Uterine cancer is the most common malignancy affecting the female reproductive organs, beginning when cells in the uterus grow out of control. Most often, people refer to endometrial cancer, which originates in the inner lining of the uterus called the endometrium, accounting for over 80% of all cases. A family history naturally raises concerns about personal risk. However, the vast majority of uterine cancer cases are sporadic, meaning they occur without a clear inherited genetic cause. While having a mother with the disease increases risk, only a small fraction of diagnoses are directly linked to an inherited gene mutation.
The Role of Heredity and Genetic Syndromes
Only about 5 to 10 percent of uterine cancer cases are attributable to a specific hereditary syndrome passed down through a family. The majority of women who develop the disease do not have a recognizable genetic predisposition identifiable through current testing. A strong family history of uterine or colorectal cancer may point toward an inherited condition that significantly elevates risk.
The primary cause of hereditary uterine cancer is Lynch Syndrome, formerly known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC). This condition results from a mutation in one of several mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). These genes normally function as proofreaders, correcting errors when DNA is copied. When a mutation disables one of these repair genes, errors accumulate, increasing the lifetime risk for several types of cancer.
For women who inherit Lynch Syndrome, the lifetime risk of developing endometrial cancer ranges from 40 to 70 percent, depending on the specific gene mutation. This risk is often higher than the risk for colorectal cancer in women with the syndrome. Lynch Syndrome is also associated with an increased chance of developing ovarian, stomach, and urinary tract cancers. It is suspected when cancers occur in multiple close relatives or when a family member is diagnosed at an unusually young age.
Non-Genetic Risk Factors
Since most uterine cancers are sporadic, non-genetic factors are responsible for the bulk of diagnoses. The most significant mechanism driving the disease is prolonged exposure to unopposed estrogen. Estrogen stimulates the growth of the endometrial lining, and without the counterbalancing effect of progesterone, this overstimulation can lead to abnormal cell growth.
Obesity is a powerful risk factor because fat tissue converts precursor hormones into estrogen, increasing the body’s overall estrogen level, particularly after menopause. This peripheral estrogen production occurs without the cyclic progesterone that normally regulates the uterine lining, substantially raising the risk. Up to 70 percent of uterine cancer cases are linked, at least in part, to obesity.
Other factors that increase unopposed estrogen exposure also elevate risk, including taking estrogen-only hormone therapy after menopause. Conditions like diabetes and metabolic syndrome are associated with a higher incidence of the disease. A longer reproductive lifespan, characterized by starting menstruation early or entering menopause late, means the uterine lining has been exposed to estrogen for more years. The average age of diagnosis is around 60, confirming that age is an independent risk factor.
Proactive Screening and Risk Management
For individuals with a family history, the first step in risk management is to gather detailed information about affected relatives, including the type of cancer and the age of diagnosis. This information should be discussed with a healthcare provider, who may recommend referral to a genetic counselor. Genetic counseling is important if there is a history of multiple family members with uterine, colorectal, or ovarian cancer, or if a relative was diagnosed before the age of 50.
If a hereditary syndrome like Lynch is confirmed, specific surveillance protocols are initiated for early detection. There is no standardized, routine screening test for uterine cancer for the average-risk population. However, high-risk individuals may be offered annual monitoring, which can involve a transvaginal ultrasound to assess the endometrial lining thickness. An endometrial biopsy, where a small tissue sample is removed for laboratory analysis, may also be performed if the ultrasound indicates an abnormality.
Primary prevention through lifestyle choices offers control over non-genetic risk factors. Maintaining a healthy body weight is a powerful way to reduce the peripheral estrogen production linked to obesity. If hormone replacement therapy is considered after menopause, using a combination of estrogen and progestogen is safer for the uterus than using estrogen alone. These proactive measures, combined with informed genetic risk assessment, allow for personalized risk reduction and early detection strategies.