Molecular characterization of appendiceal mucinous neoplasms: Stratification of KRAS, GNAS, and TP53 mutations by tumor grade

The histologic grading of appendiceal mucinous neoplasms into low grade and high grade groups identifies patients with distinct prognosis. The molecular alterations that define these unique subsets, however, are less well-known. We explored characteristic molecular alterations between two histological groups of appendiceal mucinous neoplasm and their association with overall survival. Seventy-four surgical resections of primary appendiceal mucinous neoplasms underwent mutation analysis by next-generation sequencing. These tumors were classified by degree of differentiation following the AJCC grading system, consisted of 12 low grade tumors and 53 high-grade tumors. Tumor grade was significantly associated with GNAS mutations, KRAS and GNAS co-mutation, and TP53 mutations. Low-grade appendiceal mucinous neoplasms harbored more frequent GNAS mutations (71%), either alone or in combination with KRAS (67%) than high-grade tumors (30% and 21%, respectively; p=0.01 for both). In contrast, high-grade appendiceal mucinous neoplasms had more frequent TP53 mutations (34%) than low-grade tumors (0%; p=0.002). Patients with KRAS and GNAS co-mutation showed a better overall survival than patients without these co-mutations (p=0.04). Low-grade appendiceal mucinous neoplasms have different molecular alterations such as frequent GNAS mutations and co-mutation with KRAS compared to high-grade tumors, which harbor frequent TP53 mutations. Identification of these mutations in appendiceal mucinous neoplasms may be helpful as useful diagnostic markers to aid in the distinguishing of these two clinically important subsets.