Programa de Farmacologia, Coordenação de Pesquisa, Instituto Nacional do Câncer, Rua André Cavalcanti, 37, 3° andar CEP: 20231-050, Rio de Janeiro, RJ, Brazil.
BMC Cancer. 2014 Mar 14;14:190. doi: 10.1186/1471-2407-14-190.
The epidermal growth factor receptor (EGFR) is differently expressed in breast cancer, and its presence may favor cancer progression. We hypothesized that two EGFR functional polymorphisms, a (CA)n repeat in intron 1, and a single nucleotide polymorphism, R497K, may affect EGFR expression and breast cancer clinical profile.
The study population consisted of 508 Brazilian women with unilateral breast cancer, and no distant metastases. Patients were genotyped for the (CA)n and R497K polymorphisms, and the associations between (CA)n polymorphism and EGFR transcript levels (n = 129), or between either polymorphism and histopathological features (n = 505) were evaluated. The REMARK criteria of tumor marker evaluation were followed.
(CA)n lengths ranged from 14 to 24 repeats, comprehending 11 alleles and 37 genotypes. The most frequent allele was (CA)16 (0.43; 95% CI = 0.40-0.46), which was set as the cut-off length to define the Short allele. Variant (CA)n genotypes had no significant effect in tumoral EGFR mRNA levels, but patients with two (CA)n Long alleles showed lower chances of being negative for progesterone receptor (ORadjusted = 0.42; 95% CI = 0.19-0.91). The evaluation of R497K polymorphism indicated a frequency of 0.21 (95% CI = 0.19 - 0.24) for the variant (Lys) allele. Patients with variant R497K genotypes presented lower proportion of worse lymph node status (pN2 or pN3) when compared to the reference genotype Arg/Arg (ORadjusted = 0.32; 95% CI = 0.17-0.59), which resulted in lower tumor staging (ORadjusted = 0.34; 95% CI = 0.19-0.63), and lower estimated recurrence risk (OR = 0.50; 95% CI = 0.30-0.81). The combined presence of both EGFR polymorphisms (Lys allele of R497K and Long/Long (CA)n) resulted in lower TNM status (ORadjusted = 0.22; 95% CI = 0.07-0.75) and lower ERR (OR = 0.25; 95% CI = 0.09-0.71). When tumors were stratified according to biological classification, the favorable effects of variant EGFR polymorphisms were preserved for luminal A tumors, but not for other subtypes.
The data suggest that the presence of the variant forms of EGFR polymorphisms may lead to better prognosis in breast cancer, especially in patients with luminal A tumors.
表皮生长因子受体（EGFR）在乳腺癌中的表达不同，其存在可能有利于癌症的进展。我们假设两个 EGFR 功能多态性，一个是内含子 1 中的（CA）n 重复序列，另一个是单核苷酸多态性，R497K，可能会影响 EGFR 表达和乳腺癌的临床特征。
该研究人群包括 508 名来自巴西的单侧乳腺癌且无远处转移的女性患者。对患者进行（CA）n 重复序列和 R497K 多态性的基因分型，并评估（CA）n 多态性与 EGFR 转录水平之间的关联（n = 129），或任意一种多态性与组织病理学特征之间的关联（n = 505）。遵循肿瘤标志物评估的 REMARK 标准。
（CA）n 长度范围为 14 至 24 个重复序列，包括 11 个等位基因和 37 种基因型。最常见的等位基因为（CA）16（0.43；95%CI = 0.40-0.46），将其设为短等位基因的截断长度。不同的（CA）n 基因型对肿瘤 EGFR mRNA 水平没有显著影响，但具有两个（CA）n 长等位基因的患者孕激素受体阴性的可能性较低（调整后的 OR = 0.42；95%CI = 0.19-0.91）。对 R497K 多态性的评估表明，变体（Lys）等位基因的频率为 0.21（95%CI = 0.19-0.24）。与参考基因型 Arg/Arg 相比，具有变体 R497K 基因型的患者淋巴结状态较差（pN2 或 pN3）的比例较低（调整后的 OR = 0.32；95%CI = 0.17-0.59），导致肿瘤分期较低（调整后的 OR = 0.34；95%CI = 0.19-0.63）和复发风险估计值较低（OR = 0.50；95%CI = 0.30-0.81）。两种 EGFR 多态性（R497K 的变体 Lys 等位基因和 Long/Long（CA）n）同时存在时，TNM 状态较低（调整后的 OR = 0.22；95%CI = 0.07-0.75）和 ERR 较低（OR = 0.25；95%CI = 0.09-0.71）。当根据生物学分类对肿瘤进行分层时，变体 EGFR 多态性的有利作用在管腔 A 型肿瘤中得以保留，但在其他亚型中则不然。
数据表明，变体 EGFR 多态性的存在可能导致乳腺癌预后更好，尤其是在管腔 A 型肿瘤患者中。
