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

Hum Pathol. 2019 Mar:85:260-269. doi: 10.1016/j.humpath.2018.11.011. Epub 2018 Nov 17.


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.

Keywords: AJCC eighth edition; Appendiceal mucinous neoplasms; Mutational profile; Next-generation sequencing; TP53 mutation; p53 immunohistochemistry prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Mucinous / genetics*
  • Adenocarcinoma, Mucinous / mortality
  • Adenocarcinoma, Mucinous / pathology
  • Adult
  • Aged
  • Appendiceal Neoplasms / genetics*
  • Appendiceal Neoplasms / mortality
  • Appendiceal Neoplasms / pathology
  • Biomarkers, Tumor
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • DNA Mutational Analysis
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasm Grading
  • Neoplasm Staging
  • Prognosis
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Survival Rate
  • Tumor Suppressor Protein p53 / genetics*
  • beta Catenin / genetics


  • Biomarkers, Tumor
  • CTNNB1 protein, human
  • Tumor Suppressor Protein p53
  • beta Catenin
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Proto-Oncogene Proteins p21(ras)