We evaluated the biological impact, in patients with CRC, of germline or somatic genetic variations occurring within the
EGFR 3′UTR polyA tract. First, we observed that the
EGFR polyA allelic frequency in 429 CRC patients was similar to that observed in a control sample. Considering the genetic heterogeneity of CRC, we constructed the patient sample with 4 different groups selected or not on the basis of age of tumor onset or familial history or MSI status. The first group, composed of 179 CRC patients unselected on age of tumor onset or familial history, has been, on purpose, enriched in patients with MSI tumors, which had been shown in the original study of Yuan et al. [
20] to exhibit a high rate of somatic
EGFR mutations. The second group, constituted of 62 patients without detectable mutations within MMR or adenomatous polyposis genes but whose personal or familial history was suggestive of an increased genetic risk, was analyzed to determine whether or not the
EGFR polyA polymorphism could act as a genetic risk factor for CRC. We also analyzed a series of 100 patients with Lynch syndrome to evaluate if the
EGFR polyA polymorphism could act as a modifier risk factor in patients harboring a MMR gene mutation. Finally, the last group corresponded to 88 unselected sporadic CRC. In none of these groups, could a significant difference in
EGFR allelic frequencies with controls be detected, suggesting that the
EGFR 3′UTR polyA polymorphism does not modify the genetic risk for CRC. It could be argued that the size of the patient sample or that of the different groups was insufficient to detect a significant difference, but the allelic frequency between patients and controls were remarkably similar (Table
1). We also screened for somatic mutations of the
EGFR polyA tract in the group of 179 CRC patients, whose genotypes had been characterized and found that somatic mutations, corresponding to deletions, were detected in 59% of the 80 MSI tumors but in none of the 99 MSS tumors. This confirms, on a larger sample, the results observed by Baranovskaya et al. [
28], Yuan et al. [
20] and Deqin et al. [
29] who had reported, from a series of 40, 16 and 36 MSI CRC a mutation detection rate of 92.5%, 69% and 81%, respectively. Nevertheless, we obtained two results which argue against an oncogenic effect of these somatic mutations: first, the adenine deletions occurring in the 3′UTR polyA tract did not show any specificity with respect to
EGFR since they could also be observed in 2 others genes not involved in CRC:
RAB31 and
ATP6V1G1; therefore the high frequency of somatic
EGFR polyA mutations reported in MSI tumors by other studies and this work probably reflects a particular sensitivity of mononucleotide tracts to defective DNA mismatch repair system, as recently reported for the polyT(20) tract of the
MT1X gene [
30]; second, we found that these mutations did not result into a significant increase of EGFR expression. In a study focused on the CA repeat located within the
EGFR first intron, Baranovskaya et al. [
28] have also observed, in agreement with our results, that EGFR expression was decreased in MSI CRC. In a sample composed of 16 MSI endometrial adenocarcinomas, Deqin et al. [
29] have reported that tumors with
EGFR polyA deletions exhibit a slight (1.6) but nevertheless not significant increase of EGFR expression, as compared to that without mutations. Our observation contrasts with results obtained by Yuan et al. [
20]. Indeed, these authors had reported, in colon MSI cancer cell lines, that a deletion within the
EGFR polyA tract increases
in vitro the EGFR mRNA stability. In CRC patients, we observed that, in the majority of the tumor samples with somatic
EGFR mutations (91%), the total level of EGFR mRNA was not increased but, in contrast, decreased and this result was obtained using two independent methods. The discrepancy observed between both studies highlights the need to confirm in clinical samples results previously obtained with cell lines which may not be representative of the complexity of gene regulation in clinical samples, because of the genetic drift occurring during
in vitro culture.