Several clinical trials highlighted the role KRAS exon 2 (codons 12 and 13) mutations as biomarkers of resistance to anti-EGFR monoclonal antibodies cetuximab and panitumumab. 8 RAS as a Predictive Biomarker in Colorectal Cancer Some authors described a possible negative prognostic role for RAS mutations in patients undergoing liver surgery for colorectal cancer metastases, however this data has not been confirmed in a recent series.
WIESE WECHSEL SERIES
In a retrospective series of chemo-refractory patients with metastatic colorectal cancer treated with anti-EGFR monoclonal antibodies a poorer median overall survival has been observed in NRAS and KRAS mutated tumours compared to all wild type ones. The prognostic role of RAS mutations in patients with colorectal cancer remains controversial.Ī negative effect of KRAS mutations have been reported both in the adjuvant and in metastatic setting but no definitive conclusions have been drawn. 5 RAS as a Prognostic Biomarker in Colorectal Cancer 4 Mutations in KRAS or NRAS lead to continuous activation MAPK pathway even if the EGFR is inactivated by drugs. Mutations in KRAS are considered an early event in colorectal carcinogenesis and are maintained during the colorectal cancer development, as demonstrated by the highly concordant rate (almost 95%) in paired primary cancers and metastatic samples, except between primary tumours and metastatic lymph nodes. HRAS mutations represent a negligible event. NRAS mutations are typically mutually exclusive with KRAS mutations. Mutations in NRAS are present in approximately 3% to 5% of colorectal cancer samples particularly in exon 3 codon 61 (60%) and in exon 2 codons 12, 13. The remaining mutations are mainly located in exon 3 codons 59-61 and in exon 4, which includes codons 117 and 146. In colorectal cancer KRAS is mutated in approximately 40% of cases mostly in exon 2 codons 12 (70-80%) and 13 (15-20%). Lastly HRAS mutations are most common in cancers of the head and neck and urinary tract. KRAS mutations are most commonly found in cancers of the pancreas, colon, lung and biliary tract while NRAS mutations are more common in malignant melanoma and haematopoietic system. KRAS is the most commonly mutated isoform in almost 22% of all human cancers, followed by NRAS (8%) and HRAS (3.3%).ĭifferent types of cancer appear to be related to a particular RAS isoform mutation. These mutations set proteins in a permanently activated state (GTP-bound conformation) impairing the ATPase activity.ĭeregulated Ras signalling results in increased proliferation, angiogenesis, and motility, as well as in decreased apoptosis and in altered cellular metabolism. Mutations in RAS are single nucleotide point mutations that more frequently interest the exon 2 codons 12 13 and exon 3 codon 61. 1Īctivating mutations in members of RAS family have been found in 20–25% of human cancers. Once activated, Ras recruits and stimulates number of effectors of complex signalling network pathways including Raf/MEK/ERK mitogen activated protein kinase (MAPK) pathway, the phosphoinositide 3-kinase PI3K/Akt and Ral-GEF proteins. They function as molecular switches transducing extracellular stimuli such as mitogens and differentiation factors to transcription factors and cell cycle proteins in the nucleus in order to promote cell growth, differentiation, proliferation and survival.Įxtracellular stimuli activate firstly transmembrane tyrosine kinase receptors (RTKs) which recruits adaptor proteins that catalyse the hydrolysis of GDP to GTP on Ras. The RAS gene family is widely expressed in mammalian cells where encodes four small (21 kDa), cytoplasmic proteins with GTPase activity: H-Ras, K-Ras4a, K-Ras4b, and N-Ras.
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