Intratumour microbiome associated with the infiltration of cytotoxic CD8+ T cells and patient survival in cutaneous melanoma.

OBJECTIVE: The gut microbiome plays an important role in systemic inflammation and immune response. Microbes can translocate and reside in tumour niches. However, it is unclear how the intratumour microbiome affects immunity in human cancer. The purpose of this study was to investigate the association between intratumour bacteria, infiltrating CD8+ T cells and patient survival in cutaneous melanoma. METHODS: Using The Cancer Genome Altas's cutaneous melanoma RNA sequencing data, levels of intratumour bacteria and infiltrating CD8+ T cells were determined. Correlation between intratumour bacteria and infiltrating CD8+ T cells or chemokine gene expression and survival analysis of infiltrating CD8+ T cells and Lachnoclostridium in cutaneous melanoma were performed. RESULTS: Patients with low levels of CD8+ T cells have significantly shorter survival than those with high levels. The adjusted hazard ratio was 1.57 (low vs high) (95% confidence interval: 1.17-2.10, p = 0.002). Intratumour bacteria of the Lachnoclostridium genus ranked top in a positive association with infiltrating CD8+ T cells (correlation coefficient = 0.38, p = 9.4 × 10-14), followed by Gelidibacter (0.31, p = 1.13 × 10-9), Flammeovirga (0.29, p = 1.96 × 10-8) and Acinetobacter (0.28, p = 8.94 × 10-8). These intratumour genera positively correlated with chemokine CXCL9, CXCL10 and CCL5 expression. The high Lachnoclostridium load significantly reduced the mortality risk (p = 0.0003). However, no statistically significant correlation was observed between intratumour Lachnoclostridium abundance and the levels of either NK, B or CD4+ T cells. CONCLUSION: Intratumour-residing gut microbiota could modulate chemokine levels and affect CD8+ T-cell infiltration, consequently influencing patient survival in cutaneous melanoma. Manipulating the intratumour gut microbiome may benefit patient outcomes for those undergoing immunotherapy.

Plasma miR-1273g-3p acts as a potential biomarker for early Breast Ductal Cancer diagnosis.

Circulating miRNAs presenting in plasma in a stable manner have been demonstrated their potential role as a promising biomarkers in many human diseases, such as Alzheimer's disease, melanoma and ovarian carcinoma. However, few circulating miRNAs could be used for breast ductal cancer diagnosis. Here, we identified miR-1273g-3p as a biomarker for detecting breast ductal cancer. We detected miR-1273g-3p levels in the plasma of 39 sporadic breast ductal cancer patients and 40 healthy donors by Stem-loop Quantitative Real-time PCR (qRT-PCR). The results showed the plasma miR-1273g-3p level were significantly up-regulated in breast ductal cancer patients compared with healthy donors (p=0.0139). Receiver operating characteristic (ROC) curve also revealed the significantly diagnostic ability of miR-1273g-3p in patients (p=0.0414). In addition, the plasma level of miR-1273g-3p was closely related to IIIB-IIIC TNM stage. We also confirmed the higher expression level of miR-1273g-3p in breast cancer cell lines MCF-7 (4.872±0.537) than normal breast cells (Hs 578Bst). Taken together, miR-1273g-3p could represent as a potential biomarker for early breast ductal cancer diagnosis.

High tRNA Transferase NSUN2 Gene Expression is Associated with Poor Prognosis in Head and Neck Squamous Carcinoma.

NSUN2 is a tRNA methyltransferase and plays an important role in cell development via modifying RNA methylation. We aimed to evaluate the expression of NSUN2 and its prognostic value in HNSCC. Random-effects model of meta-analysis shows 1.99-folds (95% CI: 1.89-2.09) upregulation of NSUN2 expression in HNSCC versus normal tissues. Patients with high NSUN2 levels had approximately 22 months shorter overall survival, and had a higher mortality risk than those with low one (p-trend = 0.020). In conclusion, NSUN2 is a potential independent prognostic marker and may be a potential therapeutic target in HNSCC.

Association of APEX1 and OGG1 gene polymorphisms with breast cancer risk among Han women in the Gansu Province of China.

BACKGROUND: Genetic variations in key DNA repair genes may influence DNA repair capacity, DNA damage and breast carcinogenesis. The current study aimed to estimate the association of APEX1 and OGG1 polymorphisms with the risk of breast cancer development. METHODS: A total of 518 patients with histopathologically confirmed breast cancer and 921 region- and age-matched cancer-free controls were genotyped for the APEX1 polymorphisms rs3136817 and rs1130409 and the OGG1 polymorphisms rs1052133 and rs2072668 using a QuantStudio™ 12 K Flex Real-Time PCR System. RESULTS: The rs3136817 heterozygous TC genotype along with the rs3136817 dominant model (TC + CC) was strongly associated with breast cancer susceptibility (odds ratio [OR] = 0.670, 95% confidence interval [95% CI]: 0.513 - 0.873, P = 0.003; OR = 0.682, 95% CI: 0.526 - 0.883, P = 0.004, respectively). No significant associations were observed among rs1130409, rs1052133, rs2072668 and breast cancer risk. Furthermore, an allele combination analysis revealed that APEX1 haplotypes containing C-T (alleles rs3136817 and rs1130409) conferred a significantly lower risk (corrected P < 0.001). CONCLUSION: This research is the latest report showing that an APEX1 rs3136817 heterozygous genotype may have a positive influence on DNA repair capacity in patients with breast cancer and thus may have a potential protective effect for Chinese Han women.

Association of nineteen polymorphisms from seven DNA repair genes and the risk for bladder cancer in Gansu province of China.

BACKGROUND: Balance of DNA damage and proper repair plays an important role in progression of bladder cancer. Here we aimed to assess the associations of nineteen polymorphisms from seven DNA repair-associated genes (PRAP1, OGG1, APEX1, MUTYH, XRCC1, XRCC2 and XRCC3) with bladder cancer and their interactions in the disease in a Han Chinese population. METHODOLOGY/PRINCIPAL FINDINGS: A chip-based TaqMan genotyping for the candidate genes was performed on 227 bladder cancer patients and 260 healthy controls. APEX1 rs3136817, MUTYH rs3219493, three SNPs (rs3213356, rs25487 and rs1799782) in XRCC1, and three SNPs (rs1799794, rs861531 and rs861530) in XRCC3 showed significant associations with the risk of bladder cancer. In haplotype analysis, elevated risks of bladder cancer were observed in those with either haplotype GT (OR = 1.56, P = 0.003) of APEX1, or GGGTC (OR = 2.05, P = 0.002) of XRCC1, whereas decreased risks were in individuals with either GCGCC (OR = 0.40, P = 0.001), or GCGTT (OR = 0.60, = 0.005) of XRCC1, or CCC (OR = 0.65, P = 0.004) of MUTYH, or TTTAT (OR = 0.36, P = 0.009) of XRCC3. Interaction analysis showed that the two-loci model (rs1799794 and rs861530) was the best with the maximal testing accuracy of 0.701, and the maximal 100% cross-validation consistency (P = 0.001). CONCLUSIONS: Polymorphisms and haplotypes of DNA repair genes are associated with the risk of bladder cancer, and of which the SNPs (rs1799794 and rs861530) in XRCC3 gene might be two major loci in relation to the susceptibility to bladder cancer in a northwest Chinese population.

Association analysis of ERCC5 gene polymorphisms with risk of breast cancer in Han women of northwest China.

BACKGROUND: ERCC5 plays an important role in DNA damage repair. Mutations in it will lead to DNA repair defects and genomic instability. Its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity and affect cancer susceptibility. METHODS: This study aims to evaluate the association between SNPs in ERCC5 and breast cancer susceptibility in Han women subjects genetically from northwest China. A total of 101 breast cancer patients and 101 healthy controls provided blood samples for analysis of ERCC5 rs17655 and rs751402 genotypes. RESULTS: After adjusting covariates, rs751402 homozygote AA and heterozygote AG were found to confer statistically significant protections (OR 0.052, 95% CI 0.006-0.411, P = 0.005; OR 0.145, 95% CI 0.067-0.315, P < 0.001, respectively) against breast cancer. Moreover, both of the dominant and recessive models of rs751402 also conferred a decreased risk of breast cancer (AA + AG vs. GG, OR 0.125, 95% CI 0.060-0.261, P < 0.001; AA vs. GG + AG, OR 0.082, 95% CI 0.010-0.648, P = 0.018, respectively). CONCLUSIONS: The results indicate that the rs751402 in ERCC5 may affect the risk of breast cancer and show that it is associated with breast cancer characteristics in the Han population of northwest China. However, we found no significant differences between breast cancer patients and control subjects regarding ERCC5 rs17655 polymorphism in the studied population.

DNA repair genes XRCC1 and ERCC1 polymorphisms and the risk of sporadic breast cancer in Han women in the Gansu Province of China.

AIMS: Polymorphisms in DNA damage repair genes may affect DNA repair capacity and modulate breast cancer susceptibility. In this study, we aimed to analyze two polymorphisms for each of the DNA repair genes X-ray repair cross-complementing group 1 (XRCC1) rs25487 and rs1799782 and excision repair cross-complementing group 1 (ERCC1) rs3212964 and rs11615, to evaluate their associations with the risk of sporadic breast cancer in Han women in the Gansu Province of China. METHODS: Genotypes were determined by a polymerase chain reaction-based approach for 101 patients with breast cancer and in 101 disease-free controls. RESULTS: We found that individuals with the AA genotype at XRCC1 rs25487 had a significantly increased risk of breast cancer compared with GG genotype (p<0.001, odds ratio [OR]=6.39, 95% confidence interval [CI]: 2.18-18.65). The dominant model showed that the combined rs25487 genotypes (AA+AG) increased the disease risk (p<0.001, OR=3.17, 95% CI: 1.76-5.72). However, no statistical associations were found between rs1799782 in XRCC1, or rs3212964 and rs11615 in ERCC1 and the risk of disease. In haplotype analysis, the GC haplotype in XRCC1 conferred an increased risk (p<0.001) with a 4.78-fold increase for each copy (95% CI: 2.52-8.72). Significant associations were also shown between the single nucleotide polymorphisms (SNPs) and the status of estrogen receptor (ER), progesterone receptor (PR), and HER-2. CONCLUSIONS: The results suggest that the XRCC1 rs25487 polymorphism may increase the risk of breast cancer.

Polymorphisms in the DNA repair gene ERCC2/XPD and breast cancer risk: a HapMap-based case-control study among Han Women in a Chinese less-developed area.

AIMS: Genetic variations in DNA repair genes may impact repair functions, DNA damage, and breast cancer risk. This study is aimed to assess the associations of genetic polymorphisms in excision repair cross-complementing group 2 (ERCC2) with the risk of developing breast cancer. MATERIALS AND METHODS: In total, 101 histopathologically confirmed breast cancer cases and 101 age/region-matched healthy controls were genotyped for rs 3916840, rs 1799793, and rs 238416 in ERCC2 by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The rs 238416 heterozygous GA genotype combined with the rs 238416 genotypes (GA+AA) showed a significant association with breast cancer susceptibility (corrected p<0.01, odds ratio [OR]=0.29, 95% confidence interval [CI]=0.15-0.54; corrected p<0.01, OR=0.31, 95% CI=0.17-0.56, respectively). The rs 238416 GA genotype carriers had a decreased risk of breast cancer. However, we observed no significant association between the rs 3916840 and rs 1799793 polymorphisms in ERCC2 and breast cancer risk. Moreover, haplotype analysis showed that the ACG haplotype was associated with a significantly decreased risk of breast cancer, whereas the GCG haplotype was associated with a significantly increased risk of breast cancer (corrected p=0.004 and p=0.002, respectively). Multifactor dimensionality reduction analysis demonstrated that the interactions between rs 3916840 and rs 238416 were significantly synergistic. CONCLUSION: To the best of our knowledge, this study is the first to demonstrate that the rs 238416 heterozygous genotype likely has a higher DNA repair capacity and, thus, can be protective against breast cancer in Chinese Han women.

Genetic polymorphisms in IL10RA and TNF modify the association between blood transfusion and risk of non-Hodgkin lymphoma.

We conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes may modify the association between blood transfusion and risk of non-Hodgkin lymphoma (NHL). Compared with women without blood transfusion, women with a history of transfusion had an increased risk of NHL if they carried IL10RA (rs9610) GG genotype [odds ratio (OR) = 1.9, 95% confidence interval (CI): 1.1-3.2] or TNF (rs1800629) AG/AA genotypes (OR = 1.6, 95% CI: 0.9-2.7). We also found women with a history of transfusion had a decreased risk of NHL if they carried IL10RA (rs9610) AG/AA genotypes (OR = 0.6, 95% CI: 0.4-0.9) or TNF (rs1800629) GG genotype (OR = 0.7, 95% CI: 0.5-1.0). A similar pattern was also observed for B-cell lymphoma but not for T-cell lymphoma. Statistically significant interactions with blood transfusion were observed for IL10RA (rs9610) (P(forinteraction) = 0.003) and TNF (rs1800629) (P(forinteraction) = 0.012) for NHL overall and IL10RA (rs9610) (P(forinteraction) = 0.001) and TNF (rs1800629) (P(forinteraction) = 0.019) for B-cell lymphoma. The results suggest that genetic polymorphisms in TNF and IL10RA genes may modify the association between blood transfusion and NHL risk.

Polymorphisms in Th1/Th2 cytokine genes, hormone replacement therapy, and risk of non-Hodgkin lymphoma.

We conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes modify the relationship between hormone replacement therapy (HRT) and risk of non-Hodgkin lymphoma (NHL). Compared to women without a history of HRT use, women with a history of HRT use had a significantly decreased risk of NHL if they carried IFNGR2 (rs1059293) CT/TT genotypes (OR = 0.5, 95%CI: 0.3-0.9), IL13 (rs20541) GG genotype (OR = 0.6, 95%CI: 0.4-0.9), and IL13 (rs1295686) CC genotype (OR = 0.6, 95%CI: 0.4-0.8), but not among women who carried IFNGR2 CC, IL13 AG/AA, and IL13CT/TT genotypes. A similar pattern was also observed for B-cell lymphoma but not for T-cell lymphoma. A statistically significant interaction was observed for IFNGR2 (rs1059293 P(for interaction) = 0.024), IL13(rs20541 P(for interaction) = 0.005), IL13 (rs1295686 P(for interaction) = 0.008), and IL15RA (rs2296135 P(for interaction) = 0.049) for NHL overall; IL13 (rs20541 P(for interaction) = 0.0009), IL13(rs1295686 P(for interaction) = 0.0002), and IL15RA (rs2296135 P(for interaction) = 0.041) for B-cell lymphoma. The results suggest that common genetic variation in Th1/Th2 pathway genes may modify the association between HRT and NHL risk.

Telomerase expression and telomere length in breast cancer and their associations with adjuvant treatment and disease outcome.

INTRODUCTION: Telomere length plays important roles in maintaining genome stability and regulating cell replication and death. Telomerase has functions not only to extend telomere length but also to repair DNA damage. Studies have shown that telomerase may increase cancer cell resistance to DNA-damaging anticancer agents; tamoxifen may suppress telomerase expression in breast cancer cells. This study aimed to investigate the role of telomere length and telomerase activity in breast cancer prognosis. METHODS: qPCR and qRT-PCR were used to analyze telomere length and telomerase expression, respectively, in tumor samples of 348 breast cancer patients. Cox regression analysis was performed to examine telomere length and telomerase expression in association with disease-free survival and cause-specific mortality. RESULTS: Telomere length had no relation to tumor features or disease outcomes. Telomerase expression was detected in 53% of tumors. Larger tumors or aggressive disease were more likely to have telomerase expression. Among patients treated with chemotherapy, high telomerase was found to be associated with increased risk of death (hazard ratio (HR) = 3.15; 95% CI: 1.34 to 7.40) and disease recurrence (HR = 2.04; 95% CI: 0.96 to 4.30) regardless of patient age, disease stage, tumor grade, histological type or hormone receptor status. Patients treated with endocrine therapy had different results regarding telomerase: high telomerase appeared to be associated with better survival outcomes. Telomerase expression made no survival difference in patients who received both chemotherapy and endocrine therapy. CONCLUSIONS: Overall, telomerase expression was not associated with disease outcome, but this finding may be masked by adjuvant treatment. Patients with high telomerase expression responded poorly to chemotherapy in terms of disease-free and overall survival, but fared better if treated with endocrine therapy.