Authors' Affiliations: Departments of Oncology, Surgery, and Pathology, Hadassah and Hebrew University Medical Centre, Jerusalem, Israel; and Group of Clinical Virology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Cancer Epidemiol Biomarkers Prev. 2013 Nov;22(11):2110-5. doi: 10.1158/1055-9965.EPI-13-0193. Epub 2013 Aug 21.
Previous studies indicated that BRCA haploinsufficiency was associated with activation of the EGF receptor (EGFR) signaling pathway and increased proliferative activity in mammary epithelial cells of healthy women. We hypothesized that these processes might be reflected in the expression of serologic soluble EGFR (sEGFR) and thymidine kinase 1 (TK1) activity, which signal the initial and final steps of the proliferative pathway, respectively. We found that healthy carriers of BRCA1/2 mutations (n = 80) showed a significantly higher TK1 activity than age-matched controls (P = 0.0003), and TK1 activity was similar in women with BRCA1 and BRCA2 mutations (P = 0.74). The sEGFR concentration was significantly higher in women with BRCA1 than in controls and BRCA2 mutation (P = 0.013 and 0.002, respectively). During follow-up, four of 80 BRCA1/2 mutation carriers developed breast cancer. These women showed a significantly higher TK1 activity and somewhat higher sEGFR concentrations than the other 76 BRCA1/2 carriers (P = 0.04 and 0.09, respectively). All tumors were negative for ovarian hormone receptors, but showed a high EGFR expression. This study was limited by the short-term follow-up (mean, 27 months; range, 5-45), which resulted in a small sample size. Women with BRCA1 and BRCA2 mutations that had undergone risk-reducing bilateral salpingo-oophorectomy (BSO) showed significantly lower sEGFR compared with those without surgery (P = 0.007 and 0.038, respectively). Larger, prospective studies are warranted to investigate whether TK1 and sEGFR measurements may be useful for identifying healthy BRCA1/2 carriers with high risk of developing breast cancer; moreover, sEGFR measurements may serve as effective tools for assessing risk before and after BSO.
先前的研究表明，BRCA 单倍体不足与表皮生长因子受体（EGFR）信号通路的激活以及健康女性乳腺上皮细胞增殖活性的增加有关。我们假设这些过程可能反映在血清可溶性 EGFR（sEGFR）和胸苷激酶 1（TK1）活性的表达上，分别代表增殖途径的初始和最后步骤。我们发现，BRCA1/2 突变的健康携带者（n=80）的 TK1 活性明显高于年龄匹配的对照组（P=0.0003），并且 BRCA1 和 BRCA2 突变的女性之间的 TK1 活性相似（P=0.74）。BRCA1 突变的女性 sEGFR 浓度明显高于对照组和 BRCA2 突变（P=0.013 和 0.002）。在随访期间，80 名 BRCA1/2 突变携带者中有 4 人发生乳腺癌。这些女性的 TK1 活性明显高于其他 76 名 BRCA1/2 携带者（P=0.04 和 0.09），sEGFR 浓度也略高。所有肿瘤均对卵巢激素受体呈阴性，但 EGFR 表达较高。这项研究受到短期随访（平均 27 个月；范围 5-45 个月）的限制，导致样本量较小。接受预防性双侧输卵管卵巢切除术（BSO）的 BRCA1 和 BRCA2 突变女性的 sEGFR 明显低于未接受手术的女性（P=0.007 和 0.038）。需要进行更大规模的前瞻性研究，以探讨 TK1 和 sEGFR 测量是否可用于识别具有高乳腺癌风险的健康 BRCA1/2 携带者；此外，sEGFR 测量可能是评估 BSO 前后风险的有效工具。
