• What is KRAS?
  • KRAS in Thyroid Cancer
  • KRAS c.35G>A (G12D)
  • Clinical Trials


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 1).

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.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. KRAS. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/kras/?tab=0 (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 2011).

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. 2003).

Table 1. Frequencies of Specific Mutations.
Gene Exon Amino Acid Position Amino Acid Change Nucleotide Change Frequency Among NRAS-Mutated Thyroid Cancer (COSMIC)
KRAS 2 12 p.G12C c.34G>T 12%
p.G12R c.34G>C 4%
p.G12S c.34G>A 10.6%
p.G12A c.35G>C 3.3%
p.G12D c.35G>A 25.2%
p.G12V c.35G>T 6.6%
13 p.G13R c.37G>C 1.3%
p.G13S c.37G>A 6.6%
p.G13D c.38G>A 16%
3 61 p.Q61K c.181C>A 2%
p.Q61L c.182A>T 1.3%
p.Q61P c.182A>C 2%
p.Q61R c.182A>G 4.6%
4 146 p.A146V c.437C>T 1.3%

Contributors: Allan V. Espinosa, M.D., Jill Gilbert, M.D., James Fagin, M.D.

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

KRAS c.35G>A (G12D) Mutation in Thyroid Cancer

Location of mutation P-loop region of the G domain (Exon 2; Ensembl; Schubbert, Shannon, and Bollag 2007)
Frequency of KRAS mutations in thyroid cancer 3% (COSMIC)
Frequency of G12D mutations in KRAS-mutated thyroid cancer 25.2% (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 G12D mutation results in an amino acid substitution at position 12 in KRAS, from a glycine (G) to an aspartic acid (D). The role of KRAS 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. KRAS c.35G>A (G12D) Mutation in Thyroid Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/kras/34/ (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.padiracinnovation.org to check it out!

Disclaimer: The information presented at padiracinnovation.org is compiled from sources believed to be reliable. Extensive efforts have been made to make this information as accurate and as up-to-date as possible. However, the accuracy and completeness of this information cannot be guaranteed. Despite our best efforts, this information may contain typographical errors and omissions. The contents are to be used only as a guide, and health care providers should employ sound clinical judgment in interpreting this information for individual patient care.