Polymorphisms in miRNA processing genes and their role in osteosarcoma risk.

BACKGROUND: The possible associations between genetic variants and osteosarcoma risk have been analyzed without conclusive results. Those studies were focused mainly on genes of biologically plausible pathways. However, recently, another pathway has acquired relevance in cellular transformation and tumorigenesis, the microRNA (miRNA) processing pathway. Dysregulation of the expression levels of genes in this pathway has been described in cancer. Consequently, single nucleotide polymorphisms (SNPs) in genes that codify for proteins involved in the miRNA processing pathway may affect miRNAs, and therefore their target genes, which might be associated with cancer development and progression. The aim of this study was to evaluate whether SNPs in miRNA processing genes confer predisposition to osteosarcoma. PROCEDURE: We analyzed 72 SNPs in 21 miRNA processing genes in a total of 99 osteosarcoma patients and 387 controls. RESULTS: A total of three SNPs were associated with osteosarcoma susceptibility. Interestingly, these SNPs were located in miRNA processing genes (CNOT1, CNOT4 and SND1) which are part of the RISC complex. Among them, the association of rs11866002 in CNOT1 was nearly significant after Bonferroni correction. CONCLUSIONS: This study suggests that SNPs in RISC complex genes may be involved in osteosarcoma susceptibility, especially rs11866002 in CNOT1.

Effect of ABCB1 and ABCC3 polymorphisms on osteosarcoma survival after chemotherapy: a pharmacogenetic study.

BACKGROUND: 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 (r²â€Š= 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). 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.