Inherited predisposition to endometrial cancer: Moving beyond Lynch syndrome

Endometrial cancer (EC) is the most common invasive gynecologic cancer in the United States, with American women facing a lifetime EC risk of approximately 2.73%. Although nongenetic factors such as obesity and prolonged exposure to estrogen are epidemiologically important contributing risk factors, an inherited genetic predisposition is believed to be present in approximately 5% of patients with an EC diagnosis. The identification of women with an inherited predisposition to EC has important implications for surveillance for associated cancer risks and for the identification of at-risk family members who may benefit from appropriate screening and prevention strategies. Medical and surgical oncologists play a critical role in the identification of patients who may have an inherited cancer predisposition syndrome, and they are responsible for determining whether a newly diagnosed cancer patient should be referred for a genetic cancer risk assessment. Although red flags for a hereditary cancer predisposition, including an early age at onset, multiple affected family members, and multiple primary tumors (especially in the same organ), have long been recognized, more recent research suggests that patients with specific tumor types should be considered for genetic testing regardless of their family history. Particular tumor-associated phenotypic features have been especially helpful for risk stratification and identification of individuals needing further genetic assessment for some cancer predisposition syndromes. For example, triple-negative breast cancer and microsatellite-instable colon cancers are predictive of hereditary breast and ovarian cancer and Lynch syndrome (LS), respectively. Such phenotypic associations have been incorporated into clinical guidelines such as those of the National Comprehensive Cancer Network (NCCN), and they are generally accepted by medical oncologists as features that should prompt a referral for genetic cancer risk assessment. For patients with EC, LS is the most common inherited cancer predisposition syndrome, with 1.8% of all EC cases occurring in the setting of LS. Because of the relatively high prevalence of LS and the associated high risk for other primary malignancies, recommendations for screening all women with EC diagnosed under the age of 50 years for LS via tumor analysis have been incorporated into current guidelines. Some guidelines advocate universal screening of all individuals with colorectal cancer and perhaps even all patients with EC. Regardless of the age at which it is initiated, such reflex testing of endometrial and colorectal tumors for markers of LS has simplified the workflow for many oncologists and should help to alleviate the underdiagnosis of LS. Several groups have also documented a predisposition to EC in the setting of Cowden syndrome (CS), a rare autosomal dominant disorder caused by pathogenic mutations in the phosphatase and tensin homolog (PTEN) gene located on chromosome 10q23.31. In addition to multiple hamartomas, CS has been associated with a higher risk of breast, thyroid, and endometrial cancers and, more recently, renal cancer. Although CS is considered a high-penetrance cancer susceptibility syndrome, studies of CS have noted variable and subtle clinical presentations of the disease, which suggests possible underdiagnosis and underestimation of the true prevalence. Moreover, the existing diagnostic criteria for CS are complex and cumbersome for integration into routine clinical care and are less familiar to oncologists; this further contributes to the possible underdiagnosis of the syndrome. Therefore, as in other cancer predisposition syndromes, there is a need for better phenotypic characterization of CS-associated malignancies that could help oncologists to recognize the need for further genetic evaluation in select patients.