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Heritable cancer

Cancer is a genetic disease that is caused by aberrations in the DNA. This also means that the aberrations can be passed on from the parents to their offspring, resulting in a heritable cancer. These individuals are born with one defected allele that is inherited from one of their parents.

Defected tumor suppressors are more commonly inherited than oncogenes. For tumor suppressors, both alleles need to be nonfunctional for cancer to develop. This was first explained by Alfred G. Knudson in 1971 with Knudson’s two-hit hypothesis. Alfred used retinoblastoma (a cancer that develops in the retina) that occurs in very young children. He then discovered that these children inherited a defective tumor suppressor gene called RB1 from one of their parents.

The first hit refers to the defect that is inherited, and the second hit is an event that occurs during life. This could be due to random mutations that occur during cell division or upon an external factor, such as sun radiation that results in inactivation of the second allele. Because these individuals already have the first hit, they develop cancer at a much earlier age than other individuals who are born with both healthy alleles because these individuals need to acquire both hits during their life (Figure 1)

Upper image presents tumor suppressor gene mutation in a normal cell leading to sporadic cancer. Two chromosomes with wild type tumor suppressor gene are presented. Upon new mutation in one of the presented chromosomes the cell acquires first hit. Then a second hit is introduced in the form of deletion of the part of chromosome hosting tumor suppressor gene. This leads to tumor formation since no tumor suppressor genes are present. Lower image presents tumor suppressor gene mutation in a cell with germline mutation, leading to familial cancer. Two chromosomes are presented - one with wild type allele and one with inherited germline mutation in tumor suppressor gene. The cel already has a first hit. Second hit is introduced in the form of deletion of the part of chromosome hosting tumor suppressor gene. This leads to tumor formation since no tumor suppressor genes are present.

Figure 1. Illustration of Knudson’s two-hit hypothesis of tumor suppressor inactivation in familial (hereditable) cancer. 10 Knudson, A.G. (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 68, 820-823,PubMed.

Reference

  1. Knudson AG Jr., 1971, Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. Apr;68(4):820-3.

Referred from:

Article
Cancer