In a study by Gon?alves et al[52], tumor tissue samples from pati

In a study by Gon?alves et al[52], tumor tissue samples from patients with mCRC treated with irinotecan/cetuximab were analyzed and the EGFR exon 13 variant (R521K) was associated with better PFS and OS. Indeed, the above-mentioned SNP was observed in 11 of the 21 patients who achieved an objective response or stable selleck screening library disease and in only 1 of the 11 patients who had disease progression (P = 0.02). In addition, in a third study it has been correlated with longer OS in stage II and III patients after surgery[54]. Nevertheless, in the study by Graziano et al[46], in mCRC patients treated with irinotecan/cetuximab, this SNP was not found to be associated with response to treatment or OS.

Epidermal growth factor (EGF) 5��-UTR 61A>G SNP EGF is one of the natural ligands of EGFR and upon binding it may activate DNA synthesis and cellular proliferation and it has been shown to stimulate mitosis in epidermal cells. The EGF protein is encoded by the EGF gene which is located on chromosome 4q25-27 and contains 24 exons[55]. The only functional polymorphism of the EGF gene was identified in 2002 and is located 61 base pairs (bp) downstream of the EGF promoter, in the 5��-untranslated region of the gene. It consists of a substitution of guanine (G) for adenine (A), (61��>G), it modulates the transcription of EGF and it has been correlated in vitro and in vivo with elevated serum levels[56,57]. Primarily, it has been studied in patients with melanoma and glioblastoma multiforme, but it has also been detected in 44% of the European white population[56,57].

In the study by Graziano et al[46], in 110 patients with mCRC treated with irinotecan and cetuximab, the EGF 61G/G allele was associated with a greater OS (HR, 0.44; 95% CI: 0.23-0.84, P = 0.01) but not with greater response rate, PFS and skin toxicity. The exact mechanism by which this SNP is associated with greater survival is not yet known, but, in experimental models and with different concentrations, EGF has been shown to induce apoptosis and growth inhibition rather than the usual growth-promoting effect[58]. In addition, in another study with 133 mCRC patients treated Anacetrapib with cetuximab monotherapy the EGF 61G/G allele was associated with greater PFS (P = 0.04)[47]. In contrast, in the Zhang et al[59] study with mCRC treated with cetuximab, the EGF 61A/A allele was correlated favorably with an increased OS (median OS 15 mo for EGF 61A/A, 2.3 mo for EGF 61G/G and 5.7 mo for the heterozygote EGF 61��/G). Cyclin D1 exon 4 870A>G SNP Cyclin D1 is a cell cycle regulatory protein whose upregulation has been associated with increased proliferation and poor clinical outcome in a number of neoplasms including CRC[60].

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