Hatletvedt Nora D, Engebrethsen Christina, Geisler Jürgen, Geisler Stephanie, Aas Turid, Lønning Per E, Gansmo Liv B, Knappskog Stian
Department of Clinical Science, University of Bergen, 5020, Bergen, Norway.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
BMC Cancer. 2025 Feb 20;25(1):308. doi: 10.1186/s12885-025-13675-2.
Functional polymorphisms in the MDM2 promoters have been linked to cancer risk and several non-malignant conditions. Their potential role in bone marrow function during chemotherapy is largely unknown.
We investigated the potential associations between genotypes of MDM2 SNP309 (rs2279744), SNP285 (rs117039649) and del1518 (rs3730485) and neutrophil counts in breast cancer patients receiving neoadjuvant sequential epirubicin and docetaxel, with additional G-CSF, in the DDP-trial (NCT00496795). We applied longitudinal ratios, post vs. pre-treatment, of neutrophil counts as our main measure. Differences by genotypes were tested by Jonckheere-Terpstra test for ranked alternatives, while dominant and recessive models were tested by Mann-Whitney U test, and additional sub-analyses were performed for genotype combinations.
The SNP309 reference T-allele was associated with a better sustained neutrophil count (p = 0.035). A similar association was observed for the alternative del-allele of the del1518 (p = 0.049). Additionally, in combined genotype-analyses, patients with the SNP309 TT genotype and at least one copy of the del1518 del-allele had particularly favorable sustained neutrophil counts during chemotherapy treatment (p = 0.005).
Our study provides evidence that MDM2 promoter polymorphisms may be associated with neutrophil counts and bone marrow recovery during chemotherapy treatment in breast cancer patients.
The DDP-trial was registered at ClinicalTrials.gov (NCT00496795; registration date 2007-07-04).
MDM2启动子中的功能多态性与癌症风险及多种非恶性疾病相关。其在化疗期间对骨髓功能的潜在作用尚不清楚。
在DDP试验（NCT00496795）中，我们研究了MDM2 SNP309（rs2279744）、SNP285（rs117039649）和del1518（rs3730485）的基因型与接受新辅助序贯表柔比星和多西他赛并额外使用粒细胞集落刺激因子（G-CSF）的乳腺癌患者中性粒细胞计数之间的潜在关联。我们将治疗后与治疗前中性粒细胞计数的纵向比值作为主要测量指标。通过Jonckheere-Terpstra检验对有序替代方案的基因型差异进行检验，而显性和隐性模型通过Mann-Whitney U检验进行检验，并对基因型组合进行了额外的亚组分析。
SNP309的参考T等位基因与更好的持续性中性粒细胞计数相关（p = 0.035）。del1518的替代del等位基因也观察到类似关联（p = 0.049）。此外，在联合基因型分析中，具有SNP309 TT基因型且至少有一个del1518 del等位基因拷贝的患者在化疗期间具有特别有利的持续性中性粒细胞计数（p = 0.005）。
我们的研究提供了证据，表明MDM2启动子多态性可能与乳腺癌患者化疗期间的中性粒细胞计数和骨髓恢复相关。
DDP试验在ClinicalTrials.gov注册（NCT00496795；注册日期2007年7月4日）。
