Errors in the interpretation of copy number variations due to the use of public databases as a reference.

The identification of new cryptic deletions and duplications can be used to improve prognostic classification in cancer. To obtain accurate results, it is necessary to discriminate between somatic alterations in the tumor cell and germline polymorphisms. For this purpose, copy number variation (CNV) public databases have been used as a reference. Nevertheless, the use of these databases may lead to erroneous results. Our main goal was to explore the limitations of the use of CNV databases, such as the Database of Genomic Variants (DGV), as the reference. To that end, we used pediatric acute lymphoblastic leukemia (ALL) as a model. We analyzed the genome-wide copy number profile of 23 ALL patients and conducted a comparison of the results obtained using the DGV with those obtained using the normal sample from the patient as the reference. Using only the DGV, 19% of alterations and 41% of polymorphisms were erroneously catalogued. Our results support the hypothesis that with the use of databases such as the DGV as the reference, a high percentage of the variations can be erroneously classified.

Polymorphisms of the SLCO1B1 gene predict methotrexate-related toxicity in childhood acute lymphoblastic leukemia.

BACKGROUND: Methotrexate (MTX) is an important component of the therapy for childhood acute lymphoblastic leukemia. Treatment with high-dose MTX often causes toxicity, recommending a dose reduction and/or cessation of treatment. Polymorphisms in genes involved in the MTX metabolism have been associated with toxicity with controversial results. The discrepancies could be due to differences in treatment protocols among studies, small, or non-homogeneous populations or the use of different toxicity criteria. The aim of the present study was to analyze the possible correlation of polymorphisms of genes involved in the MTX metabolism with the toxicity during therapy with the well-established LAL/SHOP protocol. PROCEDURE: We analyzed 10 polymorphisms in seven genes (MTHFR, TS, SHMT1, RFC1, ABCB1, ABCG2, and SLCO1B1) from the MTX metabolism in 115 Spanish pediatric B-ALL patients, using MTX plasma concentration as an objective and quantifiable marker of toxicity. RESULTS: We confirmed the suitability of MTX plasma levels as a toxicity marker. We found a statistically significant association between MTX plasma concentration and the SLCO1B1 rs11045879 CC genotype (P = 0.030). The rs4149081 AA genotype, in the same gene, could also be an indicator for high-MTX plasma concentrations. We did not find any significant association in the other genetic polymorphisms analyzed. CONCLUSIONS: Identification of the rs4149081 and rs11045879 SLCO1B1 polymorphisms in children with ALL could be a useful tool for monitoring patients at risk of low-MTX clearance in order to avoid MTX-related toxicity.