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 = 5.1x10(-)(5)), and three SNPs in ABCB1, rs4148737
(per-allele HR = 3.66, 95%CI = 1.85-6.11, p-value = 6.9x10(-)(5)), rs1128503 and
rs10276036 (r(2) = 1, per-allele HR = 0.24, 95%CI = 0.11-0.47 p-value =
7.9x10(-)(5)). Associations with these SNPs remained statistically significant
after correction for multiple testing (all corrected p-values [permutation test]
</= 0.03). CONCLUSIONS: 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
