HRAS
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 1).
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 Schubbert, Shannon, 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 domain.
Related Pathways
Contributors: Allan V. Espinosa, M.D., Jill Gilbert, M.D., James Fagin, M.D.
Suggested Citation: Espinosa, A., J. Gilbert, J. Fagin. 2015. HRAS. My Cancer Genome https://www.mycancergenome.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 2011).
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 2011).
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. 2003).
HRAS mutations are also found in ~25% of sporadic medullary thyroid cancers (Moura et al. 2011).
Table 1. Frequencies of Specific
Mutations.
Gene |
Exon |
Amino Acid Position |
Amino Acid Change |
Nucleotide Change |
Frequency Among HRAS-Mutated Thyroid Cancer (COSMIC) |
HRAS |
2 |
12 |
p.G12R |
c.34G>C |
≤1% |
p.G12V |
c.35G>T |
24% |
13 |
p.G13C |
c.37G>T |
1.5% |
p.G13R |
c.37G>C |
11% |
3 |
61 |
p.Q61R |
c.182A>G |
30% |
Contributors: Allan V. Espinosa, M.D., Jill Gilbert, M.D., James Fagin, M.D.
Suggested Citation: Espinosa, A., J. Gilbert, J. Fagin. 2014. HRAS in Thyroid Cancer. My Cancer Genome https://www.mycancergenome.org/content/disease/thyroid-cancer/hras/ (Updated August 8).
Last Updated: August 8, 2014
HRAS c.37G>C (G13R) Mutation in Thyroid Cancer
Properties |
Location of mutation
|
P-loop region of the G domain (Exon 2; Ensembl; Schubbert, Shannon, and Bollag 2007) |
Frequency of HRAS mutations in thyroid cancer |
4% (COSMIC) |
Frequency of G13R mutations in HRAS-mutated thyroid cancer |
11% (COSMIC) |
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 G13R mutation results in an amino acid substitution at position 13 in HRAS, from a glycine (G) 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. 2013).
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 al. 2009).
Reference |
Study Type / Phase |
Line of Treatment |
Treatment Agent |
Mutation Status |
# Patients in Study |
Response Rate |
PFS (months) |
OS (months unless otherwise indicated) |
Kloos et al. 2009 |
Phase II |
1st line or greater |
Sorafenib |
14 BRAF V600E 3 K601E |
33 PTC (of these, 28 were included in the response assessments) without previous chemotherapy |
15% |
15 |
23 (Kaplan-Meier estimate of median OS) |
8 PTC with previous chemotherapy |
13% |
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 |
0% |
4.5 (Kaplan-Meier estimate of median PFS) |
24.2 (Kaplan-Meier estimate of median OS) |
4 ATC |
0% |
|
|
Hoftijzer et al. 2009 |
Phase II |
1st line or greater |
Sorafenib |
9 BRAF V600E 1 BRAF V600E + PIK3CA mutation 2 NRAS mutations 1 KRAS mutation |
32 DTC |
25% |
13.3 |
|
NOTES: ATC = anaplastic thyroid cancer, DTC = differentiated thyroid cancer, FTC = follicular thyroid cancer, OS = overall survival, PFS = progression-free survival, PTC = papillary thyroid cancer.
Contributors: Allan V. Espinosa, M.D., Jill Gilbert, M.D., James Fagin, M.D.
Suggested Citation: Espinosa, A., J. Gilbert, J. Fagin. 2015. HRAS c.37G>C (G13R) Mutation in Thyroid Cancer. My Cancer Genome https://www.mycancergenome.org/content/disease/thyroid-cancer/hras/306/ (Updated February 17).
Last Updated: February 17, 2015
My Cancer Genome has released its new and improved cancer clinical trials search tool on our beta website. Please visit beta.mycancergenome.org to check it out!