Epidermal growth factor receptor (EGFR) family members (EGFR, HER2, HER3 and 
HER4) have been extensively investigated for its possible involvement in cancer 
development and progression. In colorectal cancer (CRC) EGFR family has been 
found frequently over-expressed, thus therapy targeting EGFR has been developed. 
Interestingly, it has been observed that genetic variants in these receptors may 
alter the therapeutic efficacy of EGFR inhibitors. Polymorphic variants in 
members of the EGFR family could influence different biologic activities, such 
as ligands affinity, dimerization efficiency, kinase activity, expression 
levels, with a consequent impact in signalling pathways and cell behaviour. This 
study aimed to verify whether single nucleotide polymorphisms (SNPs) of EGFR 
family members could represent susceptibility factors able to influence the risk 
to develop CRC. Peripheral blood of 70 Italian colon cancer patients and 72 
healthy controls was used as a source of genomic DNA to investigate EGFR, HER2 
and HER3 common non-synonymous SNPs. Genetic association tests were performed to 
verify a possible relationship with CRC. Evidence of genotype association was 
found for the R521K EGFR polymorphism under a dominant mode of inheritance 
(Mid-P=0.031). Genotypes with the variant allele of EGFR R521K SNP confer a risk 
reduction to develop CRC.