Kirsten ras Mutations in Patients With Colorectal Cancer: the Multicenter "RASCAL" Study

Andreyev, H. J. N.; Norman, A.; Cunningham, David; Oates, J.; Clarke, Paul A.

doi:10.1093/jnci/90.9.675

Cited by 658 publications

(498 citation statements)

References 27 publications

Supporting

Mentioning

395

Contrasting

Unclassified

Order By: Relevance

“…Overall evidence supports a null prognostic role of KRAS mutation even if a previous meta-analyses (Andreyev et al, 1998;Andreyev et al, 2001) led to wrong conclusions likely due to the well-known positive publication bias. Table 2).…”

Section: Kras Somatic Mutationsmentioning

confidence: 74%

Oncogenic mutations as predictive factors in colorectal cancer

2010

View full text Add to dashboard Cite

Section: Kras Somatic Mutationsmentioning

confidence: 74%

Oncogenic mutations as predictive factors in colorectal cancer

2010

View full text Add to dashboard Cite

“…Mutations in the three closely related ras genes, H-ras, K-ras, and N-ras, are among the most common mutations found in human cancer, reaching 50% in some types of tumors, such as colorectal carcinoma (Forrester et al, 1987;Andreyev et al, 1997Andreyev et al, , 1998Andreyev et al, , 2001). Vogelstein and colleagues have shown that mutations in K-ras occur early in the development of colon carcinomas (Vogelstein et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

“…This dominantly acting mutation in ras results in its constitutive activation and the subsequent triggering of its signaling pathway by influencing GTPase activity. It is clear that mutations in ras contribute both to the recurrence of the disease and to decreased survival (Andreyev et al, 1998). It is less clear, however, what the consequences of ras mutations are during the early stages of tumorigenesis.…”

mentioning

confidence: 99%

RasMutation Impairs Epithelial Barrier Function to a Wide Range of Nonelectrolytes

Mullin

Leatherman

Valenzano

et al. 2005

MBoC

View full text Add to dashboard Cite

Although ras mutations have been shown to affect epithelial architecture and polarity, their role in altering tight junctions remains unclear. Transfection of a valine-12 mutated ras construct into LLC-PK 1 renal epithelia produces leakiness of tight junctions to certain types of solutes. Transepithelial permeability of D-mannitol increases sixfold but transepithelial electrical resistance increases >40%. This indicates decreased paracellular permeability to NaCl but increased permeability to nonelectrolytes. Permeability increases to D-mannitol (M r 182), polyethylene glycol (M r 4000), and 10,000-M r methylated dextran but not to 2,000,000-M r methylated dextran. This implies a "ceiling" on the size of solutes that can cross a ras-mutated epithelial barrier and therefore that the increased permeability is not due to loss of cells or junctions. Although the abundance of claudin-2 declined to undetectable levels in the ras-overexpressing cells compared with vector controls, levels of occludin and claudins 1, 4, and 7 increased. The abundance of claudins-3 and -5 remained unchanged. An increase in extracellular signal-regulated kinase-2 phosphorylation suggests that the downstream effects on the tight junction may be due to changes in the mitogen-activated protein kinase signaling pathway. These selective changes in permeability may influence tumorigenesis by the types of solutes now able to cross the epithelial barrier. INTRODUCTIONMutations in the three closely related ras genes, H-ras, K-ras, and N-ras, are among the most common mutations found in human cancer, reaching 50% in some types of tumors, such as colorectal carcinoma (Forrester et al., 1987;Andreyev et al., 1997Andreyev et al., , 1998Andreyev et al., , 2001). Vogelstein and colleagues have shown that mutations in K-ras occur early in the development of colon carcinomas (Vogelstein et al., 1988). This dominantly acting mutation in ras results in its constitutive activation and the subsequent triggering of its signaling pathway by influencing GTPase activity. It is clear that mutations in ras contribute both to the recurrence of the disease and to decreased survival (Andreyev et al., 1998). It is less clear, however, what the consequences of ras mutations are during the early stages of tumorigenesis. In this regard, one important issue is the effect of Ras activation on epithelial barrier function, perhaps the most basic of all epithelial functions, and a function shared by all epithelial tissues. Ras can exert fundamental effects on epithelial barrier function through the extracellular signal-regulated kinase-mitogen-activated protein (ERK-MAP) kinase pathway or through direct binding to the tight junction-associated protein, AF-6, which binds to ZO-1, which in turn links the tight junction to the actin cytoskeleton. Activated Ras is known to inhibit interaction between the tight junction-associated proteins, AF-6 and ZO-1, with resultant perturbation of intercellular junctions (Yamamoto et al., 1997). Modulation of tight junctions by G proteins in ge...

show abstract

“…[3][4][5] It is estimated that MSI is present in approximately 15% of colon tumors, mutations in the Ki-ras gene in 30 -50% of colon tumors and p53 mutations generally in 30 -50% of tumors. 6,7 Small studies, including our own previous work with a small subset of Utah cases, have suggested that family history at the population level is not associated with MSI even though people who have inherited a mutation in 1 of the mismatch repair genes have unstable tumors.…”

mentioning

confidence: 99%

Associations between family history of colorectal cancer and genetic alterations in tumors

Slattery

Curtin

Schaffer

et al. 2001

Intl Journal of Cancer

View full text Add to dashboard Cite

A family history of colorectal cancer has been consistently associated with an increased risk of developing colon cancer. However, there is limited information on the association between family history of colorectal cancer and genetic alterations that occur in colon tumors. In this study, we evaluate the association among genetic alterations of Ki-ras and p53, microsatellite instability and having a family history of colorectal cancer in a study of incident colon cancer cases (n ‫؍‬ 1993) and population-based controls (n ‫؍‬ 2,410). Although there was a slight nonsignificant increase in risk of having an unstable tumor among those with a family history of colorectal cancer, this increase in risk disappeared after excluding those people with a known mutation in either of the mismatch repair genes hMLH1 or hMSH2. A family history of colorectal cancer was not associated with Ki-ras mutations overall, although those with a G to T mutation of the second base of codon 12 were more likely to have a family history of colorectal cancer than were those without this specific type of Ki-ras mutation. Cases with p53 mutations were less likely to have a family history of colorectal cancer than were cases without a p53 mutation. We believe that, given the general lack of association between having a family history of colorectal cancer and genetic alterations in tumors, these alterations are acquired through disease pathways that involve exposure from diet, lifestyle or other environmental factors.

show abstract

Kirsten ras Mutations in Patients With Colorectal Cancer: the Multicenter "RASCAL" Study

Cited by 658 publications

References 27 publications

Oncogenic mutations as predictive factors in colorectal cancer

Oncogenic mutations as predictive factors in colorectal cancer

RasMutation Impairs Epithelial Barrier Function to a Wide Range of Nonelectrolytes

Associations between family history of colorectal cancer and genetic alterations in tumors

Contact Info

Product

Resources

About