Heterogeneous mutational profile and prognosis conferred by TP53 mutations in appendiceal mucinous neoplasms

Summary The eighth edition of American Joint Committee on Cancer (AJCC) advocates a 3-tier grading system for appendiceal mucinous tumors. The mutational profile for each tumor grade and the impact of TP53 mutation on survival are unknown. We classified appendiceal mucinous tumors into 3 grades based on the eighth edition of American Joint Committee on Cancer: 21 G1 low-grade mucinous neoplasms, 21 G2 appendiceal adenocarcinomas, and 26 G3 signet ring cell carcinomas. Mutation profiles were obtained using next-generation sequencing. The impact of TP53 on prognosis was investigated by multivariable analysis. Most G1 tumors harbor KRAS/GNAS mutations with TP53 and SMAD4 in a small subset of cases. G2 and G3 tumors show a more complex mutation pattern carrying PIK3CA , BRAF , or TP53 mutations in addition to KRAS / GNAS . PTEN mutations were detected exclusively in G2 tumors. The prevalence of KRAS and GNAS mutations is significantly lower in G3 tumors relative to G1/G2, whereas TP53 , PIK3CA , or BRAF mutations are common. Mutations in NRAS , IDH2 , CDH1 , RB1 , CTNNB1 , CDKN2A , PTPN11, and KIT genes were observed in single cases. Patients with TP53 -mutated disseminated G2 and G3 tumors had worse progression-free survival than did those with wild-type TP53 tumors ( P = .0315). A trend toward worse overall survival was observed in TP53 -mutated G3 tumors ( P = .102). p53 expression correlated with mutation status. We demonstrate a distinct but overlapping pattern of gene mutations in each grade of appendiceal mucinous tumors and the independent impact of TP53 mutation on progression-free survival but not overall survival.