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Single nucleotide polymorphisms of let-7-related genes increase susceptibility to breast cancer.

ABSTRACT: BACKGROUND:Let-7 is a microRNA (miRNA) that targets the ?2 adrenergic receptor (ADRB2), hypoxia inducible factor 1 subunit alpha inhibitor (HIF1AN), and claudin 12 (CLDN12) genes. Single nucleotide polymorphisms (SNPs) in the structural or regulatory regions of these miRNA let-7-related genes may be associated with breast cancer carcinogenesis and prognosis. Low let-7 expression may increase breast cancer risk. We investigated the effects of let-7-related gene SNP (mirSNPs) on breast cancer risk and clinical outcomes. METHODS:The distribution frequencies of the three SNPs were genotyped in patients with breast cancer and controls. Multivariate logistic regression analysis was used to evaluate the association between the SNPs and susceptibility to breast cancer. We investigated the effects of these mirSNPs prospectively on disease-free survival (DFS) using the Kaplan-Meier method and the extended multivariate Cox model. RESULTS:We found that rs1042713 in the ADRB2 gene and rs11292 in the 3'-UTR of the HIF1AN gene were associated with breast cancer susceptibility (P<0.05). The CLDN12 rs1017105 genotype was associated with estrogen receptor (P=0.031) and progesterone receptor status (P=0.007). The number of risk alleles was associated with estrogen receptor (P=0.034) status in breast cancer patients. In the survival analysis, the extended Cox model demonstrated that rs1042713 (P=0.000) and rs1017105 (P=0.004) were independent predictors of DFS. The number of risk alleles of the ADRB2, HIF1AN, and CLDN12 genes was an independent predictor of DFS (P<0.001). CONCLUSION:Let-7-related mirSNPs might be associated with carcinogenesis and clinical outcome in breast cancer, suggesting that variants of miRNA let-7-related gene networks coregulate breast cancer characteristics.

SUBMITTER: Du Y

PROVIDER: S-EPMC6456510 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Single nucleotide polymorphisms of let-7-related genes increase susceptibility to breast cancer.

Du Yueyao Y Lin Yanping Y Yin Kai K Zhou Liheng L Jiang Yiwei Y Yin Wenjin W Lu Jinsong J

American journal of translational research 20190315 3

<h4>Background</h4>Let-7 is a microRNA (miRNA) that targets the β2 adrenergic receptor (<i>ADRB2</i>), hypoxia inducible factor 1 subunit alpha inhibitor (<i>HIF1AN</i>), and claudin 12 (<i>CLDN12</i>) genes. Single nucleotide polymorphisms (SNPs) in the structural or regulatory regions of these miRNA let-7-related genes may be associated with breast cancer carcinogenesis and prognosis. Low let-7 expression may increase breast cancer risk. We investigated the effects of let-7-related gene SNP (m ...[more]

PMID: 30972198

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Project description:ObjectiveThe purpose of the present study was to evaluate the associations between seven tagging single nucleotide polymorphisms (tSNPs) and risk of breast cancer assessed by tumor pathological characteristics and body mass index (BMI).MethodsSeven tSNPs of four breast cancer susceptibility genes were analyzed in 734 Chinese women with breast cancer and 672 age-matched healthy controls; then, the association with clinicopathological characteristics, BMI, molecular subtype, TNM (T, tumor; N, lymph node; M, metastasis) staging and lymph node status was determined by unconditional logistic regression.ResultsRs12951053 in TP53 and rs16945628 in BRIP1, displayed increased risk of breast cancer in the BMI ≧ 25 kg/m2 group (OR=1.50, 95% CI: 1.02-2.21, P=0.041 and OR=1.92, 95% CI: 1.13-3.26, P=0.015, respectively). The other five tSNPs (rs1805812, rs2735385 and rs6999227 in NBS1, rs7220719 in BRIP1 and rs2299941 in PTEN) displayed a decreased risk of breast cancer in the 18.5≤BMI<25 kg/m2 group. Rs12951053 in TP53 and rs7220719 in BRIP1 exhibited an increased risk of triple-negative breast cancer (OR=1.50, 95% CI: 1.05-2.15, P=0.026 and OR=2.13, 95% CI: 1.05-4.29, P=0.032, respectively), but three tSNPs in NBS1 (rs1805812, rs2735385 and rs6999227) all displayed a negative association with both luminal B and triple-negative breast cancer. The tSNP rs2299941 in PTEN also exhibited a negative association with each molecular subtype, except triple-negative breast cancer. The majority of tSNPs displayed a negative association with stage II or III breast cancer. Most tSNPs showed a negative association with breast cancer that was lymph node negative or with 1-3 positive nodes. Only rs12951053 in TP53 displayed a positive association with lymph node-negative breast cancer (OR=1.43, 95% CI: 1.08-1.91, P=0.013).ConclusionThe majority of tSNPs displayed a negative association with breast cancer and only a few tSNPs (rs12951053 in TP53, rs16945628 and rs7220719 in BRIP1) showed an increased risk of breast cancer as defined by clinicopathological characteristics.

Project description:Thyroid cancer (TC) is the most common endocrine malignancy and its incidence continues to rise worldwide. Ionizing radiation exposure is the best established etiological factor. Heritability is high; however, despite valuable contribution from recent genome-wide association studies, the current understanding of genetic susceptibility to TC remains limited. Several studies suggest that altered function or expression of the DNA mismatch repair (MMR) system may contribute to TC pathogenesis. Therefore, the present study aimed to evaluate the potential role of a panel of MMR single nucleotide polymorphisms (SNPs) on the individual susceptibility to well-differentiated TC (DTC). A case-control study was performed involving 106 DTC patients and 212 age- and gender-matched controls, who were all Caucasian Portuguese. Six SNPs present in distinct MMR genes (MLH1 rs1799977, MSH3 rs26279, MSH4 rs5745325, PMS1 rs5742933, MLH3 rs175080 and MSH6 rs1042821) were genotyped through TaqMan® assays and genotype-associated risk estimates were calculated. An increased risk was observed in MSH6 rs1042821 variant homozygotes [adjusted odds ratio (OR)=3.42, 95% CI: 1.04-11.24, P=0.04, under the co-dominant model; adjusted OR=3.84, 95% CI: 1.18-12.44, P=0.03, under the recessive model]. The association was especially evident for the follicular histotype and female sex. The association was also apparent when MSH6 was analysed in combination with other MMR SNPs such as MSH3 rs26279. Interestingly, two other SNP combinations, both containing the MSH6 heterozygous genotype, were associated with a risk reduction, suggesting a protective effect for these genotype combinations. These data support the idea that MMR SNPs such as MSH6 rs1042821, alone or in combination, may contribute to DTC susceptibility. This is coherent with the limited evidence available. Nevertheless, further studies are needed to validate these findings and to establish the usefulness of these SNPs as genetic susceptibility biomarkers for DTC so that, in the near future, cancer prevention policies may be optimized under a personalized medicine perspective.

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Single nucleotide polymorphisms of let-7-related genes increase susceptibility to breast cancer.

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Single nucleotide polymorphisms of let-7-related genes increase susceptibility to breast cancer.

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