Cancer risks by sex and variant type in PTEN Hamartoma Tumor Syndrome

Background: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67-78% at age 60), endometrial (EC, 19-28%) and thyroid cancer (TC, 6-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. Methods: A European, adult PHTS cohort study with data from medical files, registries and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios (SIR) were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. Results: 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 year, IQR : 3-10), and 159/281 females and 39/174 males with cancer. By age 60, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95%CI 43.0-66.4) to 75.8% (95%CI 60.7-88.4), with two-to-three-fold increased risks for PTEN truncating and about two-fold for phosphatase domain variants. EC risks ranged from 6.4% (95%CI 2.1-18.6) to 22.1% (95%CI 11.6-39.6), and TC risks from 8.9% (95%CI 5.1-15.3) to 20.5% (95%CI 11.3-35.4). Colorectal cancer, renal cancer and melanoma risks were each below 10.0%. Conclusion: Females have a different breast cancer risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of breast (females), endometrial and thyroid cancer. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.