Three different human RAS genes have been
identified: KRAS (homologous to the oncogene
from the Kirsten rat sarcoma virus), HRAS (homologous to the oncogene from the Harvey rat sarcoma virus), and NRAS
(first isolated from a human neuroblastoma). The different RAS genes are highly homologous but functionally distinct;
the degree of redundancy remains a topic of investigation (reviewed in Pylayeva-Gupta et
al. 2011). RAS proteins are small GTPases which cycle between inactive guanosine
diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound forms. RAS proteins
are central mediators downstream of growth factor receptor signaling and therefore are
critical for cell proliferation, survival, and differentiation. RAS can activate several
downstream effectors, including the PI3K-AKT-mTOR pathway, which is involved in cell
survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation (Figure
RAS has been implicated in the pathogenesis of several cancers. Activating mutations within the RAS gene result in constitutive activation of
the RAS GTPase, even in the absence of growth factor signaling. The result is a sustained
proliferation signal within the cell.
Specific RAS genes are recurrently mutated
in different malignancies. KRAS mutations
are particularly common in colon cancer, lung cancer, and pancreatic cancer (for reviews see
Karnoub and Weinberg
2008 and Schubbert,
Shannon, and Bollag 2007).
Figure 1. Schematic of the MAPK and PI3K
pathways. Growth factor binding to receptor
tyrosine kinase results in activation of
the MAPK signaling pathway
(RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema
denotes the tyrosine kinase domain.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. KRAS. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
KRAS in Thyroid Cancer
RAS mutations (HRAS,
NRAS and KRAS) are found in all epithelial thyroid malignancies. The frequency
of KRAS mutations in thyroid carcinomas is 3% (COSMIC).
While most non-thyroid cancers have mutations in KRAS codons 12 and 13, most thyroid tumors
have been found to have mutations in NRAS codon 61 and HRAS codon 61 (Nikiforov
Several studies have found RAS mutations to
be prevalent in follicular carcinomas, follicular variant papillary carcinomas and poorly
differentiated thyroid carcinomas. Ras-mutated thyroid cancers are prone to distant
metastases to lung and bone rather than to locoregional lymph node involvement.
RAS mutations are the second most common
mutation detected in fine-needle
aspiration (FNA) biopsy samples from thyroid nodules and have a 74–88% positive
predictive value for malignancy (Bhaijee and Nikiforov 2011).
Of note, RAS point mutations are mutually
exclusive with other thyroid mutations
such as BRAF, RET/PTC, or TRK rearrangements (Kimura et al.
2003) in papillary thyroid cancers . In follicular carcinomas, RAS mutations are
mutually exclusive with PAX8-PPARG rearrangements (Nikiforova et al.
Frequencies of Specific Mutations
||Amino Acid Position
||Amino Acid Change
||Frequency Among NRAS-Mutated Thyroid Cancer (COSMIC)
Suggested Citation: Espinosa, A., J. Gilbert, J. Fagin. 2015. KRAS in Thyroid
Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/kras/
(Updated February 17).
Last Updated: February 17, 2015
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