We have previously discussed that under normal circumstances, tumor expressor genes (oncogenes) and tumor suppressor genes are in balance in normal cells and become out of balance in malignant cells. In our last article, we reviewed the role of oncogenes in carcinogenesis. It is perhaps easier to appreciate the role played by an active over-expressed gene in causing a cell to manifest the malignant phenotype. But the other side of the equation—the tumor suppressor—can be and possibly is equally important.
A tumor suppressor gene is a gene which, when operating properly, tells a cell when to stop growing, and literally when to die (known as apoptosis). This is a normal cellular function. You may recall from an earlier article that a malignant cell is a cell that has lost normal cell regulation and proliferation, i.e., it does not know when to stop growing and in addition does not know when to die. It is the loss of the tumor suppressor gene function that removes these capabilities and permits unrestricted growth and immortality.
Our cells have 46 chromosomes arranged in 23 pairs, and thus every gene is diploid, i.e., exists in two copies, one on each of the 23 pairs. The same is true for the tumor suppressor genes. This is a brilliant evolutionary protection for the species because it means that whatever the protein each particular gene is producing, if that gene were to be inactivated by a mutation, its partner on the other chromosome could produce enough of the protein to provide the function that is necessary. This leads us to the concept of homozygous and heterozygous—for many genes, you do not manifest an abnormality until you have a genetic defect in both members of the pair (homozygosity). A commonly known example of this is Tay-Sachs disease.
The same principles apply to the tumor suppressor gene. A mutation that inactivates one copy of the gene is insufficient to cause a problem as the other gene copy can pick up the slack and prevent malignancy from manifesting itself. It requires mutations or inactivation of both copies of the gene to allow cancer to appear. This is known as the two-hit hypothesis, put forward by Al Knudson of Fox Chase Cancer Center in 1971. For most genes, a mutation is an unlikely random statistical event that can take years to develop in the absence of an external environmental exposure (like radiation or a carcinogenic chemical). So for two hits (or mutations) to occur in both copies of a specific tumor suppressor gene would really be rare and could take years to occur sporadically or randomly. That is why most cancers take many years to develop—it is just statistically highly unlikely so we (luckily) don’t get cancer typically until our older years.
But aside from exposure to highly carcinogenic exposures, there is one other way that someone can increase their rate of tumor suppressor gene inactivation—they can inherit a gene mutation. Virtually all of the uncommon but high-risk genetic mutations we talk about are tumor suppressor genes. A well-known example is BRCA1.
Under normal circumstances, the BRCA1 gene’s product is involved in DNA repair and helps the cell to grow and function properly. However, mutations in certain critical areas of the BRCA1 gene may render the gene inactive. These mutations are inherited in a recessive fashion. An inherited BRCA1 mutation notably gives increased risk for breast and ovarian cancers (as well as pancreatic cancer, prostate cancer and melanoma). In line with our discussion, it is noteworthy that almost all breast and ovarian cancers have almost absent expression of BRCA1, i.e., whether they were BRCA1 gene carriers or not, the tumor itself does not express BRCA1, meaning their BRCA1 genes were inactivated somewhere along the way in the carcinogenesis pathway. Thus, inactivation of this tumor suppressor gene is a critical step for breast and ovarian carcinogenesis.
As we know, if you inherit the mutated gene, you get these cancers at an earlier age than generally. This can be easily understood by the two-hit hypothesis—in effect, you have already acquired the first hit at birth and thus you only need to acquire one more hit in order to get the cancer, so this occurs at an earlier age than is normal.
In Ashkenazi Jews, a BRCA1 mutation is present in about 1 in 40. (People who fit the profile should be tested for it.) Interestingly, there has never been a recorded birth of a BRCA1 homozygote—apparently a total lack of the tumor suppressor gene protein is lethal during development.
Other tumor suppressor genes include BRCA2, the APC gene (familial adenomatous polyposis), p53 (Li-Fraumeni Syndrome), the Rb gene (familial retinoblastoma) and the RET proto oncogene (multiple endocrine neoplasia type 2). For many of these genes, one can do screening and then implement prophylactic measures in the carrier, or screen family members of a carrier. So knowledge of one’s genetic risk can be helpful.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
