NRAS Mutations Are Rare in Colorectal Cancer

Irahara, Natsumi; Baba, Yoshifumi; Nosho, Katsuhiko; Shima, Kaori; Yan, Liying; Dias‐Santagata, Dora; Iafrate, A. John; Fuchs, Charles S.; Haigis, Kevin M.; Ogino, Shuji

doi:10.1097/pdm.0b013e3181c93fd1

Cited by 168 publications

(137 citation statements)

References 49 publications

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“…KRAS mutation prevalence in cholangiocarcinoma ranged from 16% to 38%. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] …”

Section: Frequency Of Ras Mutation In Gastrointestinal Cancermentioning

confidence: 99%

Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

Kodaz

2017

EJMO

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T he RAS oncogene affects numerous cellular functions, including growth, proliferation, apoptosis, migration, division, and differentiation of the cells. It has 3 known isoforms: Harvey-RAS (HRAS), Kirsten-RAS (KRAS), and neuroblastoma-RAS (NRAS). RAS has an intrinsic GTPase activity; it encodes proteins binding the guanine nucleotides. KRAS and HRAS were discovered in studies conducted on cancer-causing viruses. Retroviral oncogenes related to murine sarcoma virus genes (Kristen rat sarcoma virus and Harvey rat sarcoma virus) were discovered in 1982. These 2 oncogenes are similar to human KRAS. Approximately 30% of all human cancers have RAS gene involvement. Mutations in KRAS account for about 85% of all RAS mutations in human tumors, NRAS for about 11% to 15%, and HRAS for about 1%. Frequency of RAS mutation in intracranial tumorsGliomas constitute 80% of malignant brain tumors. RAS mutations are very rare in malignant gliomas; no RAS mutation was found in a study in which 30 glioblastoma multiforme (GBM) patients were evaluated. The frequency of NRAS mutation was 2.1% in another study, although KRAS and HRAS mutations were not detected. It was reported that RAS mutation frequency was 12% in a study of isocitrate-dehydrogenase 1-mutant malignant glioma. RAS genes were studied in 21 cases of glioblastoma multiforme, 4 cases of fibrillary astrocytoma, 4 cases of anaplastic astrocytoma, and 15 normal specimens. RAS mutation was de-RAS oncogene affects numerous cellular functions including growth, proliferation, apoptosis, migration, division and differentiation of the cells. It has 3 known isoforms as Harvey-RAS (HRAS), Kirsten -RAS (KRAS) and Neuroblastoma-RAS (NRAS). RAS has an intrinsic GTPase activity. It encodes proteins binding the guanine nucleotides. KRAS and HRAS were discovered in studies carried out on viruses leading to cancer. Retroviral oncogenes related to murine sarcoma virus genes (Kristen Rat Sarcoma Virus and Murine Sarcoma Virus) were discovered in 1982. These two oncogenes are similar to human KRAS. Approximately 30% of all human cancers have ras genes. Mutations in KRAS account for about 85% for all RAS mutations in human tumors, NRAS is about 11-15%, and HRAS is about 1%.

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“…KRAS mutation prevalence in cholangiocarcinoma ranged from 16% to 38%. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] …”

Section: Frequency Of Ras Mutation In Gastrointestinal Cancermentioning

confidence: 99%

Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

Kodaz

2017

EJMO

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“…Activating mutations in other members of the RAS oncogene family (HRAS and NRAS) have also been described, although they are significantly less frequent. NRAS appears in ~2% of patients with advanced CRC (12). The presence of NRAS mutations has also recently been associated with a lack of benefit from anti-EGFR therapies (13), and has been incorporated in clinical practice as a predictive biomarker to select first-line treatment for patients with advanced CRC.…”

Section: Introductionmentioning

confidence: 99%

Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis

Noguera

Jantus‐Lewintre²,

Gil‐Raga

et al. 2017

Molecular and Clinical Oncology

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Abstract. The role of Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations as negative predictors for anti-epidermal growth factor receptor (EGFR) therapies in metastatic colorectal cancer (CRC) has been firmly established. However, whether the RAS mutation status plays a role as a biomarker for anti-vascular endothelial growth factor (VEGF) treatment remains controversial. Data from 93 CRC patients who received first-line cytotoxic chemotherapy with fluoropyrimidines and oxaliplatin, with or without bevacizumab, were analyzed. We investigated the association between the RAS mutation status and clinical outcomes in terms of response rate, progression-free survival (PFS) and overall survival (OS). Mutations in RAS genes were observed in 47 (52.6%) patients (45 KRAS and 2 NRAS mutations). Patients with tumours harbouring RAS mutations were less suitable for primary tumour resection, were more likely to develop lung metastases, and received bevacizumab treatment for a shorter time period compared with those with wild-type tumours. The response rate to chemotherapy did not differ according to the RAS mutation status, and there were no significant differences in PFS [RAS mutation: 12 months, 95% confidence interval (CI): 8.7-15.2 vs. RAS wild-type: 12 months, 95% CI: 9.67-14.32; P=0.857] or OS (RAS mutation: 20 months, 95% CI: 14.3-25.6 vs. RAS wild-type: 24 months, 95% CI: 18.7-29.2; P=0.631). Patients with RAS mutation vs. those with RAS wild-type exhibited a favourable trend in PFS when treated with bevacizumab (13 months, 95% CI: 6.5-19.4 vs. 10 months, 95% CI: 4.2-15.7, respectively; P=0.07) and OS (27 months, 95% CI: 18.5-35.4 vs. 15 months, 95% CI: 12.4-17.5, respectively; P=0.22). In conclusion, RAS mutations are not a prognostic marker for PFS and OS in CRC patients receiving fluoropyrimidine-oxaliplatine treatment, with or without bevacizumab. RAS mutations are not predictive of the lack of efficacy of bevacizumab, and these patients appear to benefit from anti-angiogenic treatment.

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“…A c.182A.G substitution in codon 61 leading to KRAS or NRAS Q61R mutation at the protein level is rare and has been reported in no more than 1% of colorectal carcinomas. [13][14][15] In vitro studies on genetically engineered mice demonstrated phenotypic differences between KRAS and NRAS mutants. 16 In colorectal cancer, NRAS mutation correlates with less favorable clinical outcome and might require different treatment strategies.…”

Section: Resultsmentioning

confidence: 99%

SP174, NRAS Q61R Mutant-Specific Antibody, Cross-Reacts With KRAS Q61R Mutant Protein in Colorectal Carcinoma

Lasota¹,

Kowalik²,

Felisiak-Gołąbek³

et al. 2017

Archives of Pathology &Amp; Laboratory Medicine

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Context.-NRAS is a member of the RAS family oncoproteins implicated in cancer. Gain-of-function NRAS mutations were reported in a subset of colorectal cancers. These mutations occur at codons 12, 13, and 61 and are detected by molecular genetic testing. Recently, an antibody (clone SP174) became available to immunohistochemically pinpoint NRAS Q61R mutant protein. In malignant melanoma, NRAS Q61R mutant-specific immunohistochemistry was shown to be a valuable supplement to traditional genetic testing.Objective.-To evaluate the significance of NRAS Q61R mutant-specific immunohistochemistry in a cohort of colorectal carcinomas.Design.-A total of 1185 colorectal carcinomas were immunohistochemically evaluated with SP174 antibody. NRAS Q61R mutant-specific immunohistochemistry was validated by molecular genetic testing including Sanger sequencing, quantitative polymerase chain reaction (qPCR), and next-generation sequencing.Results.-Twelve tumors showed strong SP174 immunoreactivity. Sanger sequencing detected an identical c.182A.G substitution, causing NRAS Q61R mutation at the protein level, only in 8 SP174-positive cases. These results were confirmed by qPCR study. Subsequently, NRAS wild-type tumors with strong SP174 staining were evaluated by next-generation sequencing and revealed KRAS c.182A.G substitutions predicted to cause KRAS Q61R mutation. Review of colorectal carcinomas with known KRAS and NRAS genotype revealed that none of 62 wildtype tumors or 47 mutants other than Q61R were SP174 positive.Conclusion.-SP174 immunohistochemistry allows sensitive detection of NRAS and KRAS Q61R mutants. However, molecular genetic testing is necessary to determine specifically which RAS gene is mutated.

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NRAS Mutations Are Rare in Colorectal Cancer

Cited by 168 publications

References 49 publications

Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis

SP174, NRAS Q61R Mutant-Specific Antibody, Cross-Reacts With KRAS Q61R Mutant Protein in Colorectal Carcinoma

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