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 that cycle between inactive guanosine
diphosphate–bound and active guanosine triphosphate–bound forms. RAS proteins
are central mediators downstream of growth factor receptor signaling and therefore are
critical for cell proliferation, survival, and differentiation. RAS proteins 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
Specific RAS genes are recurrently mutated
in different malignancies. HRAS mutations
are particularly common in salivary gland, urinary tract, upper aerodigestive tract,
cervical, and thyroid (for reviews see Karnoub and Weinberg 2008 and
and Bollag 2007).
Figure 1. Simplified schematic of RAS signaling pathways.
Growth factor binding to receptor tyrosine
kinases results in RAS activation. The letter
"K" within the schema denotes the tyrosine kinase
Suggested Citation: Espinosa, A., J. Gilbert, J. Fagin. 2015. HRAS. My
Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/hras/?tab=0
(Updated December 7).
Last Updated: December 7, 2015
HRAS in Thyroid Cancer
RAS mutations (HRAS, NRAS and KRAS)
are found in all epithelial thyroid malignancies. The frequency of HRAS mutations in thyroid carcinomas is 4% (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
RAS mutations are identified in 10–20%
of papillary carcinomas, 40–50% of follicular carcinomas and 20–40% of poorly
differentiated and anaplastic carcinomas (Nikiforov
Several studies have found RAS mutations
to be prevalent in follicular carcinomas, follicular variant papillary carcinomas and poorly
differentiated thyroid carcinomas. Ras mutant 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.
HRAS mutations are also found in ~25% of
sporadic medullary thyroid cancers (Moura et al. 2011).
Frequencies of Specific Mutations
||Amino Acid Position
||Amino Acid Change
||Frequency Among HRAS-Mutated Thyroid Cancer (COSMIC)
Suggested Citation: Espinosa, A., J. Gilbert, J. Fagin. 2014. HRAS in Thyroid
Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/hras/
(Updated August 8).
Last Updated: August 8, 2014
My Cancer Genome has released its new and improved cancer clinical trials search tool on our
beta website. Please visit beta.padiracinnovation.org
to check it out!