Question

answer to:

a) What is haploinsufficiency? How might it affect cancer risk?

b) Why do mutations in genes that encode DNA-repair enzymes often produce a predisposition to cancer?

Answer 1

Haploinsufficiency and cancer:

Haploinsufficiency is a condition where one allele of a gene is not functional (because of inactivation or deletion) and the other allele of the gene is not sufficient enough to produce the required gene output in order to exhibit its wild-type phenotype (i.e., normal function).

Any alterations in the coding sequence of DNA results in a mutation. The mutation may be of dominant type ( if the heterozygous mutant displays mutant phenotype) or recessive type ( if the heterozygous mutant displays normal phenotype. This occurs in either “gain of function “(dominant mutation) or “loss of function” (recessive mutation) manner.

Haploinsufficiency occurs due to “loss of function” condition resulting in a recessive mutation. In this type of loss of function condition, one of the alleles becomes nonfunctional and the remaining allele is unable to express the normal function of that particular gene. Haploinsufficiency condition is usually seen in tumour suppressor genes. In general, the tumour suppressor genes function is to prevent the oncogenes from getting activated. Because of loss of function condition, tumour suppressor genes are unable to display their unusual function resulting in the activation of oncogenes leading to cancer.

Example of haploinsufficiency can be seen in “Retinoblastoma” gene ( a tumour suppressor gene). In general, a single allele of Rb gene is sufficient to exhibit its tumour-suppressing activity. If the remaining single allele is also mutated and become non-functional, then the cells will lead to the development of cancer.

Some other syndromes caused due to haploinsufficiency are - CHARGE syndrome, Cleidocranial dysostosis, Ehlers–Danlos syndrome, Marfan syndrome and Polydactyly

Why do mutations in genes that encode DNA-repair enzymes often produce a predisposition to cancer?

DNA damage occurs either by external sources like UV rays or internal sources like oxidative stress and Reactive oxygen species generation. Each and every cell has an efficient endogenous DNA repair mechanisms like nucleotide excision repair, base excision repair, mismatch repair etc. Efficient DNA repair ensures the cancer-free survival of organisms. Any alterations to DNA repair mechanisms/ enzymes result in erroneous DNA that progress to cancer.

Epigenetic inactivation of DNA repair genes by methylation activity in promoter regions of the genes causes cancer. This epigenetic inactivation results in genetic instability leading to tumorigenesis of the cell because of inefficient/ poor DNA repair. Inefficient DNA repair generally results in poor cell survival, but also could lead to uncontrolled cell proliferation, a characteristic of a cancer cell. Eg: Mutation in the gene TP 53.

Sometimes epigenetic events result in the conversion of proto-oncogenes to oncogenes and in loss of function of tumour suppressor genes. Both these events also lead to the predisposition of cancer.