Polymerase Chain Reaction/Pyrosequencing
- Use to detect activating NRAS mutations (codons 12, 13, 61) associated with relative resistance to anti-EGFR therapy in colorectal cancer (CRC).
- Use to predict response to anti-EGFR and MAPK pathway therapies in a variety of malignancies (eg, melanoma and CRC).
Metastatic melanoma is associated with a poor prognosis and poor response to traditional chemotherapy or radiation therapy, as is metastatic CRC. Targeted therapy may play a role in treatment of disseminated disease. Genetic variants guide utilization of targeted therapy for melanoma (BRAF, NRAS, KIT) and CRC (BRAF, KRAS, NRAS). NRAS mutation detection screens for individuals with melanoma who may respond to therapy targeted at downstream genes in the MAPK signaling pathway and screens for individuals with CRC who may show relative resistance to anti-EGFR therapies. (For more information, see the Colorectal Cancer - Predictive Testing for Anti-EGFR Therapy Test Fact Sheet).
GTPase-encoding gene in the RAS/RAF/MAPK pathway
- Majority of activating mutations are in exon 2 (codons 12 and 13) and exon 3 (codon 61).
- NRAS, KRAS, and BRAF mutations are mutually exclusive in individuals with CRC.
- NRAS mutations rarely overlap with BRAF and KIT mutations in melanoma.
- Guidelines suggest extended RAS testing in CRC, which includes codons 12, 13, 59, 61, 117, and 146.
Oncogenic NRAS mutation detected
No oncogenic NRAS mutation detected
- Limit of detection: 10% mutant alleles
- Does not cover extended RAS; oncogenic mutations outside of codons 12, 13, and 61 will not be detected.
- Presence or absence of mutations does not guarantee a response or lack of response to anti-EGFR therapies or therapies targeted at downstream genes in the MAPK signaling pathway.
Domingues B, Lopes JM, Soares P, et al. Melanoma treatment in review. Immunotargets Ther. 2018;7:35-49.
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, colon cancer, Version 2.2021. [Updated: Jan 2021; Accessed: Feb 2021]
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: melanoma: cutaneous, Version 1.2020. [Last update: Jan 2021; Accessed: Feb 2021]
Heppt MV, Siepmann T, Engel J, et al. Prognostic significance of BRAF and NRAS mutations in melanoma: a German study from routine care. BMC Cancer. 2017;17(1):536.
Nagakubo Y, Hirotsu Y, Amemiya K, et al. Accurate detection of KRAS, NRAS and BRAF mutations in metastatic colorectal cancers by bridged nucleic acid-clamp real-time PCR. BMC Med Genomics. 2019;12(1):162.
Dummer R, Schadendorf D, Ascierto PA, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(4):435-445.