Germline PTEN Mutations As a Cause of Early-Onset Endometrial Cancer

Abstract

TO THE EDITOR: In the article by Lu et al, 1 the investigators conducted a prospective assessment of the prevalence of Lynch syndrome in women diagnosed with endometrial cancer before age 50 years. Although they identified germline Lynch syndrome–associated mutations in 9% of their patient population, their data also suggest that for 91% of patients with early-onset endometrial cancer, the genetic basis is unclear. One genetic condition that could contribute is Cowden syndrome (CS), which is another inherited cancer susceptibility syndrome in which early endometrial cancer can occur. CS is characterized by germline mutations in the tumor suppressor PTEN that is located on chromosome 10q23.3. Loss of PTEN increases activation of the Akt/mTOR pathway, increases tumorigenesis in many organs in preclinical studies (including the uterus), and is a poor prognostic factor for many types of cancer. Germline mutations in PTEN are associated with a number of hamartomatous syndromes, of which CS is the prototype. CS patients develop thyroid, breast, and endometrial cancers at an earlier age than the general population, and have an overall increased incidence of these cancers compared with the general population. In a young woman diagnosed with endometrial cancer, a thorough history and physical examination evaluating signs of CS such as macrocephaly, mucocutaneous lesions (ie, facial trichilemmomas, acral keratoses, papillomatous lesions, or mucosal lesions) should be performed. If a patient meets established clinical criteria for CS, 2 or has a family member diagnosed with CS, referral for genetic testing and sequencing for germline mutation of PTEN should be considered. Although Lynch syndrome and CS can independently contribute to early-onset endometrial cancer, defects in mismatch repair (MMR), microsatellite instability (MSI), and PTEN mutations might be etiologically related. For example, in a population-based study of patients with sporadic endometrial cancer, 3 tumors with MSI had a higher frequency of PTEN mutations. Patients whose tumors harbored MSI and PTEN mutations were more likely to be diagnosed at an advanced stage and exhibited a worse prognosis. Zhou et al 4 demonstrated that a high frequency of somaticPTEN mutations, especially