SNP rs2071095 in LincRNA H19 is associated with breast cancer risk

Purpose

An increasing number of long intergenic non-coding RNAs (lincRNAs) appear to play critical roles in cancer development and progression. To assess the association between SNPs that reside in regions of lincRNAs and breast cancer risk, we performed a large case-control study in China.

Methods

We carried out a two-stage case-control study including 2881 breast cancer cases and 3220 controls. In stage I, we genotyped 17 independent (r²?<?0.5) SNPs located in 6 tumor-related lincRNAs by using the TaqMan platform. In stage II, SNPs potentially associated with breast cancer risk were replicated in an independent population. Quantitative real-time PCR was used to measure H19 levels in tissues from 228 breast cancer patients with different genotypes.

Results

We identified 2 SNPs significantly associated with breast cancer risk in stage I (P?<?0.05), but not significantly replicated in stage II. We combined the data from stage I and stage II, and found that, compared with the rs2071095 CC genotype, AA and CA?+?AA genotypes were associated with significantly decreased risk of breast cancer (adjusted OR 0.83, 95% CI 0.69–0.99; adjusted OR 0.88, 95% CI 0.80–0.98, respectively). Stratified analyses showed that rs2071095 was associated with breast cancer risk in estrogen receptor (ER)-positive patients (P?=?0.002), but not in ER-negative ones (P?=?0.332). Expression levels of H19 in breast cancer cases with AA genotype were significantly lower than those with CC genotype.

Conclusions

We identified that rs2071095 may contribute to the susceptibility of breast cancer in Chinese women via affecting H19 expression. The mechanisms underlying the association remain to be investigated.

     

Effect of rs6983267 polymorphism in the 8q24 region and rs4444903 polymorphism in EGF gene on the risk of sporadic colorectal cancer in Iranian population

Colorectal cancer (CRC) is among the major causes of cancer-related morbidity, mortality, and human health problem worldwide. Single-nucleotide polymorphisms (SNPs) in different genes are reported to be effective in increased risk of CRC in different ethnic population. We conducted a case–control study in patients diagnosed with sporadic colorectal cancer (n = 115) and healthy controls based on colonoscopy evidences (n = 120).In this replicative study, we aimed to investigate the association of two previously reported polymorphisms, rs6983267 and rs4444903, with sporadic colorectal cancer in a subset of Iranian patients. Genotyping was performed via polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) assay. A significant relation was found between rs6983267 variant in the 8q24 region and colorectal cancer. The distribution of G/G genotypes among sporadic CRC patients was more frequent than that in the control group (P value = 0.001). The frequency of the G allele in the colorectal cancer patient group was also higher than that in the control group (65% vs. 48%; P value = 0.001). Compared with GG genotype, individuals with G/T and T/T genotypes had lower risk to develop sporadic CRC (OR = 0.357, 95% CI = 0.201–0.635). For the rs4444903 SNP, no significant association (P value = 0.149) was found with colorectal cancer risk. In conclusion, our findings suggest that the 8q24 rs6983267 SNP may play a pivotal role in the development of sporadic CRC in Iranian population. Therefore, it may be included as a potential genetic susceptibility marker for sporadic CRC.     

Effects of G/A polymorphism, rs266882, in the androgen response element 1 of the PSA gene on prostate cancer risk, survival and circulating PSA levels

Prostate-specific antigen (PSA) is a protease produced in the prostate that cleaves insulin-like growth factor binding protein-3 and other proteins. Production is mediated by the androgen receptor (AR) binding to the androgen response elements (ARE) in the promoter region of the PSA gene. Studies of a single nucleotide polymorphism (PSA -158 G/A, rs266882) in ARE1 of the PSA gene have been conflicting for risk of prostate cancer and effect on plasma PSA levels. In this nested case-control analysis of 500 white cases and 676 age- and smoking-matched white controls in the Physicians' Health Study we evaluated the association of rs266882 with risk and survival of prostate cancer and prediagnostic total and free PSA plasma levels, alone or in combination with AR CAG repeats. We used conditional logistic regression, linear regression and Cox regression, and found no significant associations between rs266882 (GG allele vs AA allele) and overall prostate cancer risk (RR=1.21, 95% confidence intervals (CI): 0.88-1.67) or prostate cancer-specific survival (RR=0.94, 95%CI: 0.56-1.58). Similarly, no associations were found among high grade or advanced stage tumours, or by calendar year of diagnosis. There was no significant association between rs266882 and baseline total or free PSA levels or the AR CAG repeats, nor any interaction associated with prostate cancer risk. Meta-analysis of 12 studies of rs266882 and overall prostate cancer risk was null.     

Germline variation in NCF4, an innate immunity gene,is associated with an increased risk of colorectal cancer

Chronic inflammation has been implicated in the etiology of colorectal adenoma and cancer; however, few key inflammatory genes mediating this relationship have been identified. In this study, we investigated the association of germline variation in innate immunity genes in relation to the risk of colorectal neoplasia. Our study was based on the analysis of samples collected from the prostate, lung, colorectal and ovarian (PLCO) Cancer Screening Trial. We investigated the association between 196 tag single nucleotide polymorphisms (SNPs) in 20 key innate immunity genes with risk of advanced colorectal adenoma and cancer in 719 adenoma cases, 481 cancer cases and 719 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). After Bonferroni correction, the AG/GG genotype of rs5995355, which is upstream of NCF4, was associated with an increased risk of colorectal cancer (OR = 2.43, 95% CI = 1.73–3.39; p < 0.0001). NCF4 is part of the NAPDH complex, a key factor in biochemical pathways and the innate immune response. While not definitive, our analyses suggest that the variant allele does not affect expression of NCF4, but rather modulates activity of the NADPH complex. Additional studies on the functional consequences of rs5995355 in NCF4 may help to clarify the mechanistic link between inflammation and colorectal cancer.     

Genetic association of PLCE1, C11orf92-C11orf93, and NOC3L with colorectal cancer risk in the Han population

Colorectal cancer (CRC) is a common malignant tumor that is influenced by an interaction between genetic and environmental factors. Currently, the inherited factors of CRC are unclear. Our study selected 19 tag single nucleotide polymorphisms (tSNPs) to investigate whether they were associated with CRC in the Han population. In this Han Chinese case–control study, we genotyped 203 CRC cases and 296 controls using Sequenom MassARRAY technology and analyzed their associations with CRC using χ² tests, SNPStats software, and SHEsis software. Based on χ² tests, PLCE1 -rs2077218, rs11187877 (p?=?0.049) and C11orf92-C11orf93-rs3802842 (p?=?0.023) correlate with CRC risk. In the genetic model analyses, we found the genotype “CC” of rs3802842 in C11orf92-C11orf93 may significantly increase CRC risk in the recessive model (p?=?0.0071), whereas “GT” of rs17109928 in NOC3L may decrease the risk in the over-dominant model (p?=?0.0091). Using SHEsis software, we found PLCE1 and NOC3L are strongly linked, and the “GCCATTCTGTC” haplotype may increase the risk of CRC (p?=?0.049). We found three genes (PLCE1, C11orf92-C11orf93, and NOC3L) are associated with CRC susceptibility. In combination with previous reports, our results suggest that these genes may be associated with CRC in the Han population.     

E-selectin rs5361 and FCGR2A rs1801274 variants were associated with increased risk of gastric cancer in a Chinese population

Host immune responses are critical steps for carcinogenesis. Single nucleotide polymorphisms (SNPs) in immunoregulatory genes may influence gastric cancer risk. We performed a genotyping analysis for immunoregulatory genes in 311 gastric cancer cases and 425 controls from a Chinese population. We found that there were significant differences of E‐selectin variant rs5361 (A>C) and FCGR2A variant rs1801274 (T>C) between cases and controls (P = 0.022 and P = 0.0001, respectively). Logistic regression analysis indicated that genotype of E‐selectin rs5361AC increased the risk of gastric cancer significantly (P = 0.026, adjusted Odds ratio (OR) = 2.84, 95% confidence interval (CI) = 1.13–7.12). C allele of E‐selectin rs5361 showed a significant increased frequency in cases (P = 0.023). However, the E‐selectin variant did not affect the protein expression. E‐selectin protein was observed not only in tumor interstitial vascular endothelial cells, but also in gastric cancer cells at primary and metastatic sites. The protein was associated with clinicopathological characteristics of gastric cancer, such as age (P = 0.008), tumor size (P = 0.027), differentiation (P = 0.000), and tumor‐node‐metastasis (TNM) stage (P = 0.006). CT and CC + CT genotypes of FCGR2A variant rs1801274 increased gastric cancer risk (P = 0.000, adjusted OR = 1.92, 95%CI = 1.36–2.72; P = 0.003, adjusted OR = 1.68, 95%CI = 1.20–2.35, respectively). Interleukin‐4 receptor (IL‐4R) variant rs2107356 presented negative correlations to E‐selectin variant rs5361 and FCGR2A variant rs1801274 (P = 0.035 and P = 0.023) in conferring susceptibility to gastric cancer. We concluded E‐selectin variant rs5361 and FCGR2A variant rs1801274 were significantly associated with gastric cancer risk. Expression of E‐selectin protein would promote progression of gastric cancer. © 2011 Wiley Periodicals, Inc.     

The earwax-associated SNP c.538G>A (G180R) in ABCC11 is not associated with breast cancer risk in Europeans

Genetic polymorphisms of human ABC-transporter genes have been suggested to modulate breast cancer risk in the general population. In particular ABCC11 (MRP8), which is highly expressed in breast cancer tissue and involved in the efflux of conjugated estrogen metabolites such as estrone-3-sulfate and estradiol-17beta-glucuronide, has recently been proposed as a potential risk factor for female breast cancer. The wet earwax-associated G-allele of the c.538G>A polymorphism was associated with an increased risk for breast cancer in Japanese women. In contrast, no evidence for such an association could be observed in Caucasian women. We aimed to confirm/refute the association of the c.538G>A variant in ABCC11 with breast cancer risk and/or histo-pathological tumor characteristics in an independent population-based breast cancer case-control study from Germany comprising 1021 cases and 1015 age-matched controls. No association for allele and genotype frequencies of the 538G>A variant in ABCB11 with breast cancer risk was found. Our data suggest that the c.538G>A variation in ABCC11 does not contribute to breast carcinogenesis in women of European descent.     

XPG Asp1104His,XRCC2 rs3218536 A/G and RAD51 135G/C gene polymorphisms and colorectal cancer risk: A meta-analysis

Background: DNA repair mechanisms are crucial for sustaining DNA integrity and preventing carcinogenesis. The xeroderma pigmentosum group G (XPG), X-ray repair cross complementing group 2 (XRCC2) and RAD51 are candidate genes for DNA repair pathways. Methods: We performed a meta-analysis of 26 studies that assessed the impact of XPG Asp1104His, XRCC2 rs3218536 A/G and RAD51 135G/C polymorphisms on colorectal cancer (CRC) risk. This study included 10288 CRC patients and 11885 controls, and odds ratio (OR) with its 95% confidence interval (CI) were used to calculate the strength of association. Results: The results of overall meta-analysis suggested an association between the XPG Asp1104His polymorphism and CRC susceptibility in allele (OR=1.06; 95%CI=1.01-1.12) and heterozygote model (OR=1.16; 95%CI=1.02-1.31). In the subgroup analysis based on ethnicity and source of control, we found significantly increased CRC cancer risk in Asians (OR=1.12, 95%CI=1.04-1.21) and in hospital-based (OR=1.22, 95%CI=1.08-1.38) populations. Moreover, the RAD51 135 G/C polymorphism increased the risk of CRC in total using allele (OR=1.21) and recessive models (OR=1.62). However, XRCC2 rs3218536 A/G was not associated with the risk of CRC in total or in subgroups. Conclusions: According to the results of our meta-analysis, the XPG Asp1104His and RAD51 135 G/C polymorphisms might influence colorectal cancer risk.     

Mammographic density and its interaction with other breast cancer risk factors in an Asian population

Background:

Joint effects of mammographic density and other risk factors on breast cancer risk remain unclear.

Methods:

From The Singapore Breast Screening Project, we selected 491 cases and 982 controls. Mammographic density was measured quantitatively. Data analysis was by conditional logistic regression.

Results:

Density was a significant risk factor, adjusting for other factors. Density of 76–100% had an odds ratio of 5.54 (95% CI 2.38–12.90) compared with 0–10%. Density had significant interactions with body mass index and oral contraceptive use (P=0.02).

Conclusions:

Percent density increases breast cancer risk in addition to effects of other risk factors, and modifies the effects of BMI and OCs.     

Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer

BackgroundEarly indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a marker of therapeutic efficacy.Patients and methodsThis prospective study involved 53 mCRC patients receiving standard first-line chemotherapy. Both ctDNA and CEA were assessed in plasma collected before treatment, 3 days after treatment and before cycle 2. Computed tomography (CT) scans were carried out at baseline and 8–10 weeks and were centrally assessed using RECIST v1.1 criteria. Tumors were sequenced using a panel of 15 genes frequently mutated in mCRC to identify candidate mutations for ctDNA analysis. For each patient, one tumor mutation was selected to assess the presence and the level of ctDNA in plasma samples using a digital genomic assay termed Safe-SeqS.ResultsCandidate mutations for ctDNA analysis were identified in 52 (98.1%) of the tumors. These patient-specific candidate tissue mutations were detectable in the cell-free DNA from the plasma of 48 of these 52 patients (concordance 92.3%). Significant reductions in ctDNA (median 5.7-fold; P < 0.001) levels were observed before cycle 2, which correlated with CT responses at 8–10 weeks (odds ratio = 5.25 with a 10-fold ctDNA reduction; P = 0.016). Major reductions (≥10-fold) versus lesser reductions in ctDNA precycle 2 were associated with a trend for increased progression-free survival (median 14.7 versus 8.1 months; HR = 1.87; P = 0.266).ConclusionsctDNA is detectable in a high proportion of treatment naïve mCRC patients. Early changes in ctDNA during first-line chemotherapy predict the later radiologic response.     

A specific diplotype defined by PPP1R13L rs1970764, CD3EAP rs967591 and ERCC1 rs11615 and lung cancer risk in a Chinese population

Haplotypes defined by multiple loci may be more precise and useful than genotypes in providing risk estimates for particular cancers. Diplotype is defined as a specific combination of two haplotypes. A Chinese case-control analysis comprising 370 cases and 388 controls was conducted to evaluate the effects of the high-risk diplotype predefined as PPP1R13L rs1970764(AA)-CD3EAP rs967591(GG)-ERCC1 rs11615(AA) among Caucasians and three SNPs alone or other haplotypes combined for lung cancer risk. Both the variant G-allele of PPP1R13L rs1970764 and the variant A-allele of CD3EAP rs967591 were significantly over-represented among cases (P=0.03 and P=0.002, respectively). The variant GG-homozygotes of PPP1R13L rs1970764 had increased risk [GG versus AA: adjusted OR (95% CI)=1.30 (1.04-1.62), P=0.02]. The carriers of variant A-allele of CD3EAP rs967591 also presented increased risk [AA versus GG: adjusted OR (95% CI)=1.40 (1.12-1.75), P=0.004; AG versus GG: adjusted OR (95% CI)=1.47 (1.05-2.07), P=0.03 and AG+AA versus GG: adjusted OR (95% CI)=1.26 (1.07-1.48), P=0.005]. Interaction between CD3EAP rs967591 and smoking duration was observed (P=0.003). Only haplotype 1 (the common haplotype) defined as PPP1R13L rs1970764(G)-CD3EAP rs967591(A)-ERCC1 rs11615(G) showed marginally increased risk [OR (95% CI)=1.38 (1.09-1.75), P=0.009] after Bonferroni correction. The frequency of the high-risk diplotype predefined among Caucasians was 1% in controls and no significant evidence of the diplotype distribution between cases and controls was detected in present study. In conclusion, we found that variant alleles of PPP1R13L rs1970764 and CD3EAP rs967591 may contribute to risk factors of lung cancer, but the high-risk diplotype predefined among Caucasians was rare and the diplotype is unlikely to confer lung cancer risk in a Chinese population.     

Leptin is associated with an increased female colorectal cancer risk: a nested case-control study in Japan

OBJECTIVE: To elucidate whether leptin is involved in the etiology of female colorectal cancer. METHODS: A case-control study nested in the Japan Collaborative Cohort Study. We compared serum leptin levels in 58 cases of female colorectal cancer with those in 145 controls matched for study area and age. Data were analyzed using a conditional logistic regression model with adjustments for known risk factors for the development of colorectal cancer. Quintile cutoff points were determined on the distribution of leptin levels in cases and controls combined. RESULTS: Serum geometric mean levels of leptin were 6.88 ng/ml in cases and 6.00 ng/ml in controls. The odds ratios of female colorectal cancer risk were 1.40 (95% confidence interval, CI: 0.41-4.78) for the category of the second and third quintiles combined, and 4.84 (CI: 1.29-18.1) for the category of the fourth and fifth quintiles combined relative to the first quintile after adjustment for body mass index (BMI), life-style factors, reproductive factors, and hormonal variables including insulin-like growth factor and its binding protein. CONCLUSION: Our results suggest that leptin most likely increases the risk of female colorectal cancer substantially independent of BMI.     

A case of multiple liver metastases showing good response by administration of carmofur alone in an aged patient with colorectal cancer

An 85-year-old woman had an elevated serum tumor marker CEA, and CT examination revealed multiple liver metastases. The patient was treated with oral administration of 200 mg/day of carmofur (HCFU) alone in our hospital. As a result, more than 60% of the focuses of liver metastasis disappeared, and the level of CEA decreased. The present case seems to show that liver metastases were significantly decreased by chemotherapy with oral administration of HCFU by itself. Thus, the case suggests that HCFU is useful for the treatment of liver metastases from colorectal cancer.     

A case of toxicity caused by drug interaction between capecitabine and phenytoin in patient with colorectal cancer

We present a case of toxicity caused by a drug interaction between capecitabine and phenytoin (PHT). The drug combination elevated the plasma level of PHT in a patient on chemotherapy with capecitabine for colorectal cancer. Our patient was a 44-year-old woman diagnosed with epilepsy in her 20's, being treated with valproic acid (VPA) and PHT. Adjuvant chemotherapy with capecitabine began following surgery for colorectal cancer. Seven weeks later, she developed numbness, dizziness, dysarthria and difficulty walking, and was hospitalized for investigation. Her serum PHT level was elevated at 35. 1 μg/ mL. This case suggests that when capecitabine and PHT are coadministered, PHT levels should be monitored frequently, and that PHT dosage should be adjusted accordingly if it cannot be replaced by an alternative anticonvulsant.