Link between colorectal cancer and polymorphisms in the uridine-diphosphoglucuronosyltransferase 1A7and 1A1 genes

AIM: To investigate the relationship between single nucleotide polymorphisms in the uridine-diphosphoglucurono-syltransferase (UGT) UGT1A7 and UGT1A1 genes and patients suffering from colorectal cancer (CRC). METHODS: A case-control study was designed in order to investigate the genotypes of the UGT1A7 and UGT1A1 genes, which were identified by the polymerase chain reaction-restriction fragment length polymorphism (RFLP) method, for 268 CRC patients and 441 healthy controls. RESULTS: The results of simple logistical regressions revealed odds ratios (ORs) of 1.97 (P<0.001),1.91 (P<0.001),and 2.03 (P<0.001) for patients who carried the UGT1A7*1/*3 genotype,UGT1A7*3 allele,and variant-211 UGT1A1 allele.The interaction of UGT1A7*3 allele and variant-211 UGT1A1 allele produced an additive effect on the risk for the development of CRC [observed OR (2.34) greater than expected OR (1.59)]. For the 268 patients, the results of simple logistical regressions indicated that the OR of developing metastases was 4.90 (P<0.001) and 4.89 (P<0.001) for the individuals possessing UGT1A7*3 allele and variant-211 UGT1A1 allele, respectively. The results of multivariate logistical regressions confirmed these findings (OR = 2.51, P= 0.01; and OR=2.71,P=0.01,respectively).The interaction of these two variants resulted in an additive effect on the risk for metastases amongst patients [observed OR (6.83) greater than expected OR (4.56)]. CONCLUSION: In conclusion, carriage of the UGT1A7*3 allele, as well as variant-211 UGT1A1 allele represents a risk factor for the development of, and a determinant for, metastases associated with CRC patients.

Potential unreliability of ALK variant allele frequency in the efficacy prediction of targeted therapy in NSCLC

Anaplastic lymphoma kinase(ALK)is the most common fusion gene involved in non-small cell lung cancer(NSCLC),and remarkable response has been achieved with the use of ALK tyrosine kinase inhibitors(ALK-TKIs).However,the clinical efficacy is highly variable.Pre-existing intratumoral heterogeneity(ITH)has been proven to contribute to the poor treatment response and the resistance to targeted therapies.In this work,we investigated whether the variant allele frequencies(VAFs)of ALK fusions can help assess ITH and predict targeted therapy efficacy.Through the application of next-generation sequencing(NGS),7.2%(326/4548)of patients were detected to be ALK positive.On the basis of the adjusted VAF(adjVAF,VAF normalization for tumor purity)of four different threshold values(adjVAF<50%,40%,30%,or 20%),the association of ALK subclonality with crizotinib efficacy was assessed.Nonetheless,no statistical association was observed between median progression-free survival(PFS)and ALK subclonality assessed by adjVAF,and a poor correlation of adjVAF with PFS was found among the 85 patients who received first-line crizotinib.Results suggest that the ALK VAF determined by hybrid capture-based NGS is probably unreliable for ITH assessment and targeted therapy efficacy prediction in NSCLC.

Novel Y-chromosome Short Tandem Repeat Variants Detected Through the Use of Massively Parallel Sequencing

Massively parallel sequencing （MPS） technology is capable of determining the sizes of short tandem repeat （STR） alleles as well as their individual nueleotide sequences. Thus, single nucleotide polymorphisms （SNPs） within the repeat regions of STRs and variations in the pattern of repeat units in a given repeat motif can be used to differentiate alleles of the same length. In this study, MPS was used to sequence 28 forensically-relevant Y-chromosome STRs in a set of 41 DNA samples from the 3 major U.S. population groups （African Americans, Caucasians, and Hispanics）. The resulting sequence data, which were analyzed with STRait Razor v2.0, revealed 37 unique allele sequence variants that have not been previously reported. Of these, 19 sequences were variations of documented sequences resulting from the presence of intra-repeat SNPs or alternative repeat unit patterns. Despite a limited sampling, two of the most frequently-observed variants were found only in African American samples. The remaining 18 variants represented allele sequences for which there were no published data with which to compare. These findings illustrate the great potential of MPS with regard to increasing the resolving power of STR typing and emphasize the need for sample population characterization of STR alleles.