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
HRAS c.182A>G (Q61R) Mutation in Thyroid Cancer
|Location of mutation
||Switch II region of the G domain (Exon 3, coding exon 2; Ensembl; Schubbert,
Shannon, and Bollag 2007)
|Frequency of HRAS mutations in
|Frequency of Q61R mutations in
HRAS-mutated thyroid cancer
|Implications for Targeted Therapeutics
|Response to MEK inhibitor in combination with radioactive iodine therapy
||May confer increased sensitivitya
|Response to sorafenib
||Unknown at this timeb
The Q61R mutation results in an amino acid substitution at position 61 in
HRAS, from a glutamine (Q) to an arginine (R). The role of HRAS mutations for selecting/prioritizing anti-cancer
treatment, including cytotoxic chemotherapy and targeted agents, is unknown at this time.
a A clinical trial showed that the MEK inhibitor selumetinib increased
responses to radioactive iodine in patients with radioactive iodine–refractory
metastatic thyroid cancer, particularly in RAS-mutated tumors (Ho et al.
2013). In this trial, 5 of 5 patients with NRAS-mutated tumors achieved greater
radioiodine incorporation into metastatic sites after selumetinib. Partial responses to
therapeutic radioiodine were observed in 4 of the patients, and stable disease was observed
in the 5th (Ho et al.
b While sorafenib has had beneficial effects for patients with metastatic
MTC and DTC, it is unknown whether mutation
status affects sensitivity to sorafenib (Hoftijzer et al.
2009, Kloos et
||Study Type / Phase
||Line of Treatment
||# Patients in Study
||OS (months unless otherwise indicated)
et al. 2009
||1st line or greater
||14 BRAF V600E
|33 PTC (of these, 28 were included in the response assessments) without previous
||23 (Kaplan-Meier estimate of median OS)
|8 PTC with previous chemotherapy
||10 (Kaplan-Meier estimate of median PFS)
||37.5 (Kaplan-Meier estimate of median OS)
|BRAF, HRAS, and NRAS wild type
||11 HTC or FTC
||4.5 (Kaplan-Meier estimate of median PFS)
||24.2 (Kaplan-Meier estimate of median OS)
||1st line or greater
||9 BRAF V600E
1 BRAF V600E + PIK3CA mutation
1 KRAS mutation
NOTES: ATC = anaplastic thyroid cancer, DTC = differentiated thyroid cancer, FTC = follicular
thyroid cancer, OS = overall survival, PFS = progression-free survival, PTC = papillary thyroid
Suggested Citation: Espinosa, A., J. Gilbert, J. Fagin. 2017. HRAS c.182A>G
(Q61R) Mutation in Thyroid Cancer. My
Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/hras/307/
(Updated January 16).
Last Updated: January 16, 2017
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