Endometrial cancer, also known as uterine cancer, begins in the endometrium, the inner lining of the uterus. It represents the most common cancer affecting the female reproductive organs. While many cases develop without a clear inherited cause, a notable percentage of endometrial cancers are linked to genetic factors passed down through families.
The Role of Genetics in Endometrial Cancer
Cancers are broadly categorized into two types: sporadic and hereditary. Sporadic cancers, which account for about 90% of all cancers, arise from random genetic changes that occur during a person’s lifetime, often influenced by environmental or lifestyle factors. Hereditary cancers, by contrast, result from specific gene mutations inherited from a parent, increasing an individual’s predisposition to developing certain cancers. Approximately 5% to 15% of all endometrial cancers are considered hereditary, a distinction that has significant implications for risk assessment and management.
Hereditary Cancer Syndromes
Lynch syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), represents the most frequent cause of hereditary endometrial cancer. This inherited condition is caused by germline mutations in DNA mismatch repair (MMR) genes, specifically MLH1, MSH2, MSH6, PMS2, and sometimes EPCAM. These genes are normally responsible for correcting errors that occur during DNA replication, acting as a cellular proofreading system. When a mutation is present in one of these genes, the DNA repair mechanism is impaired, leading to an accumulation of genetic errors and an increased risk of cancer.
Women with Lynch syndrome face a significantly elevated lifetime risk of developing endometrial cancer, ranging from approximately 40% to 60%. This cancer often manifests at a younger age, 10 to 15 years earlier than sporadic cases. Lynch syndrome also increases the risk for other cancers, including colorectal, ovarian, stomach, small bowel, urinary tract, and pancreatic cancers.
Another, less common hereditary condition linked to endometrial cancer is Cowden syndrome. This syndrome is caused by an inherited mutation in the PTEN gene, a tumor suppressor gene. The PTEN gene normally helps regulate cell growth and prevent tumor formation; a mutation can disrupt this function, leading to uncontrolled cell proliferation. Individuals with Cowden syndrome have an increased lifetime risk of endometrial cancer, estimated to be between 5% and 30%. This syndrome is also associated with an elevated risk of breast, thyroid, and kidney cancers.
Identifying Your Risk
Recognizing patterns in your family’s health history can provide important clues about a possible hereditary predisposition to endometrial cancer. One indicator is a personal or close family history of endometrial cancer diagnosed at a younger age, particularly before 50 years old. A family history of multiple cancer diagnoses in a single individual, especially if those cancers are linked to Lynch syndrome, such as colorectal, ovarian, or stomach cancer, also warrants attention.
The presence of several relatives on the same side of the family with these cancers, even if diagnosed at older ages, can suggest an inherited risk. If a close blood relative has already been identified with a known inherited gene mutation associated with cancer, this directly indicates an increased risk within the family. If any of these “red flags” are present in your family’s medical history, discussing them with a healthcare provider is a sensible next step to assess your individual risk.
Genetic Counseling and Testing
If your family history suggests a potential hereditary cancer risk, genetic counseling can provide valuable guidance. Genetic counseling involves meeting with a specialized professional, such as a genetic counselor, who reviews your personal and family medical history in detail. During this session, the counselor discusses the likelihood of an inherited cancer syndrome, explains the potential benefits and limitations of genetic testing, and addresses the emotional and psychological implications of receiving test results.
Genetic testing involves providing a small sample of blood or saliva, which is then sent to a specialized laboratory for analysis. These tests use “panel tests” that examine multiple genes simultaneously for known mutations linked to various cancers. Results are available within two to six weeks. A positive result indicates the presence of a specific inherited mutation, while a negative result means no known mutation was detected in the genes tested. Sometimes, a “variant of uncertain significance” (VUS) may be identified, meaning a genetic change was found but its clinical importance is not yet clear.
Medical Management for High-Risk Individuals
For individuals confirmed to have a high-risk genetic mutation, proactive medical management strategies can significantly reduce cancer risk or facilitate early detection. Increased surveillance is a common approach, involving more frequent screenings to monitor for early signs of cancer. For endometrial cancer, this may include annual endometrial biopsies or transvaginal ultrasounds.
Risk-reducing surgery is another option, particularly after childbearing is complete. A prophylactic total hysterectomy, which involves the removal of the uterus, can eliminate the risk of endometrial cancer. This procedure is combined with a bilateral salpingo-oophorectomy, the removal of the fallopian tubes and ovaries, to reduce the risk of ovarian cancer, which is also associated with some hereditary syndromes like Lynch syndrome. While these surgeries significantly lower the risk, they do not eliminate it entirely, as microscopic cells can remain.