Germline alterations in RASAL1 in Cowden syndrome patients presenting with follicular thyroid cancer and in individuals with apparently sporadic epithelial thyroid cancer

Context: RASAL1 has recently been identified as an important tumor suppressor for sporadic thyroid tumorigenesis, particularly for follicular thyroid cancer (FTC) and anaplastic thyroid cancer. Thyroid cancer is an important component of Cowden syndrome (CS). Patients with germline PTEN mutations have an overrepresentation of FTC over other histological subtypes. Objective: To determine the prevalence of germline RASAL1 mutations in PTEN mutation-positive and wild type CS patients. Setting and Design: We reviewed our prospective database of more than 3000 CS/CS-like patients and retrospectively identified a subset of patients who presented with thyroid cancer for RASAL1 mutation analysis. We reviewed data from The Cancer Genome Atlas (TCGA) sporadic papillary thyroid cancer (PTC) database with germline data for RASAL1 mutations to determine the prevalence of germline RASAL1 mutations in CS-related thyroid cancer patients. Results: We scanned 155 CS/CS-like patients with thyroid cancer for germline RASAL1 mutations. Of the 155 patients, 39 had known germline pathogenic PTEN mutations (PTEN^mut+) and 116 were PTEN mutation negative (PTEN^WT). Among these 155 patients, we identified RASAL1 germline alterations suspected as being deleterious in two patients. Both were patients with PTEN^WT who had FTC (2/48, 4.1%). This was in contrast to patients with PTEN^mut+ who had thyroid cancer (0/39). Of 339 sporadic patients with PTC from the TCGA study, 62 (18%) had germline RASAL1 variants predicted to be deleterious. TCGA patients with follicular-variant PTC were statistically overrepresented (21/62, 34%) among patients with deleterious RASAL1 variants compared with those without (57/277, 21%). Conclusions: Germline RASAL1 alterations are uncommon in patients with CS but may not be infrequent in patients with apparently sporadic follicular-variant PTC.