Loss of hetrozygosity associated with ?
Ans. is 'c' i.e., Retinoblastoma Retinoblastoma is a prime example of a tumour which is associated with loss of heterozygosity. This term is mostly used in the context of oncogenesis. o The mutations required to produce retinoblastomes involves the RB gene located on chromosome 13 q14. o RB gene is a tumour suppressor gene. RB gene is active in hypophosphorylated state and phosphorylation causes inactivation of RB, i.e. phosphorylated RB is inactive. o Retinoblastoma develops when both the normal alleles of the RB gene are inactivated or altered. o In familial case of retinoblastoma, children are born with one normal and one defective copy of the RB gene. Such a child is said to be heterozygous at the RB locus (one allele of the gene is normal while the other one is a mutant). This implies that heterozygosity for the RB gene does not affect cell behaviour i.e., (cancer does not develop as long as one gene is normal) o Cancer develops when both the alleles are mutant i.e., when the cell becomes homozygous for the mutant allele or you can put it in another way, when the cell loses heterozygosity for the normal RB gene (a condition known as loss of heterozygosity). o Make it clear that in oncology, loss of heterozygosity occurs when the remaining functional allete in a somatic cell of the off spring becomes inactivated by mutation. This results in no normal tumour suppressor gene being produced and almost ceainly results in tumourogenesis. o It is a common occurrence in cancer, where it indicates the absence of a functional tumour suppressor gene in the lost region. o Loss of heterozygosity is the basis of two hit hypothesis of cancers (Knudson's hypothesis) o In hereditary cases of Retinoblastoma one genetic change (first hit) is inherited from the affected parent therefore it is present in all the somatic cells of the body. But one genetic change is not sufficient to produce cancer. o The second mutation (second hit) is required to produce cancer. It occurs in the retinal cells (which are carrying the first mutation). The mutation occuring in Retinal cells is acquired. In sporadic cases both mutations (hits) occur somatically within a single retinal cell whose progeny then form the tumour.
Acute myeloid leukemia
ALL
Retinoblastoma
Promyelocitic leukemia