Landscape of Genetic Mutations in Appendiceal Cancers

Abstract

In appendiceal cancers, the most frequently mutated genes are (i) KRAS, which, when reactivated, restores signal transduction via the RAS-RAF-MEK-ERK signaling pathway and stimulates cell proliferation in the early stages of tumor transformation, and then angiogenesis; (ii) TP53, whose inactivation leads to the inhibition of programmed cell death; (iii) GNAS, which, when reactivated, links the cAMP pathway to the RAS-RAF-MEK-ERK signaling pathway, stimulating cell proliferation and angiogenesis; (iv) SMAD4, exhibiting typical tumor-suppressive activity, blocking the transmission of oncogenic TGFB signals via the SMAD2/SMAD3 heterodimer; and (v) BRAF, which is part of the RAS-RAF-MEK-ERK signaling pathway. Diverse mutations are reported in other genes, which are part of secondary or less critical signaling pathways for tumor progression, but which amplify the phenotypic diversity of appendiceal cancers. In this review, we will present the main genetic mutations involved in appendix tumors and their roles in cell proliferation and survival, and in tumor invasiveness, angiogenesis, and acquired resistance to anti-growth signals.

Keywords: KRAS genes; adenocarcinomas; appendix tumor; point mutations; signaling pathways.

Figure 1

The 105 genes in which mutations are reported in appendiceal cancers. AC, appendiceal carcinoma; SSWD, sigmoid sinus wall dehiscence; SLD, single-lineage dysplasia; MNA, myelocytomatosis amplification; LAMN, low-grade appendiceal mucinous neoplasm; HAMN, high-grade appendiceal mucinous neoplasm; AAd, appendiceal adenocarcinoma; MAd, mucinous adenocarcinoma; SRCA, extragastric signet ring cell adenocarcinoma; AGCA, advanced gastric cancer; WDNT, well-differentiated neuroendocrine tumor. Green, genes reported in appendiceal cancers; white, genes not associated with appendiceal cancers.

Figure 2

The signaling pathways important in cancer (adapted from KEGG Pathways, 2020 [14]).

Figure 3

RAS–RAF–MEK–ERK signaling pathway in cancer, pointing the appendiceal cancer types in which members of RAS (KRAS, HRAS, and NRAS) and RAF (BRAF) gene families, and the MYC/cMYC gene are mutated (adapted from KEGG Pathways, 2020 [14]).

Figure 4

Receptors of PI3K–PKB/AKT, JAK–STAT, and RAS–RAF–MEK–ERK signaling pathways in cancer, pointing out the appendiceal cancer types in which the most important members are mutated (adapted from KEGG Pathways, 2020 [14]).

Figure 5

TP53 signaling pathway in cancer, pointing out the appendiceal cancer types in which TP53 gene is mutated (adapted from KEGG Pathways, 2020 [14]).

Figure 6

PI3K–PKB/AKT and JAK–STAT signaling pathways in cancer, pointing out the appendiceal cancer types in which PIK3CA, PTEN, and JAK3 genes are mutated (adapted from KEGG Pathways, 2020 [14]).

Figure 7

WNT, angiogenesis, and NOTCH signaling pathways in cancer, pointing out the appendiceal cancer types in which GNAS, RHOA, NOTCH1, NOTCH4, and APC genes are mutated (adapted from KEGG Pathways, 2020 [14]).

Figure 8

TGFB signaling pathway in cancer, pointing out the appendiceal cancer types in which TGFBR2, SMAD2, SMAD3, and SMAD4 genes are mutated (adapted from KEGG Pathways, 2020 [14]).

Figure 9

Comparative analysis of gene mutation frequency in appendiceal, colorectal, small bowel, and gastric cancers. According to it, the frequency of mutations in TP53 and PIK3CA genes is lower in appendiceal tumors compared to the other tumor types, and the frequency of mutations in APC gene in appendiceal cancers is comparable to that in small bowel tumors, differentiating appendiceal tumors from tumors of the middle and lower digestive tract. However, the frequency of mutations in the KRAS and SMAD4 genes is comparable to the frequency of mutations in these genes in colorectal and small bowel cancers, indicating the possibility of common genetic causes for all three tumors.

Figure 10

Number of genes in which mutations occur in appendiceal cancers.

Figure 11

Chromosome distribution of genes that are mutated in appendiceal cancers.