Molecular basis of low-penetrance retinoblastoma

Clinical background

Retinoblastoma is the most common intraocular malignancy in children and is the prototype inherited cancer predisposition syndrome. About 60% of new patients exhibit unilateral ocular involvement with familial inheritance pattern. The remaining patients have a heritable form of retinoblastoma, which is often associated with bilateral ocular involvement, germline transmission to offspring, and second primary tumors. In most retinoblastoma families, the penetrance (the proportion of individuals with a germline mutation in the RB gene who develop clinical manifestations of the disease) is about 90%. However, about one in seven families will exhibit reduced penetrance as low as 30–60%. This chapter will focus on features that are specific to low-penetrance retinoblastoma ( Box 49.1 ). The features of retinoblastoma in general are covered in Chapter 48 .

Box 49.1

Low-penetrance retinoblastoma

  • Pathologically indistinguishable from full-penetrance retinoblastoma

  • Displays decreased penetrance and expressivity

  • Caused by distinct types of mutations in the retinoblastoma gene

The diseased-eye ratio (DER), calculated by dividing the number of eyes containing tumors by the number of mutation carriers in a family, has been devised as a means of more precisely defining low-penetrance families. A DER less than 1.5 is consistent with low-penetrance retinoblastoma. Retinoblastoma patients in low-penetrance families will often exhibit reduced expressivity (the extent to which an affected individual expresses the disease phenotype), such as unilateral ocular involvement, fewer ocular tumors, and benign retinal tumors called retinomas or retinocytomas. The clinical appearance of retinoblastoma in low-penetrance patients is indistinguishable from that in full-penetrance retinoblastoma patients, which is described in Chapter 48 .


The pathologic appearance of retinoblastomas in low-penetrance patients is indistinguishable from that in full-penetrance retinoblastoma patients, which is described in Chapter 48 .


The rate-limiting event in the development of low-penetrance retinoblastoma, like that of full-penetrance retinoblastoma, is thought to be mutation of the retinoblastoma (RB) tumor suppressor gene on chromosome 13q. The existence of a putative tumor suppressor gene responsible for retinoblastoma was first suggested by Knudson in 1971, and confirmed by the discovery of the RB gene. RB gene mutation can be demonstrated in the vast majority of retinoblastomas, as well as some other types of cancer. The mechanisms by which the RB gene is mutated, and how this leads to retinal tumors, is covered in more detail in Chapter 48 .


Most retinoblastoma families demonstrate autosomal-dominant inheritance with almost complete penetrance and high expressivity, due to the transmission of an inactive copy of the RB gene and subsequent loss of the remaining copy in somatic retinal cells. However, about one in seven families displays decreased penetrance and reduced expressivity. Low-penetrance retinoblastoma has been recognized for many years, and various mechanisms have been proposed, including immunologic factors, DNA methylation, epigenetic mechanisms, delayed mutation, host resistance factors, a second retinoblastoma locus, and “modulator genes.” However, recent advances in our understanding of the structure and function of the retinoblastoma protein (pRB) have shown that low-penetrance retinoblastoma results from special types of mutations at the RB gene that result in a reduced amount or activity of pRB.

Genetic mechanisms of low-penetrance retinoblastoma

In one of the first reports of low-penetrance retinoblastoma, a family was described that transmitted a constitutional chromosomal deletion involving the RB gene locus at chromosome 13q14 with unaffected carriers retaining a balanced insertional translocation. Although chromosomal rearrangements now appear to be a rare cause of low-penetrance retinoblastoma, this study was important in demonstrating that low-penetrance retinoblastoma could be caused by alterations at the RB locus without invoking other nongenetic mechanisms. Subsequently, it was suggested that low-penetrance retinoblastoma may be caused by RB gene mutations that result in a “weak” copy (or allele) of the RB gene that can partially suppress tumorigenesis. In this theory, as long as one normal allele is present, an individual carrying a weak allele would be protected from retinoblastoma. In this same individual, a developing somatic retinal cell that lost the normal allele, such as by nondisjunction, and duplicated the weak allele, such as by reduplication or mitotic recombination, would have a low risk for retinoblastoma. However, if the normal allele is lost and the weak allele is not duplicated, the risk for retinoblastoma would be high ( Figure 49.1 ). This theory appears to explain most low-penetrance retinoblastoma. Approximately 60% of second hits that would be tumorigenic with full-penetrance mutations would have a low risk for causing tumors with a weak, or low-penetrance, mutation.

Figure 49.1

Chromosomal events leading to tumorigenesis in retinoblastoma according to the Knudsen “two-hit” hypothesis. The first “hit” or mutation of the RB gene occurs either in the germline or in a somatic cell (i.e., retinoblast). The second hit, which is always a somatic event, disrupts the remaining RB allele by one of the indicated mechanisms (their approximate frequencies in retinoblastoma tumors are indicated). The predicted result of the two hits (high versus low tumor risk) is indicated when the first hit involves a full-penetrance versus a low-penetrance mutation. These predictions are based on the assumption that two copies of a low-penetrance mutation may be sufficient to suppress tumorigenesis. Approximately 60% of second hits that are tumorigenic with full-penetrance mutations may not cause tumors with low-penetrance mutations. RB, chromosome 13q bearing mutant copy of RB; WT, chromosome 13q bearing wild-type (normal) copy of RB gene.

In recent years, the molecular nature of many of these “weak” RB gene alleles has been elucidated ( Box 49.2 ). At least 14 different RB gene mutations have now been described in low-penetrance retinoblastoma families ( Tables 49.1 and 49.2 ). These mutations fall into two functional classes: (1) mutations that reduce the level of expression of normal pRB; and (2) mutations that result in a mutant pRB that is partially inactivated. There may also be mutations that both reduce protein levels and partially inactivate the protein, although these have not yet been convincingly proven.

Box 49.2

Low-penetrance retinoblastoma mutations

  • Type 1 mutations result in decreased production of normal retinoblastoma protein

  • Type 2 mutations result in the production of partially inactivated retinoblastoma protein

Table 49.1

Type 1 low-penetrance retinoblastoma mutations that reduce expression of normal retinoblastoma protein

Mutation number Diseased-eye ratio DNA alteration Location Functional significance References
1 0.88 G > A at -198 Promoter SP1 binding site
2 1.00 G > T at -189 Promoter ATF binding site
3 0.83 G > A at -189 Promoter ATF binding site
4 0.34 G > C at -149 Promoter Transcription factor binding site
5 NR A > G at 1331 Exon 13 Exon splice site
6 0.64 G > A at 2215 Exon 21 Exon splice site
7 NR G > A at 2325 Exon 22 Exon splice site

NR, not reported.

Table 49.2

Type 2 low-penetrance retinoblastoma mutations that partially inactivate the retinoblastoma protein

Mutation number Diseased-eye ratio Affect on protein Domain affected Nuclear localization Phosphorylation LxCXE binding E2F binding Colony suppression Differentiation Temperature-sensitive References
1 0.4 Delete AA1–112 Amino terminus Yes Yes NR NR Yes NR NR
2 0.65 Delete AA127–166 (exon 4) Amino terminus (G2/M Kinase-binding site) Yes Minimal NR Reduced Yes Yes NR
3 0.5 Delete AA287–313 (exon 9) Amino terminus (lobe B) NR NR NR NR NR NR NR
4 1 Delete AA480 (exon 16) A box Yes Yes Reduced Minimal Yes NR Yes
5 1 Arg661 Trp (exon 20) B box Yes Yes Reduced Minimal Yes Yes Yes
6 0.5 Cys712Arg (exon 21) B box (adjacent to LxCxE-binding site) NR Yes Minimal Minimal NR NR Yes
7 0.78 Delete AA830–887 (exon 24–25) Carboxy terminus (NLS, E2F, MDM2-binding sites) Reduced NR NR Reduced Minimal NR NR

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Aug 26, 2019 | Posted by in OPHTHALMOLOGY | Comments Off on Molecular basis of low-penetrance retinoblastoma

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