Le Morvan V, Litière S, Laroche-Clary A, Ait-Ouferoukh S, Bellott R, Messina C, Cameron D, Bonnefoi H, Robert J
INSERM U916, Institut Bergonié, Université Bordeaux Segalen, Bordeaux, France.
European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium.
Pharmacogenomics J. 2015 Feb;15(1):63-8. doi: 10.1038/tpj.2014.24. Epub 2014 Jun 24.
Using cell line panels we identified associations between single-nucleotide polymorphisms (SNPs) and chemosensitivity. To validate these findings in clinics, we genotyped a subset of patients included in a neoadjuvant breast cancer trial to explore the relationship between genotypes and clinical outcome according to treatment received and p53 status. We genotyped 384 selected SNPs in the germline DNA extracted from formalin-fixed paraffin-embedded non-invaded lymph nodes of 243 patients. The polymorphisms of five selected genes were first studied, and then all 384 SNPs were considered. Correction for multiple testing was applied. CYP1B1 polymorphism was significantly associated with pathological complete response (pCR) in patients who had received DNA-damaging agents. MDM2, MDM4 and TP53BP1 polymorphisms were significantly associated with pCR in patients harboring a p53-positive tumor. In the complete SNP panel, there was a significant association between overall survival (OS) and a SNP of ADH1C, R272Q (P=0.0023). By multivariate analysis, only ADH1C genotype and p53 status were significantly associated with OS.
我们使用细胞系面板确定了单核苷酸多态性（SNP）与化疗敏感性之间的关联。为了在临床中验证这些发现，我们对一项新辅助乳腺癌试验中的部分患者进行基因分型，以根据接受的治疗和p53状态探索基因型与临床结局之间的关系。我们对从243例患者福尔马林固定石蜡包埋的未受侵袭淋巴结中提取的种系DNA中的384个选定SNP进行了基因分型。首先研究了五个选定基因的多态性，然后考虑了所有384个SNP。应用了多重检验校正。在接受DNA损伤剂治疗的患者中，CYP1B1多态性与病理完全缓解（pCR）显著相关。在携带p53阳性肿瘤的患者中，MDM2、MDM4和TP53BP1多态性与pCR显著相关。在完整的SNP面板中，总生存期（OS）与ADH1C的一个SNP，即R272Q之间存在显著关联（P = 0.0023）。通过多变量分析，只有ADH1C基因型和p53状态与OS显著相关。
