Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre, Madrid, Spain.
PLoS One. 2011;6(10):e26091. doi: 10.1371/journal.pone.0026091. Epub 2011 Oct 7.
Standard treatment for osteosarcoma patients consists of a combination of cisplatin, adriamycin, and methotrexate before surgical resection of the primary tumour, followed by postoperative chemotherapy including vincristine and cyclophosphamide. Unfortunately, many patients still relapse or suffer adverse events. We examined whether common germline polymorphisms in chemotherapeutic transporter and metabolic pathway genes of the drugs used in standard osteosarcoma treatment may predict treatment response.
METHODOLOGY/PRINCIPAL FINDINGS: In this study we screened 102 osteosarcoma patients for 346 Single Nucleotide Polymorphisms (SNPs) and 2 Copy Number Variants (CNVs) in 24 genes involved in the metabolism or transport of cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide. We studied the association of the genotypes with tumour response and overall survival. We found that four SNPs in two ATP-binding cassette genes were significantly associated with overall survival: rs4148416 in ABCC3 (per-allele HR = 8.14, 95%CI = 2.73-20.2, p-value = 5.1×10⁻⁵), and three SNPs in ABCB1, rs4148737 (per-allele HR = 3.66, 95%CI = 1.85-6.11, p-value = 6.9×10⁻⁵), rs1128503 and rs10276036 (r² = 1, per-allele HR = 0.24, 95%CI = 0.11-0.47 p-value = 7.9×10⁻⁵). Associations with these SNPs remained statistically significant after correction for multiple testing (all corrected p-values [permutation test] ≤ 0.03).
Our findings suggest that these polymorphisms may affect osteosarcoma treatment efficacy. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of osteosarcoma, helping in the design of individualized therapy.
骨肉瘤患者的标准治疗包括在手术切除原发性肿瘤前联合使用顺铂、阿霉素和甲氨蝶呤，然后进行包含长春新碱和环磷酰胺的术后化疗。然而，许多患者仍会复发或出现不良反应。我们研究了标准骨肉瘤治疗中使用的药物的化疗转运体和代谢途径基因中的常见种系多态性是否可预测治疗反应。
方法/主要发现：在这项研究中，我们对 102 名骨肉瘤患者进行了筛查，检测了与顺铂、阿霉素、甲氨蝶呤、长春新碱和环磷酰胺代谢或转运相关的 24 个基因中的 346 个单核苷酸多态性（SNP）和 2 个拷贝数变异（CNV）。我们研究了基因型与肿瘤反应和总生存的关联。我们发现两个 ABC 转运体基因中的四个 SNP 与总生存显著相关：ABCC3 中的 rs4148416（每个等位基因的 HR=8.14，95%CI=2.73-20.2，p 值=5.1×10⁻⁵），以及 ABCB1 中的三个 SNP，rs4148737（每个等位基因的 HR=3.66，95%CI=1.85-6.11，p 值=6.9×10⁻⁵），rs1128503 和 rs10276036（r²=1，每个等位基因的 HR=0.24，95%CI=0.11-0.47，p 值=7.9×10⁻⁵）。经过多重检验校正后，这些 SNP 仍具有统计学意义（所有校正后的 p 值[置换检验]≤0.03）。
我们的研究结果表明，这些多态性可能会影响骨肉瘤的治疗效果。如果这些关联得到独立验证，这些变体可作为骨肉瘤治疗中临床结果的遗传预测因子，有助于设计个体化治疗。
