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KRAS
KRas proto-oncogene, GTPase
The KRAS gene encodes the K-Ras protein, a vital cellular switch involved in relaying signals that regulate cell growth, division, and differentiation, with mutations frequently implicated in cancer development. KRAS is a proto-oncogene that plays a critical role in normal cellular processes by controlling communication pathways within cells.
KRAS is located on the short (p) arm of chromosome 12, at band 12p12.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The KRAS gene, also known as the KRas proto-oncogene, GTPase, is a crucial component of cell signalling networks. It provides the genetic blueprint for the K-Ras protein, a member of the Ras family of small GTPases. This protein acts as an intracellular messenger, transmitting signals from outside the cell to the nucleus, thereby influencing fundamental cellular activities like growth, division, and maturation. Because of its pivotal role in cell regulation, alterations in the KRAS gene are frequently studied in relation to various human diseases.
The KRAS gene is classified as a proto-oncogene, meaning that in its normal state, it supports healthy cell function. However, when specific changes occur in the gene, it can transform into an oncogene, potentially leading to uncontrolled cell growth and contributing to cancer development. Comprehensive understanding of KRAS function and its variants is essential for both diagnostics and therapeutic strategies.
What the gene does
The central role of the KRAS gene lies in encoding the K-Ras protein, a key player in the RAS/MAPK signalling pathway. This pathway is a complex network that communicates extracellular signals to the cell's nucleus, effectively dictating cellular behaviour. The K-Ras protein functions as a molecular switch through its ability to bind to guanosine triphosphate (GTP) and hydrolyse it to guanosine diphosphate (GDP).
When K-Ras binds to GTP, it adopts an active conformation, enabling it to relay signals that promote cell growth, proliferation, and differentiation. Conversely, when K-Ras hydrolyses GTP to GDP, it switches to an inactive state, ceasing signal transmission. This GTPase activity is crucial for the precise regulation of cellular responses. Therefore, the K-Ras protein ensures that cells only respond to appropriate signals when required.
KRAS is one of three genes in the Ras family (alongside HRAS and NRAS), all of which contribute to orchestrating cell division, cell differentiation, and apoptosis (programmed cell death). Dysfunction, particularly overactivity, of the K-Ras protein due to genetic changes can lead to persistent signal activation, which overrides normal cellular controls and fosters the uncontrolled cell growth characteristic of cancer.
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Chromosome location
The KRAS gene is situated on the short arm (p) of chromosome 12. Its precise location is designated as 12p12.1. This specific genomic address signifies the gene's position within the intricate structure of the human genome. Genes located in this region are often involved in various biological processes, and their alteration can have diverse phenotypic consequences.
Protein structure
The K-Ras protein is composed of 189 amino acids. Its functional activity is mediated by distinct structural regions. A critical functional segment is the Effector region, spanning amino acids 32-40. This region is vital for interacting with downstream signalling molecules, enabling the K-Ras protein to transmit signals within the cell. Another significant part is the Hypervariable region, located at amino acids 166-185. This region contributes to the specific localisation of the K-Ras protein within the cell membrane and can influence its interactions with other proteins.
Key variants
Variants in the KRAS gene can encompass a range of genetic changes, from single nucleotide alterations to larger rearrangements. These variants can affect the K-Ras protein's function, often leading to its constitutive activation - meaning it remains in an 'on' state regardless of external signals. Such sustained activation can disrupt the delicate balance of cell growth and division.
Germline variants, which are present in all cells of the body, can be inherited and are associated with certain developmental syndromes. Somatic variants, conversely, are acquired during a person's lifetime and are typically found only in specific cells, such as those within a tumour. The functional consequences of KRAS variants are extensively studied, particularly in oncology, where they can influence disease progression and treatment responses.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.101C>T | p.Pro34Leu | Pathogenic | ★★★☆ | Noonan syndrome |
c.173C>T | p.Thr58Ile | Pathogenic | ★★★☆ | Noonan syndrome |
c.178G>C | p.Gly60Arg | Pathogenic | ★★★☆ | Cardio-facio-cutaneous syndrome |
c.40G>A | p.Val14Ile | Pathogenic | ★★★☆ | RASopathy |
c.458A>T | p.Asp153Val | Pathogenic | ★★★☆ | RASopathy |
c.65A>G | p.Gln22Arg | Pathogenic | ★★★☆ | RASopathy |
c.15A>T | p.Lys5Asn | Pathogenic | ★★★☆ | RASopathy |
c.101C>G | p.Pro34Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Cardiofaciocutaneous syndrome 2 |
c.108A>G | p.Ile36Met | Pathogenic/Likely pathogenic | ★★☆☆ | RASopathy |
c.204G>C | p.Arg68Ser | Pathogenic/Likely pathogenic | ★★☆☆ | RASopathy |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the KRAS gene are associated with a spectrum of conditions, reflecting its fundamental role in cellular regulation. Germline variants in KRAS are an infrequent cause of cardiofaciocutaneous syndrome, a developmental disorder characterised by distinctive facial features, heart defects, and skin abnormalities. KRAS variants are also implicated in Noonan syndrome and autoimmune lymphoproliferative syndrome.
Somatic or mosaic KRAS changes are observed in conditions such as Linear sebaceous naevus syndrome. Furthermore, KRAS variants are well-recognised drivers in the development of various cancers, including cholangiocarcinoma and core binding factor acute myeloid leukaemia, where they contribute to uncontrolled cell proliferation and tumourigenesis.
Inheritance pattern
Conditions caused by pathogenic KRAS variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the KRAS gene is widely recognised for its clinical significance and is included on numerous NHS Genomic Medicine Service (GMS) national genomic test directories, indicating its importance for diagnostic and management pathways. KRAS is listed with a 'green' status on PanelApp UK for a broad range of conditions, signifying strong evidence for its gene-disease association. These include panels for Adult solid tumours cancer susceptibility, Childhood solid tumours, and Childhood solid tumours cancer susceptibility, highlighting its role in inherited cancer risk.
Additionally, KRAS is found on panels relating to developmental disorders and rare syndromes, such as RASopathies, Foetal anomalies (R21), Intellectual disability, Monogenic short stature (R453), Paediatric or syndromic cardiomyopathy (R135), and Rare syndromic craniosynostosis or isolated multisuture synostosis (R100). Its inclusion on panels like Mosaic skin disorders - Deep sequencing (R327) and Pigmentary skin disorders further demonstrates its involvement in a diverse array of conditions relevant to clinical genomics in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
For individuals with KRAS variants, general healthy lifestyle recommendations typically align with those for the broader population, focusing on overall well-being. A balanced diet rich in fruits, vegetables, and whole grains, combined with regular physical activity, is generally encouraged. Maintaining a healthy weight and avoiding smoking and excessive alcohol consumption are also beneficial for general health.
While research continues to explore the interplay between lifestyle factors and genetic predispositions, there is no specific lifestyle intervention conclusively proven to prevent the onset or progression of conditions directly related to KRAS variants. Lifestyle choices can broadly support health, but should not be considered a substitute for medical management or genetic counselling.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent, treat, or mitigate the effects of conditions associated with KRAS variants. General nutritional supplements might be considered for overall health based on individual dietary needs, but these should always be discussed with a healthcare provider.
It is important to understand that no supplement can correct genetic mutations or alter gene function. Any decisions regarding supplement intake should be made in consultation with a doctor or a registered dietitian to ensure safety and appropriateness, particularly given potential interactions with medications or existing health conditions.
Frequently asked questions
What is the main function of the KRAS gene?
The KRAS gene provides instructions for the K-Ras protein, which acts as a molecular switch within cells. It relays signals from outside the cell to the nucleus, regulating critical processes like cell growth, division, and differentiation.
How does the K-Ras protein act as a switch?
The K-Ras protein functions by binding to GTP (guanosine triphosphate) to turn 'on' and transmit signals. It turns 'off' when it converts GTP to GDP (guanosine diphosphate), stopping signal transmission. This on/off mechanism precisely controls cellular responses.
What types of health conditions are associated with KRAS variants?
Variants in KRAS are linked to various conditions, including developmental disorders like cardiofaciocutaneous syndrome and Noonan syndrome. They are also frequently implicated in several types of cancer, such as cholangiocarcinoma and acute myeloid leukaemia, where they contribute to uncontrolled cell growth.
What is the difference between germline and somatic KRAS variants?
Germline variants are inherited and present in all cells of the body from birth, potentially leading to developmental syndromes. Somatic variants are acquired during a person's lifetime, typically found only in specific cells like tumour cells, and are not inherited.
Is KRAS considered an oncogene?
KRAS is a proto-oncogene, meaning it normally promotes healthy cell growth. However, when mutated, it can become an oncogene, which has the potential to drive uncontrolled cell proliferation and contribute to cancer development.
References
- Addissie YA, Kotecha U, Hart RA. Craniosynostosis and Noonan syndrome with KRAS mutations: Expanding the phenotype with a case report and review of the literature. American journal of medical genetics. Part A. 2015. PMID: 26249544
- Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014. PMID: 25079552
- Karachaliou N, Mayo C, Costa C. KRAS mutations in lung cancer. Clinical lung cancer. 2013. PMID: 23122493
- Gremer L, Merbitz-Zahradnik T, Dvorsky R. Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders. Human mutation. 2011. PMID: 20949621
- Tidyman WE, Rauen KA. Mutational and functional analysis in human Ras/MAP kinase genetic syndromes. Methods in molecular biology (Clifton, N.J.). 2010. PMID: 20812000
- Romano AA, Allanson JE, Dahlgren J. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010. PMID: 20876176
- Zenker M, Lehmann K, Schulz AL. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. Journal of medical genetics. 2007. PMID: 17056636
- Nava C, Hanna N, Michot C. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. Journal of medical genetics. 2007. PMID: 17704260
- Schubbert S, Bollag G, Lyubynska N. Biochemical and functional characterization of germ line KRAS mutations. Molecular and cellular biology. 2007. PMID: 17875937
- Quezada E, Gripp KW. Costello syndrome and related disorders. Current opinion in pediatrics. 2007. PMID: 18025929
- Furukawa T, Sunamura M, Horii A. Molecular mechanisms of pancreatic carcinogenesis. Cancer science. 2006. PMID: 16367914
- Niihori T, Aoki Y, Narumi Y. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nature genetics. 2006. PMID: 16474404
- Schubbert S, Zenker M, Rowe SL. Germline KRAS mutations cause Noonan syndrome. Nature genetics. 2006. PMID: 16474405
- Pérez-Mancera PA, Tuveson DA. Physiological analysis of oncogenic K-ras. Methods in enzymology. 2006. PMID: 16757361
- Carta C, Pantaleoni F, Bocchinfuso G. Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype. American journal of human genetics. 2006. PMID: 16773572
- Bell DA. Origins and molecular pathology of ovarian cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2005. PMID: 15761464
- Castagnola P, Giaretti W. Mutant KRAS, chromosomal instability and prognosis in colorectal cancer. Biochimica et biophysica acta. 2005. PMID: 16112461