Su1851 Family History and Pathology Features in Early-Onset Colorectal Cancer Cases With a BRAF P.V600e Mutation

FFPE tissue slides were immunostained for β-catenin, P53 and phospho-S6 (a downstream target of mTOR). Furthermore, we performed DNA mutation analyses for BRAF, KRAS, and P53, and LOH analyses for LKB1 and P53. Results: Twenty-eight of the 144 patients (19%, 64% males) from 20 families developed 30 GI malignancies at a median age of 44 years (IQR 35-57) at diagnosis of first cancer (Table). Two patients were diagnosed with two primary GI carcinomas. Three (10%) malignancies were discovered during surveillance; all carcinomas in situ (one colorectal and two gastric lesions). Twenty-three patients (82%) deceased at a median age of 54 years (IQR 36-61); 19 (68%) of whom had died as a direct cause of GI cancer. Of these 23 patients, median survival after GI cancer diagnosis was 6 months (IQR 1-18). Of 16 carcinomas FFPE tissue was available for molecular analysis. Nuclear β-catenin was detected in 3/5 (60%) primary intestinal carcinomas. Overexpression of P53 was observed in 7/16 (44%) carcinomas, and a total absence of P53 was observed in one (6%) sample. All available samples showed heterogeneous expression of pS6, in which epithelial expression was more pronounced compared to the stromal component in 9/14 (64%) cases. Mutation and LOH analyses are currently being performed. Conclusion: Gastrointestinal cancer often affects PJS patients already at a young age. Alterations in Wnt/ β-catenin signaling and in P53 are observed in a subset of PJS carcinomas, while activation of mTOR signaling seems to be altered in the majority of these carcinomas, predominantly in the epithelial compartment. These results suggest that treatment with mTOR inhibitors may be beneficial in the anti-cancer treatment of PJS patients. Location of gastrointestinal carcinomas in Peutz-Jeghers syndrome patients