EGFR Polymorphisms Linked to Efficacy of Lung Cancer Chemotherapy

Human EGF is a 6045 Da protein with 53 amino acid residues and three intramolecular disulfide bonds.

EGF acts by binding with high affinity to EGFR on the cell surface and stimulating the intrinsic protein-tyrosine kinase activity of the receptor. The tyrosine kinase activity in turn initiates a signal transduction cascade, which results in a variety of biochemical changes within the cell--a rise in intracellular calcium levels, increased glycolysis and protein synthesis, and increases in the expression of certain genes including the gene for EGFR--that ultimately lead to DNA synthesis and cell proliferation.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) measured how often three EGFR polymorphisms (the length of a repeat sequence called CA-SSR1, and two single nucleotide variations [SNPs])--all of which probably affect how much protein is made from the EGFR gene--occurred in normal tissue from 250 individuals and in NSCLC tissue from 556 East Asians and individuals of European descent. They also looked for mutations in the EGFR tyrosine kinase and allelic imbalance in the tumors, and then determined which genetic variations and alterations tended to occur together in people with the same ethnicity.

The researchers reported in the April 23, 2007, online edition of the journal Public Library of Science Medicine that among many associations, shorter alleles of CA-SSR1 and the minor forms of the two SNPs occurred less often in East Asians than in individuals of European descent. They also confirmed that EGFR kinase mutations were more common in NSCLCs in East Asians than in European-descent individuals. Furthermore, mutations occurred more often in tumors with allelic imbalance. In tumors where there was allelic imbalance and an EGFR mutation, the mutant allele was amplified more often than the wild-type allele.

These results suggest that because of the polymorphisms in the EGFR gene commonly seen in East Asians, people from this ethnic group make less EGFR protein than people from other ethnic groups. This would explain why, if a threshold level of EGFR is needed to drive cells towards malignancy, East Asians have a high frequency of amplified EGFR tyrosine kinase mutations in their tumors--mutation followed by amplification would be needed to activate EGFR signaling.

"Genetic differences may help explain why so many Asian women who never smoked develop lung cancer,” said senior author Dr. Adi Gazdar, professor of pathology at the University of Texas Southwestern Medical Center.


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University of Texas Southwestern Medical Center