Which of the following statements regarding the inherited form of retinoblastoma is/are correct?

b. Clinical disease results after chromosomal loss in a retinal cell after birth

c. Retinoblastoma results from the loss of a tumor suppressor gene

Genetic events leading to oncogene activation result in either increased gene expression or increased activity of the oncoprotein. Another distinct class of genes has been described as negative regulators of cell proliferation. These genes have been referred to as tumor-suppressor genes. The loss of these genes allow tumor development by the loss of normal growth-inhibitory signals.

Genetic analysis of families with hereditary and sporadic retinoblastomas (Rb) has provided evidence for the role of tumorsuppressor genes in human tumors. In inherited retinoblastomas, an abnormal Rb gene is transmitted to half the offspring. As long as a normal allele is present, the tumor does not develop, and the abnormal germ-line mutation behaves in a recessive fashion; however, a second mutation of the normal allele (somatic cell mutation) may occur in a retinal cell, leading to the development of the tumor. In sporadic retinoblastomas, development of a tumor requires two somatic mutations. The genetic loss in retinoblastomas involves deletion of DNA from chromosome 13q14.

Using the technique of restriction-fragment-length polymorphism (RFLP), tumor suppressor genes may be identified through the loss of heterozygosity of the allele in question or a specific marker associated with that allele. Heterozygosity refers to the presence of two different alleles for a given gene. In the Rb gene example, presence of heterozygosity at the Rb locus prevents tumor development because of the influence of the normal wild-type allele. Loss of this wild-type allele in a second genetic event results in the absence of a normal tumor suppressor gene product and subsequent tumor formation.