BACKGROUND: Tumour growth in colorectal cancer and other solid cancers is 
frequently supported by activating mutations in the epidermal growth factor 
receptor (EGFR) signaling pathway (Patholog Res Int 2011:932932, 2011). 
Treatment of metastatic colorectal cancer with targeted anti-EGFR therapeutics 
such as cetuximab extends survival in only 25% of patients who test wild-type 
for KRAS, while the majority of patients prove resistant (J Clin Oncol 
28(7):1254-1261, 2010).Prediction of cetuximab responsiveness for KRAS wild-type 
colorectal cancers is currently not well defined, and prognostic biomarkers 
would help tailor treatment to individual patients. Somatic mutation of the EGFR 
signalling pathway is a prevalent mechanism of resistance to cetuximab (Nature 
486(7404):532-536, 2012). If the human genome harbours variants that influence 
susceptibility of the EGFR pathway to oncogenic mutation, such variants could 
also be prognostic for cetuximab responsiveness.
METHODS: We assessed whether patient genetic variants may associate with somatic 
mutation of the EGFR signalling pathway. We combined tumour mutation data from 
the Cancer Genome Atlas with matched patient genetic data, and tested for 
germline variants that associate with somatic mutation of the EGFR pathway 
(including EGFR, KRAS, BRAF, PTEN and PIK3CA).
RESULTS: Two single nucleotide polymorphisms (SNPs) located 90 kb upstream of 
the TERT oncogene associated with somatic mutation of the EGFR pathway beyond 
the threshold of genome-wide significance: rs7736074 (P = 4.64 × 10-9) and 
rs4975596 (P = 5.69 × 10-9). We show that allelic variants of rs7736074 and 
rs4975596 modulate TERT expression levels in multiple cancer types, and exhibit 
preliminary prognostic value for response to cetuximab.
CONCLUSIONS: We have identified two germline SNPs that associate with somatic 
mutation of the EGFR pathway, and may be prognostic for cetuximab 
responsiveness. These variants could potentially contribute to a panel of 
prognostic biomarkers for assessing whether metastatic colorectal cancer 
patients are likely to derive benefit from cetuximab treatment. Genotyping of a 
large cohort of cetuximab-treated colorectal cancer patients is called for to 
further clarify the association.