoma), which may be flat or mulberry-like in appearance; cerebral tubers; ash-leaf skin lesions; subungual fibromas; and facial angiofibromas. In children, facial angiofibromas are thought to arise from second hits caused by exposure to UV radiation.
All of these genetic disorders can be inherited (with affected persons usually having multiple tumors) or sporadic (with affected persons having isolated tumors). The latter may occur from 2 hits in a somatic cell. One phakomatosis that is not inherited (possibly because germline mutations are not compatible with life) is Sturge-Weber syndrome (SWS; also called encephalofacial angiomatosis). SWS is caused by a somatic mutation in the GNAQ gene, which functions to control the development of blood vessels. SWS is characterized by vascular lesions that affect the skin; when the skin lesion is around the eyelids, there can also be vascular lesions of the choroid (hemangioma) and, in many cases, glaucoma. Glaucoma occurs either from trabeculodysgenesis or elevated episcleral venous pressure.
See BCSC Section 5, Neuro-Ophthalmology; Section 6, Pediatric Ophthalmology and Strabismus; and Section 12, Retina and Vitreous, for additional discussion of these disorders.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.