Single Nucleotide Polymorphisms Status Research Articles

The allelic distribution of a single nucleotide polymorphism in the PDCD5 gene locus of Japanese non-small cell lung cancer patients

It has been reported that the rs1862214 single nucleotide polymorphism (SNP) in the programmed cell death 5 gene (PDCD5) is associated with smoking-related lung cancer risk and prognosis in a European population with a history of smoking. The aim of this study was to investigate the status and impact of SNPs in the PDCD5 locus of a Japanese population. We developed an assay based on real-time PCR with melting curve analysis for determining the rs1862214 SNP, and examined this SNP in 165 lung cancer patients and 180 healthy volunteers. Of the 165 lung cancer patients (107 smokers), 25 (17), 72 (47) and 68 (43) had the CC, CG and GG genotypes of rs1862214, respectively. Of the 180 volunteers (117 smokers), 31 (24), 81 (52) and 68 (41) had the CC, CG and GG genotypes of rs1862214, respectively. No significant difference in allelic distribution was found between Japanese patients and healthy controls, even among smokers. Based on the published data, the distribution of this SNP appears to be significantly different in Japanese and European populations. No significant difference in prognosis according to the SNP was observed, either in patients with a history of smoking or in the total number of patients. This too differs from the results from a European population. In conclusion, we developed a convenient real-time PCR-based assay for the genotyping of rs1862214 in the PDCD5 locus. The distribution of the rs1862214 SNP in our Japanese population differs from its distribution in a European population, and is not related to the risk of cancer or to poor prognosis in lung cancer. This suggests the presence of an ethnicity-related difference in the role of PDCD5 in the pathogenesis of lung cancer.

Intrinsic genetic characteristics determine tumor-modifying capacity of fibroblasts: matrix metalloproteinase-3 5A/5A genotype enhances breast cancer cell invasion

BackgroundStromal fibroblasts can contribute to tumor invasion through the release of matrix metalloproteinases (MMPs). Population studies have suggested that single nucleotide polymorphisms (SNPs) in MMP genes influence levels of expression and may be associated with breast cancer risk and with disease progression. This study directly examined the impact of MMP SNP genotype on the ability of host fibroblasts to promote tumor cell invasion.MethodsPrimary breast fibroblasts were isolated from patients with (n = 13) or without (n = 19) breast cancer, and their ability to promote breast cancer cell invasion was measured in in vitro invasion assays. Fibroblast invasion-promoting capacity (IPC) was analyzed in relation to donor type (tumor or non-tumor patient), MMP-1, MMP-3, and MMP-9 SNP genotype and MMP activity using independent samples t test and analysis of variance. All statistical tests were two-sided.ResultsTumor-derived fibroblasts promoted higher levels of invasion than normal fibroblasts (p = 0.041). When IPC was related to genotype, higher levels of IPC were generated by tumor fibroblasts with the high-expressing MMP-3 5A/5A genotype compared with the 5A/6A and 6A/6A genotypes (p = 0.05 and 0.07, respectively), and this was associated with enhanced MMP-3 release. The functional importance of MMP-3 was demonstrated by enhanced invasion in the presence of recombinant MMP-3, whereas reduction occurred in the presence of a specific MMP-3 inhibitor. An inverse relationship was demonstrated between fibroblast IPC and the high-expressing MMP-1 genotype (p = 0.031), but no relationship was seen with MMP-9 SNP status. In contrast, normal fibroblasts showed no variation in IPC in relation to MMP genotype, with MMP-3 5A/5A fibroblasts exhibiting significantly lower levels of IPC than their tumor-derived counterparts (p = 0.04).ConclusionThis study has shown that tumor-derived fibroblasts exhibit higher levels of IPC than normal fibroblasts and that the MMP-3 5A/5A genotype contributes to this through enhanced MMP-3 release. Despite a high-expressing genotype, normal fibroblasts do not exhibit higher IPC or enhanced MMP release. This suggests that more complex changes occur in tumor-derived fibroblasts, enabling full expression of the MMP SNP genotype and these possibly are epigenetic in nature. The results do suggest that, in women with breast cancer, a high-expressing MMP-3 genotype may promote tumor progression more effectively.

Association of Breast Cancer Outcome With Status of p53 and MDM2 SNP309

A common single-nucleotide polymorphism (SNP) in the promoter region of the MDM2 gene, known as T-309G and referred to as SNP309 for this study, leads to increased expression of Mdm2 protein and attenuated function of the p53 tumor suppressor protein. We investigated whether genetic variants in MDM2 were associated with breast cancer incidence and survival and whether the variant status could interact with the tumor p53 status to modify breast cancer survival. We used multivariable logistic and Cox regression analyses to study the relationship of SNP309 status and the status of a second MDM2 SNP in exon 12 at codon 354 (SNP354) with breast cancer incidence and with disease-specific survival among 293 case patients and 317 cancer-free control subjects. Survival analysis included 248 of the 293 case patients who had known tumor p53 status. All statistical tests were two-sided. We did not observe an association between SNP309 status and breast cancer incidence in the unstratified analysis, but we did find a statistically significant association between SNP354 status and breast cancer incidence (odds ratio = 3.34, 95% confidence interval [CI] = 1.88 to 5.93). We also discovered a statistically significant interaction between SNP309 status and tumor p53 expression for breast cancer survival (P(interaction) = .002). Among homozygous carriers of the common MDM2 SNP309 allele (T/T), a mutant p53 status (risk ratio [RR] of death = 2.33, 95% CI = 1.08 to 5.03) and aberrant p53 protein expression (RR = 2.61, 95% CI = 1.22 to 5.57) in breast tumors were associated with poor survival. Tumor p53 status was not associated with breast cancer survival among carriers of the variant MDM2 SNP309 allele (G/T or G/G), which is consistent with a dominant effect of the variant allele. A strong interaction between SNP309 status and tumor p53 status appears to modify the association between p53 status and breast cancer survival.

Anger Regulation Style, Postoperative Pain, and Relationship to the A118G Mu Opioid Receptor Gene Polymorphism: A Preliminary Study

Greater trait anger-out is associated with elevated pain responsiveness. Previous work suggests this effect may be mediated by deficient endogenous opioid analgesia, possibly reflecting diminished opioid receptor sensitivity. The A118G single nucleotide polymorphism (SNP) of the mu opioid receptor gene influences both opioid receptor sensitivity and clinical responsiveness to opioid analgesics. Therefore, this study tested whether this SNP either mediated or moderated the effects of anger-out on postsurgical pain outcomes. Forty-eight patients undergoing coronary artery bypass graft surgery provided genetic samples, and completed measures of anger-out and postsurgical pain. Postsurgical opioid analgesic use was also recorded. Anger-out was positively associated with postsurgical pain ratings (p < 0.05). Anger-out was not associated with A118G SNP status (p > 0.10), suggesting the latter is unlikely to mediate anger-out's pain-related effects. A significant anger-out x A118G interaction was observed on analgesic use (p < 0.05), due to a much stronger positive relationship between anger-out and analgesic demands in patient with the A118G SNP (b = 0.53) than those with the wild-type receptor (b = 0.07). These results suggest that the A118G SNP may moderate but not mediate the effects of anger-out on postoperative pain responses.

Dihydropirimidin dehydrogenase (DPD29) single nucleotide polymorphism but not ERCC1, XPD, cytidine deaminase (CD) or DPD543, predicts duration of response to cisplatin/5FU based chemotherapy in oropharyngeal carcinoma

5547 Background: Single nucleotide polymorphisms (SNPs) correlate with response to chemotherapy. ERCC1 and XPD are DNA repair genes which SNPs predict response to cisplatin in non-small cell lung cancer. CD and DPD are intermediate pathways enzymes in the metabolism of the pirimidine analogues. We evaluated the presence of SNPs of these genes in patients (pts) with oropharyngeal carcinoma and its relationship with chemotherapy response. Methods: We analysed paraffin-embedded biopsies from 24 consecutive pts with locally advanced oropharyngeal carcinoma who received chemoradiotherapy based on platinum (Pt) and 5-fluorouracil (5FU) for SNPs of genes ERCC1 (Lys259Thr), XPD (Lys751Gln), CD intron (in an intronic region T/C), CD (Lys27Gln), DPD543 (Ile543Val) and DPD29 (Arg29Cys). The status of alleles (wild type or at least 1 polymorphism) was correlated with response rate (RR), time to progression (TTP) and overall survival (OS). Results: All 24 pts received Pt (n=24) or 5FU plus Pt (n=19). Overall RR was 75% (16/24) with a median TTP of 12 months (95% CI 6–18m) and a median OS of 32 months (95% CI 14–50m). The status of SNPs was classified as not available/wild type/heterozygous SNP/homozygous SNP, which frequencies were 5/16/3/0 in ERCC1; 2/8/12/2 in XPD; 2/2/10/10 in CD; 2/21/0/1 in CD intron; 1/18/5/0 in DPD543; and 1/15/7/1 in DPD29 respectively. Response rate in DPD29 was 70% for wild type vs 40% for polymorphism (p= 0.656). Only significant differences were seen in TTP between pts with wild type vs polymorphic DPD29 (p=0.037). No difference in survival was observed. Conclusions: SNPs of DPD29 predict duration of response to chemotherapy containing Pt-5FU in pts with oropharyngeal carcinoma. No significant financial relationships to disclose.