a Department of Immunology , Maria Sklodowska-Curie Institute - Oncology Center , Warsaw , Poland.
b Department of Pathology and Laboratory Diagnostics , Maria Sklodowska-Curie Institute - Oncology Center , Warsaw , Poland.
Cancer Biol Ther. 2019;20(6):843-854. doi: 10.1080/15384047.2019.1579955. Epub 2019 Mar 1.
DNA repair pathways are potential targets of molecular therapy in cancer patients. The FANCD2, BRIP1, BRCA1/2, and FANCF genes are involved in homologous recombination DNA repair, which implicates their possible role in cell response to DNA-damaging agents. We evaluated a clinical significance of pre-treatment expression of these genes at mRNA level in 99 primary, advanced-stage ovarian carcinomas from patients, who later received taxane-platinum (TP) or platinum-cyclophosphamide (PC) treatment.
Gene expression was determined with the use of Real-Time PCR. The BRCA2 and BRIP1 gene sequence was investigated with the use of SSCP, dHPLC, and PCR-sequencing.
Increased FANCD2 expression occurred to be a negative prognostic factor for all patients (PC+TP:HR 3.85, p = 0.0003 for the risk of recurrence; HR 1.96, p = 0.02 for the risk of death), and this association was even stronger in the TP-treated group (HR 6.7, p = 0.0002 and HR 2.33, p = 0.01, respectively). Elevated BRIP1 expression was the only unfavorable molecular factor in the PC-treated patients (HR 8.37, p = 0.02 for the risk of recurrence). Additionally, an increased FANCD2 and BRCA1/2 expression levels were associated with poor ovarian cancer outcome in either TP53-positive or -negative subgroups of the TP-treated patients, however these groups were small. Sequence analysis identified one protein truncating variant (1/99) in BRCA2 and no mutations (0/56) in BRIP1.
Our study shows for the first time that FANCD2 overexpression is a strong negative prognostic factor in ovarian cancer, particularly in patients treated with TP regimen. Moreover, increased mRNA level of the BRIP1 is a negative prognostic factor in the PC-treated patients. Next, changes in the BRCA2 and BRIP1 genes are rare and together with other analyzed FA genes considered as homologous recombination deficiency may not affect the expression level of analyzed genes.
DNA 修复途径是癌症患者分子治疗的潜在靶点。FANCD2、BRIP1、BRCA1/2 和 FANCF 基因参与同源重组 DNA 修复，这暗示它们可能在细胞对 DNA 损伤剂的反应中发挥作用。我们评估了 99 例晚期卵巢癌患者预处理时这些基因在 mRNA 水平的表达，这些患者随后接受了紫杉烷-铂（TP）或铂-环磷酰胺（PC）治疗。
使用实时 PCR 测定基因表达。使用 SSCP、dHPLC 和 PCR 测序研究 BRCA2 和 BRIP1 基因序列。
FANCD2 表达增加被认为是所有患者的不良预后因素（PC+TP：复发风险的 HR 为 3.85，p = 0.0003；死亡风险的 HR 为 1.96，p = 0.02），在接受 TP 治疗的患者中这种相关性更强（复发风险的 HR 为 6.7，p = 0.0002；死亡风险的 HR 为 2.33，p = 0.01）。BRIP1 表达升高是 PC 治疗患者中唯一不利的分子因素（复发风险的 HR 为 8.37，p = 0.02）。此外，FANCD2 和 BRCA1/2 表达水平的增加与 TP 治疗患者中 TP53 阳性或阴性亚组的不良卵巢癌结局相关，但这些亚组较小。序列分析在 BRCA2 中发现了一个蛋白截断变异体（1/99），在 BRIP1 中未发现突变（0/56）。
我们的研究首次表明，FANCD2 过表达是卵巢癌的一个强烈的不良预后因素，特别是在接受 TP 方案治疗的患者中。此外，BRIP1 mRNA 水平的升高是 PC 治疗患者的不良预后因素。再者，BRCA2 和 BRIP1 基因的变化很少见，与其他分析的 FA 基因一起被认为是同源重组缺陷，可能不会影响分析基因的表达水平。
