Defects in Tumor Suppressor Genes Remove Normal Restraints on Cell Division

Tumor suppressor genes encode proteins that normally restrain cell division. Mutation in one or more of these genes can lead to tumor formation.

Unregulated growth due to defective tumor suppressor genes, unlike that due to oncogenes, is genetically recessive; tumors form only if both chromosomes of a pair contain a defective gene. In a person who inherits one correct copy and one defective copy, every cell has one defective copy of the gene. If any one of those 1012 somatic cells undergoes mutation in the one good copy, a tumor may grow from that doubly mutant cell. Mutations in both copies of the genes for pRb, p53, or p21 yield cells in which the normal restraint on cell division is lost and a tumor forms.

Retinoblastoma is a cancer of the retina that occurs in children who have two defective Rb alleles. Very young children who develop retinoblastoma commonly have multiple tumors in both eyes. Each tumor is derived from a single retinal cell that has undergone a mutation in its one good copy of the Rb gene. (A fetus with two mutant alleles in every cell is nonviable.) Retinoblastoma patients also have a high incidence of cancers of the lung, prostate, and breast.

A far less likely event is that a person born with two good copies of a gene will have two independent mutations in the same gene in the same cell, but this does occur. Some individuals develop retinoblastomas later in childhood, usually with only one tumor in only one eye. These individuals were presumably born with two good copies of Rb in every cell, but both Rb genes in a single retinal cell have undergone mutation, leading to a tumor.

Mutations in the gene for p53 also cause tumors; in more than 90% of human cutaneous squamous cell carcinomas (skin cancers) and about 50% of all other human cancers, p53 is defective. Those very rare individuals who inherit one defective copy of p53 commonly have the Li-Fraumeni cancer syndrome, in which multiple cancers (of the breast, brain, bone, blood, lung, and skin) occur at high frequency and at an early age. The explanation for multiple tumors in this case is the same as that for Rb mutations: an individual born with one defective copy of p53 in every somatic cell is likely to suffer a second p53 mutation in more than one cell in his or her lifetime.

Mutations in oncogenes and tumor suppressor genes do not have an all-or-none effect. In some cancers, perhaps in all, the progression from a normal cell to a malignant tumor requires an accumulation of mutations (sometimes over several decades), none of which, alone, is responsible for the end effect. For example, the development of colorectal cancer has several recognizable stages, each associated with a mutation (Fig. 12-49). If a normal epithelial cell in the colon undergoes mutation of both copies of the tumor suppressor gene APC (adenomatous polyposis coli), it begins to divide faster than normal and produces a clone of itself, a benign polyp (early adenoma). For reasons not yet known, the APC mutation results in chromosomal instability; whole regions of a chromosome are lost or re-

12.10 Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment