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 … Show more
“…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].…”
Section: Pik3camentioning
confidence: 99%
“…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].…”
Section: Pik3camentioning
confidence: 99%
“…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.…”
The increasing interest of the oncology community in tumour classification and prediction of outcome to targeted therapies has put emphasis on an improved identification of tumour types. Colorectal mucinous adenocarcinoma (MC) is a subtype that is characterized by the presence of abundant extracellular mucin that comprises at least 50% of the tumour volume and is found in 10-15% of colorectal cancer patients. MC development is poorly understood, however, the distinct clinical and pathological presentation of MC suggests a deviant development and molecular background. In this review we identify common molecular and genetic alterations in colorectal MC. MC is characterized by a high rate of MUC2 expression. Mutation rates in the therapeutically important RAS/RAF/MAPK and PI3K/AKT pathways are significantly higher in MC compared with non-mucinous adenocarcinoma. Furthermore, mucinous adenocarcinoma shows higher rates of microsatellite instability and is more frequently of the CpG island methylator phenotype. Although the majority of MCs arise from the large intestine, this subtype also develops in other organs, such as the stomach, pancreas, biliary tract, ovary, breast and lung. We compared findings from colorectal MC with tumour characteristics of MCs from other organs. In these organs, MCs show different mutation rates in the RAS/RAF/MAPK and PI3K/ AKT pathways as well, but a common mucinous pathway cannot be identified. Identification of conditions and molecular aberrations that are associated with MC generates insight into the aetiology of this subtype and improves understanding of resistance to therapies.
“…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].…”
Section: Pik3camentioning
confidence: 99%
“…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].…”
Section: Pik3camentioning
confidence: 99%
“…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.…”
The increasing interest of the oncology community in tumour classification and prediction of outcome to targeted therapies has put emphasis on an improved identification of tumour types. Colorectal mucinous adenocarcinoma (MC) is a subtype that is characterized by the presence of abundant extracellular mucin that comprises at least 50% of the tumour volume and is found in 10-15% of colorectal cancer patients. MC development is poorly understood, however, the distinct clinical and pathological presentation of MC suggests a deviant development and molecular background. In this review we identify common molecular and genetic alterations in colorectal MC. MC is characterized by a high rate of MUC2 expression. Mutation rates in the therapeutically important RAS/RAF/MAPK and PI3K/AKT pathways are significantly higher in MC compared with non-mucinous adenocarcinoma. Furthermore, mucinous adenocarcinoma shows higher rates of microsatellite instability and is more frequently of the CpG island methylator phenotype. Although the majority of MCs arise from the large intestine, this subtype also develops in other organs, such as the stomach, pancreas, biliary tract, ovary, breast and lung. We compared findings from colorectal MC with tumour characteristics of MCs from other organs. In these organs, MCs show different mutation rates in the RAS/RAF/MAPK and PI3K/ AKT pathways as well, but a common mucinous pathway cannot be identified. Identification of conditions and molecular aberrations that are associated with MC generates insight into the aetiology of this subtype and improves understanding of resistance to therapies.
“…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).…”
Section: Signalling Pathways and Oncogenic Mutations In Colorectal Camentioning
“…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.…”
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