Structural differences between valine-12 and aspartate-12 Ras proteins may modify carcinoma aggression

Al-Mulla, Fahd; Milner‐White, E. James; Going, James J.; Birnie, G.D.

doi:10.1002/(sici)1096-9896(199903)187:4<433::aid-path273>3.0.co;2-e

Cited by 93 publications

(33 citation statements)

References 32 publications

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“…There is now clear evidence from several clinical studies in CRC3, 4 and lung cancer5 for differences in the biological properties of various types of Ki‐ ras mutations. Biochemical differences between the codon 12 aspartate and valine mutations have also been reported6. Valine mutations and possibly some of the other minor codon 12 mutations appear to be more aggressive than the aspartate mutations in codon 12 or codon 13.…”

Section: Discussionmentioning

confidence: 94%

“…This agrees with concurrent observations in CRC4 as well as earlier studies in lung carcinoma, showing the codon 12 valine mutation to be associated with a poorer prognosis than the codon 12 aspartate mutation5. Various structural differences have recently been described6 between the valine and aspartate mutant Ki‐ ras proteins that could account for these in vivo differences in tumour behaviour. Differences in the prognostic significance of various types of TP53 mutation have also been reported in CRC7, 8.…”

Section: Introductionmentioning

confidence: 99%

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Ki‐ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes' C colorectal cancer

Gnanasampanthan

Elsaleh

McCaul

et al. 2001

The Journal of Pathology

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Ki-ras mutations are associated with an increased risk of relapse and death in colorectal cancer (CRC) patients, with some mutations being more aggressive than others. The present study examined the predictive value of different Ki-ras mutation types in a retrospective series of 430 Dukes' C stage CRC patients, of whom 208 (48%) had received adjuvant chemotherapy with 5-fluorouracil/levamisole or 5-fluorouracil/leucovorin. A total of 140 mutations were detected, the majority (58%, 81/140) being glycine to aspartate mutations in codons 12 and 13. Glycine to valine mutations in codon 12 (14%, 20/140) and other less frequent, non-specified mutation types (28%, 39/140) accounted for the remaining mutations. Kaplan-Meier survival analysis revealed that both Ki-ras wild-type and mutant patient groups derived significant survival benefit from chemotherapy. However, when patients were stratified according to the type of mutation, those with non-aspartate mutations appeared to gain more benefit from this treatment than those with aspartate mutations. Multivariate analysis that included other possible predictive factors in Dukes' C CRC (tumour site, patient sex, TP53 mutation) demonstrated that non-aspartate mutations in particular were associated with a significant survival benefit from chemotherapy (HR=0.11, 95% CI: 0.04-0.30, p<0.001). These results suggest that the type of Ki-ras mutation could be a clinically useful molecular marker for the identification of CRC subgroups that are likely to benefit from 5-fluorouracil-based adjuvant chemotherapy.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Ki‐ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes' C colorectal cancer

Gnanasampanthan

Elsaleh

McCaul

et al. 2001

The Journal of Pathology

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“…Despite variations in the frequency of types of mutations per region (Table 2), our results showed that more than 30% of the patients in each region harboured KRAS mutations (Table 1). Regarding prognosis, previously published data showed that Gly12Val substitutions are more aggressive having a poorer prognosis than those with Gly12Asp mutation, thus revealing a connection between survival and KRAS mutation type [23,25-27]. In relation to codon 13, some studies have shown that mutations in this codon could be less aggressive than in codon 12 and that patients with KRAS Gly13Asp mutant tumours could benefit from anti-EGFR therapies [28,29].…”

Section: Discussionmentioning

confidence: 99%

KRAS mutations: variable incidences in a Brazilian cohort of 8,234 metastatic colorectal cancer patients

et al. 2014

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BackgroundKRAS mutations are frequently found in colorectal cancer (CRC) indicating the importance of its genotyping in the study of the molecular mechanisms behind this disease. Although major advances have occurred over the past decade, there are still important gaps in our understanding of CRC carcinogenesis, particularly whether sex-linked factors play any role.MethodsThe profile of KRAS mutations in the Brazilian population was analyzed by conducting direct sequencing of KRAS codons 12 and 13 belonging to 8,234 metastatic CRC patient samples. DNA was extracted from paraffin-embedded tissue, exon 1 was amplified by PCR and submitted to direct sequencing. The data obtained was analysed comparing different geographical regions, gender and age.ResultsThe median age was 59 years and the overall percentage of wild-type and mutated KRAS was 62.8% and 31.9%, respectively. Interestingly, different percentages of mutated KRAS patients were observed between male and female patients (32.5% versus 34.8%, respectively; p = 0.03). KRAS Gly12Asp mutation was the most prevalent for both genders and for most regions, with the exception of the North where Gly12Val was the most frequent mutation found.ConclusionsTo the best of our knowledge this is one of the largest cohorts of KRAS genotyping in CRC patients and the largest to indicate a higher incidence of KRAS mutation in females compared to males in Brazil. Nevertheless, further research is required to better address the impact of gender differences in colorectal cancer.

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“…The crystal structures of the K ras protein with substitutions of glycine with aspartic acid or valine at codon 12 have been compared, and it was proposed that the mutant ras with a glycine-to-valine change at codon 12 may generate a more stable signal compared to the glycine-to-aspartic acid mutant or wild-type ras protein (13). A novel heterozygous mutation, i.e., GAA (glutamic acid) to AAA (lysine), was found at codon 31 in one of the tumor samples.…”

Section: Resultsmentioning

confidence: 99%

Spectrum of K ras mutations in Pakistani colorectal cancer patients

Murtaza

Bibi

Rashid

et al. 2013

Braz J Med Biol Res

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The incidence of colorectal cancer (CRC) is increasing daily worldwide. Although different aspects of CRC have been studied in other parts of the world, relatively little or almost no information is available in Pakistan about different aspects of this disease at the molecular level. The present study was aimed at determining the frequency and prevalence of K ras gene mutations in Pakistani CRC patients. Tissue and blood samples of 150 CRC patients (64% male and 36% female) were used for PCR amplification of K ras and detection of mutations by denaturing gradient gel electrophoresis, restriction fragment length polymorphism analysis, and nucleotide sequencing. The K ras mutation frequency was found to be 13%, and the most prevalent mutations were found at codons 12 and 13. A novel mutation was also found at codon 31. The dominant mutation observed was a G to A transition. Female patients were more susceptible to K ras mutations, and these mutations were predominant in patients with a nonmetastatic stage of CRC. No significant differences in the prevalence of K ras mutations were observed for patient age, gender, or tumor type. It can be inferred from this study that Pakistani CRC patients have a lower frequency of K ras mutations compared to those observed in other parts of the world, and that K ras mutations seemed to be significantly associated with female patients.

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Structural differences between valine-12 and aspartate-12 Ras proteins may modify carcinoma aggression

Cited by 93 publications

References 32 publications

Ki‐ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes' C colorectal cancer

Ki‐ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes' C colorectal cancer

KRAS mutations: variable incidences in a Brazilian cohort of 8,234 metastatic colorectal cancer patients

Spectrum of K ras mutations in Pakistani colorectal cancer patients

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