Dataset Information

The Frequency of Ras Mutations in Cancer.

ABSTRACT: Ras is frequently mutated in cancer, however, there is a lack of consensus in the literature regarding the cancer mutation frequency of Ras, with quoted values varying from 10%-30%. This variability is at least in part due to the selective aggregation of data from different databases and the dominant influence of particular cancer types and particular Ras isoforms within these datasets. To provide a more definitive figure for Ras mutation frequency in cancer, we cross-referenced the data in all major publicly accessible cancer mutation databases to determine reliable mutation frequency values for each Ras isoform in all major cancer types. These percentages were then applied to current U.S. cancer incidence statistics to estimate the number of new patients each year that have Ras-mutant cancers. We find that approximately 19% of patients with cancer harbor Ras mutations, equivalent to approximately 3.4 million new cases per year worldwide. We discuss the Ras isoform and mutation-specific trends evident within the datasets that are relevant to current Ras-targeted therapies.

SUBMITTER: Prior IA

PROVIDER: S-EPMC7367715 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The Frequency of Ras Mutations in Cancer.

Prior Ian A IA Hood Fiona E FE Hartley James L JL

Cancer research 20200324 14

Ras is frequently mutated in cancer, however, there is a lack of consensus in the literature regarding the cancer mutation frequency of Ras, with quoted values varying from 10%-30%. This variability is at least in part due to the selective aggregation of data from different databases and the dominant influence of particular cancer types and particular Ras isoforms within these datasets. To provide a more definitive figure for Ras mutation frequency in cancer, we cross-referenced the data in all ...[more]

PMID: 32209560

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Project description:BackgroundThe OPUS study demonstrated that addition of cetuximab to 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX4) significantly improved objective response and progression-free survival (PFS) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). In patients with KRAS exon 2 mutations, a detrimental effect was seen upon addition of cetuximab to FOLFOX4. The current study reports outcomes in subgroups defined by extended RAS testing.Patients and methodsSamples from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons (exons 3-4) and six NRAS codons (exons 2-4) using BEAMing. A cutoff of ⩾5% mutant/wild-type sequences was selected to define RAS status; we also report an analysis using a cutoff based on the technical lower limit for mutation identification (0.1%).ResultsOther RAS mutations were detected in 31/118 (26%) evaluable patients. In the extended analysis of RAS wild-type tumours (n=87), objective response was significantly improved by addition of cetuximab to FOLFOX4 (58% versus 29%; odds ratio 3.33 [95% confidence interval 1.36-8.17]; P=0.0084); although limited by population size, there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group. There was no evidence that patients with other RAS mutations benefited from cetuximab, but small numbers precluded precise estimations of treatment effects. In the combined population of patients with any RAS mutation (KRAS exon 2 or other RAS), a clear detrimental effect was associated with addition of cetuximab to FOLFOX4.ConclusionPatients with RAS-mutant mCRC, as defined by mutations in KRAS and NRAS exons 2-4, derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit.

Project description:Colorectal cancer (CRC) is the second most common cause of cancer-specific death in both sexes in Western countries. KRAS mutations occur in about 50% of metastatic CRCs (mCRCs). The prognostic value of specific KRAS mutations still remains unexplored and unclear. Two hundred and forty KRAS wild-type and 206 KRAS/NRAS mutant consecutive unresectable mCRC patients with PS Eastern Cooperative Oncology Group (ECOG) 0 or 1, aged < 80 years, and with a life expectancy >3 months entered into this study. DNA was extracted from paraffin-embedded formalin-fixed tumour tissues, and it was sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Data were analysed using the Torrent Suite Software v5.0 (Thermo Fisher Scientific). The primary outcome was the analysis of the prognostic role of different KRAS mutations in terms of overall survival (OS). There were no significant differences among the most prevalent mutations (p.G12D, p.G12V, p.G13D, p.G12A, p.G12C, and p.G12S) in terms of age (<65 vs. ≥65 years), gender (male vs. female), grading (G1/G2 vs. G3), side of primary tumour (left vs. right), pT, and pN. At the median follow-up of 25.6 months, there were 77 deaths in KRAS-mutated patients and 94 in wild-type patients. Three homogeneous prognostic groups were identified: wild-type patients (group A, median survival: 27.5 months), p.G13D/p.G12A/p.G12V/p.G12D mutants (group B, median survival: 17.3 months), and p.G12C/p.G12S mutants (group C, median survival: 5.0 months, p < 0.0001 according to Log Rank test). Upon multivariate analysis, metastatic involvement and p.G12C/p.G12S KRAS mutation group C (vs. other mutations) emerged as independent prognostic variables for survival. We show that mutant KRAS is a negative prognostic factor and that p.G12C/p.G12S variants present the worst clinical courses. This information suggests a clear difference among KRAS mutations, and it will be useful to test potentiated and/or innovative therapeutic strategies in p.G12C/p.G12S metastatic CRC patients.

Dataset Information

The Frequency of Ras Mutations in Cancer.

Publications

The Frequency of Ras Mutations in Cancer.

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