PIK3CA Mutation in Colorectal Cancer: Relationship with Genetic and Epigenetic Alterations

Abstract

Somatic PIK3CA mutations are often present in colorectal cancer. Mutant PIK3CA activates AKT signaling, which up-regulates fatty acid synthase (FASN). Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. However, the relationship between PIK3CA mutation, MSI and CIMP remains uncertain. Using Pyrosequencing technology, we detected PIK3CA mutations in 91 (15%) of 590 population-based colorectal cancers. To determine CIMP status, we quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). PIK3CA mutation was significantly associated with mucinous tumors [P = .0002; odds ratio (OR) = 2.44], KRAS mutation (P < .0001; OR = 2.68), CIMP-high (P = .03; OR = 2.08), phospho-ribosomal protein S6 expression (P = .002; OR = 2.19), and FASN expression (P = .02; OR = 1.85) and inversely with p53 expression (P = .01; OR = 0.54) and beta-catenin (CTNNB1) alteration (P = .004; OR = 0.43). In addition, PIK3CA G-to-A mutations were associated with MGMT loss (P = .001; OR = 3.24) but not with MGMT promoter methylation. In conclusion, PIK3CA mutation is significantly associated with other key molecular events in colorectal cancer, and MGMT loss likely contributes to the development of PIK3CA G>A mutation. In addition, Pyrosequencing is useful in detecting PIK3CA mutation in archival paraffin tumor tissue. PIK3CA mutational data further emphasize heterogeneity of colorectal cancer at the molecular level.

The molecular background of mucinous carcinoma beyond MUC2

“…The PI3K pathway is normally inhibited by tumour suppressor gene PTEN. PIK3CA is more commonly mutated in MC (9-50%) than in NMC (7-12%) and a RR of 1.79 (95% CI 1.46-2.19) was found for MC in an analysis on mutational PIK3CA status [34, 58,59,[71][72][73][74]. Also, PIK3CA mutations occur more frequently in tumours that are localized in the proximal colon, as are MCs [3,4,34,73].…”

“…Also, PIK3CA mutations occur more frequently in tumours that are localized in the proximal colon, as are MCs [3,4,34,73]. PIK3CA mutations are commonly found in combination with KRAS mutations and are associated with high levels of CIMP, which are both linked to MC [51,72,73]. An association between PIK3CA mutation and MSI has not been demonstrated [72].…”

“…PIK3CA mutations are commonly found in combination with KRAS mutations and are associated with high levels of CIMP, which are both linked to MC [51,72,73]. An association between PIK3CA mutation and MSI has not been demonstrated [72]. In the literature, Mutations in ERBB2 (which encodes HER-2) are considered uncommon in CRC and were found in only 7.1% and 6.3% of MC and NMC samples, respectively.…”

Oncogenic mutations as predictive factors in colorectal cancer

“…Although the EGFR gene is not or very rarely mutated in colorectal tumours, activating mutations of KRAS or BRAF, involved in the RAS/MAPK pathway, are present in 32-37% and in 10-17% of the cases in large population-based studies, respectively (Samowitz et al, 2000;Rajagopalan et al, 2002;Brink et al, 2003;Samowitz et al, 2005a;Nosho et al, 2008a;de Vogel et al, 2009;Ogino et al, 2009b), and mutations of PI3KCA that encodes the catalytic subunit of the PI3K protein involved in the PI3K/AKT pathway are observed in 15% of the cases (Bamford et al, 2004;Barault et al, 2008b;Nosho et al, 2008b).…”

Desenlaces del manejo no quirúrgico posterior a neoadyuvancia del cáncer localmente avanzado de recto

“…Aunque esten aún en investigación y no sea clara su significacia como factores pronósticos, la determinación de marcadores inmunohistoquímicos como p53, Ki67 y moleculares como Kras podrian correlacionarse con el comportamiento del tumor y la respuesta a los tratamientos sobre él [42][43][44][45][46][47][48][49][50] . En un reporte de Lin et al 46 , los autores comparan la expresión de p53, p27 y bcl-2 antes y después de la terapia neoadyuvante, mostrando un incremento de p27 y bcl-2 en los especímenes resecados, al compararse con la biopsia inicial, considerándose que la positividad de p27 parece mejorar el pronóstico.…”