Genetic Abnormalities – KRAS

Approximately 15-25% of patients with non-small cell lung cancer (NSCLC) with adenocarcinomas have mutations on the KRAS gene. KRAS mutations are found in tumors among both smokers and non-smokers, and they are less common among patients of East Asian descent. KRAS mutations are also common in colon and pancreatic cancers.1,2

The Role of KRAS

The KRAS gene produces a protein called K-Ras that is involved in regulating cell division. The protein relays signals to the cell about cell growth, division, maturation, or differentiation.3

The KRAS gene is in a class of genes called oncogenes. Damage to these oncogenes, or mutations, has the potential to change healthy cells into cancer cells. When there is a mutation to KRAS gene, the malignant (cancerous) cells are activated to divide and multiply.1-3

Mutations to KRAS

In the majority of cases, KRAS mutations generally occur on their own without other mutations, such as EGFR or ALK, and the presence of KRAS mutation defines a unique subset of NSCLC. At this time, it is unclear whether KRAS mutation may be used as a predictive or prognostic factor, and few clinical studies have been completed to determine how KRAS mutation may impact therapeutic options. Some data suggests that the presence of KRAS mutation is associated with a resistance to treatments that target EGFR, such as Tarceva (erlotinib), Iressa (gefitinib), and Gilotrif (afatinib). There are currently no direct therapies that target KRAS.2,4

Specific KRAS Mutations

There are several different mutations that researchers have identified with KRAS, although the therapeutic value of each has yet to be determined:

KRAS c.34G>T (G12C)

This mutation makes up 42% of all KRAS mutations in lung adenocarcinomas and results in an amino acid substitution from a glycine (G) to a cysteine (C).

KRAS c.34G>C (G12R)

This mutation occurs in 2% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glycine (G) to an arginine (R).

KRAS c.34G>A (G12S)

This mutation occurs in 5% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glycine (G) to a serine (S).

KRAS c.35G>C (G12A)

This mutation occurs in 7% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glycine (G) to an alanine (A).

KRAS c.35G>A (G12D)

This mutation occurs in 17% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glycine (G) to an aspartic acid (D).

KRAS c.35G>T (G12V)

This mutation makes up 20% of all KRAS mutations in lung adenocarcinomas and results in an amino acid substitution from a glycine (G) to a valine (V).

KRAS c.37G>T (G13C)

This mutation makes up 3% of all KRAS mutations in lung adenocarcinomas and results in an amino acid substitution from a glycine (G) to a cysteine (C).

KRAS c.37G>C (G13R)

This mutation occurs in less than 1% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glycine (G) to an arginine (R).

KRAS c.37G>A (G13S)

This mutation occurs in less than 1% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glycine (G) to a serine (S).

KRAS c.38G>C (G13A)

This mutation occurs in less than 1% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glycine (G) to an alanine (A).

KRAS c.38G>A (G13D)

This mutation occurs in 2% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glycine (G) to an aspartic acid (D).

KRAS c.181C>A (Q61K)

This mutation occurs in less than 1% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glutamine (Q) to a lysine (K).

KRAS c.182A>T (Q61L)

This mutation occurs in less than 1% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glutamine (Q) to a leucine (L).

KRAS c.182A>G (Q61R)

This mutation occurs in less than 1% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glutamine (Q) to an arginine (R).

KRAS c.183A>C (Q61H)

This mutation occurs in less than 1% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glutamine (Q) to a histidine (H).

KRAS c.183A>T (Q61H)

This mutation occurs in less than 1% of all KRAS-mutated lung adenocarcinomas, resulting in an amino acid substitution from a glutamine (Q) to a histidine (H).2

Written by: Emily Downward | Last reviewed: January 2017.
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