Our understanding of cancer and its triggers is still in its infancy. However, recent research offers new insights to better understand what causes cancer cells to proliferate. Of particular interest is tumor suppressor genes that help stop the uncontrolled cell division and growth that permit cancer-causing mutations. Moreover, these important cells also promote cell death, a necessary component in the life cycle of healthy cells. Of critical importance, these tumor suppressor genes also play a role in DNA repair, preventing the accumulation of mutations that may lead to the development of cancer. Considering the importance of these genes in preventing cancer, any disturbance in the functioning of these tumor suppressor genes can cause irreparable damage that might ultimately lead to cancer.
The Two-Hit Hypothesis
All genes, including cancer suppressor genes, are subjected to a number of mutations. Fortunately, in the case of cancer suppressor genes, the mutations that interfere with normal functioning are typically recessive. That is, for the mutation to lead to cancer, both tumor suppressor genes in a given cell must have the same mutation. In the early 1970s, Alfred Knudson coined the term “two-hit hypothesis” to describe this phenomenon.
Case Study: RetinoblastomaKnudson, a geneticist, discovered this important concept while studying a rare type of cancer that strikes children. Known as retinoblastoma (Rb ), this cancer affects the retina, the part of the eye that detects light. Normally, retinoblasts, or immature cells in the retina, have stopped growing and dividing by the time an embryo has developed. At this point, retinoblasts typically become differentiated, resulting in distinct photoreceptor and nerve cells within the retina. In children with retinoblastoma, however, differentiation does not occur. Rather, the retinoblasts continue to divide, leading to the development of retinal tumors. Detection and treatment is essential because, as with other cancers, untreated retinoblastoma can metastasize and affect other parts of the body.
In order to better understand this ailment, Knudson conducted a 25-year study starting in the mid-1940s. In particular, Knudson wished to understand how parents diagnosed with retinoblastoma could have children free of the malady, but whose own children were later diagnosed with retinoblastoma. The geneticist took a closer look at two groups of patients. The first group was made up of 23 patients with bilateral hereditary retinoblastoma. In bilateral hereditary retinoblastoma, cancer is detected in both eyes there is a history of retinoblastoma in the family. The second group consisted of 25 patients with unilateral nonhereditary retinoblastoma.
Age at diagnosis became particularly important at this point because of the time necessary for mutations to occur and accumulate. If the cancer were the result of mutations in a single gene, then both copies would have to mutate at the same rate for the cancer to occur. Thus, patients who inherited one mutated gene allele would only need to accumulate one mutation on the other gene allele for the cancer to occur. Those who did not inherit the mutation would need to accumulate a mutation on both alleles, a process that would take considerably more time. He noted that for his patients, bilateral hereditary retinoblastoma was diagnosed earlier than the unilateral nonhereditary variety, supporting his hypothesis that two mutations were required. Originally dubbed the two-mutation hypothesis, this phenomenon is now known as the two-hit hypothesis.
Tumor Suppressor Gene Inactivation
The two-hit hypothesis is essential to understanding the process by which tumor suppressor genes become inactive or non-functioning. During a process known as loss of heterozygosity, or dissimilarity, the second copy of a tumor suppressor gene becomes inactive when the gene is “hit” again. That is, the functioning copy undergoes a mutation, making the pair homozygous, or similar, in terms of the mutated gene. With this double mutation, the tumor suppressor gene becomes unable to fulfill its normal function.
Advances in Understanding Tumor Suppressor Genes
Once scientists were able to map the human genome, they were able to identify the particular gene (Rb1) responsible for suppressing retinoblastoma tumor growth. Researchers then used mice to examine how the Rb1 gene works and what happens when two “hits” affect this gene. They have since identified a number of other tumor suppressor genes. Future research will focus on using this growing knowledge base to better diagnose and treat a variety of cancers.
Other tumor suppressor genes: p53, VHL, WT1, BRCA1, MLH1, PTEN