Effect of ABCB1 and ABCC3 Polymorphisms on Osteosarcoma Survival after Chemotherapy: A Pharmacogenetic Study

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

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 (r 2 = 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 therapyThis work was supported by the AECC (Asociación Española contra el Cáncer), FIS (Fondo de Investigación Sanitaria-Instituto de Salud Carlos III) and the ‘‘Inocente Inocente’’ Foundatio

Genome Sequence of African Swine Fever Virus BA71, the Virulent Parental Strain of the Nonpathogenic and Tissue-Culture Adapted BA71V

The strain BA71V has played a key role in African swine fever virus (ASFV) research. It was the first genome sequenced, and remains the only genome completely determined. A large part of the studies on the function of ASFV genes, viral transcription, replication, DNA repair and morphogenesis, has been performed using this model. This avirulent strain was obtained by adaptation to grow in Vero cells of the highly virulent BA71 strain. We report here the analysis of the genome sequence of BA71 in comparison with that of BA71V. They possess the smallest genomes for a virulent or an attenuated ASFV, and are essentially identical except for a relatively small number of changes. We discuss the possible contribution of these changes to virulence. Analysis of the BA71 sequence allowed us to identify new similarities among ASFV proteins, and with database proteins including two ASFV proteins that could function as a two-component signaling network.This study was supported by grants from the Spanish Ministerio de Economía y Competitividad (AGL2013-43998-C2-1/2-R) and by an institutional grant from Fundación Ramón Areces. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Genomic sequences used in this study.

<p>The table shows general information about the genomic sequences of the ASFV strains used in this study. Left and right indicates the size of the left and right genome variable regions. The left variable region includes the nucleotides from the 5’- end of the genome until gene A224L, whereas the right variable region includes the nucleotides from the 3’- end of the genome until gene DP238L.</p><p>Genomic sequences used in this study.</p

Differences between BA71 and BA71V: Variations in the number or in the sequence of tandem repeats.

<p>The positions in the genome of BA71 and BA71V of the sequences affected are indicated along with the number of repeats involved in the variation, and the identity of the genomic feature affected by the change. The size of the region not present in either of the genomes is indicated in brackets. In the case of difference 33, the highly variable central region located in ORF B602L, 4 of the 29 repeats of 12 nucleotides that compose this region have different sequence but there is no variation in the number of nucleotides.</p><p>Differences between BA71 and BA71V: Variations in the number or in the sequence of tandem repeats.</p

5’- and 3’- ends of the ASFV BA71 and BA71V genomes.

<p>The figure shows dot plot comparisons of the 5’- (A) and 3’-end (B) variable regions. For each of the four large deletions observed between the genomes, the deleted region is indicated by a light blue box in the corresponding axis and the position where the deletion occurred is indicated by an arrow in the opposite axis. ORFs are indicated by arrows, and the different groups of ORFs are identified by colors: MGF 360, violet; MGF 110, yellow; MGF 300, green; MGF 505, red; MGF 100, rose; p22 family, gray, other ORFs, black.</p

Differences between BA71 and BA71V: changes in polynucleotide sequences.

<p>The position of the differences in each genome is indicated along with the size of the change, in brackets. The nature of the polynucleotide and the ORF affected, if any, are also indicated.</p><p>Differences between BA71 and BA71V: changes in polynucleotide sequences.</p

Comparison of the genomic structure of BA71 with BA71V and OURT88/3 around difference 49.

<p>The figure shows a representation to scale of the genomes of BA71, BA71V and OURT88/3 around the position of BA71-BA71V difference 49 (the exact positions are indicated for each of the genomes). Red arrows delimit non-identical regions. Blue lines connect arrows at equivalent positions. The different groups of ORFs are identified by colors as shown in the figure. The dash at the beginning of the names of some ORFs indicates where the prefix BA71- has been removed to avoid clutter.</p

Differences between BA71 and BA71V: Large deletions/insertions.

<p>The positions in the genome of BA71 and BA71V of the sequences affected are indicated along with the size of the region not present in either of the genomes, in brackets. The genes affected by theses differences are also indicated.</p><p>Differences between BA71 and BA71V: Large deletions/insertions.</p