HER2 Ile655Val polymorphism is negatively associated with breast cancer susceptibility

Background

The HER2 (human epidermal growth factor receptor‐2) Ile655Val (rs1136201) genetic polymorphism can alter the receptor structure and its auto‐activation, which can modify the signal transduction and, consequently, the cell cycle regulation. For this reason, this polymorphism has been extensively investigated as a candidate marker for breast cancer (BC). In this context, the aim of this study was to evaluate the possible influence of HER2 Ile655Val in BC susceptibility and prognostic factors in a Brazilian population.

Methods

Polymorphism genotype was assessed through RFLP‐PCR in 107 BC patients with clinicopathological data available and in 150 women with no evidence of neoplasia and with no familial history of BC as control group. Association between this polymorphism and BC susceptibility and clinical parameters was evaluated through odds ratio (OR) and chi‐squared or Fisher's exact test, respectively.

Results

A significant negative association between valine allele and BC susceptibility in dominant model was found (OR 0.5; 95% CI 0.27‐0.93, P = .036). No significant association was found in relation to BC clinicopathological features (tumor size, lymph nodes commitment, histological grade, HER2 overexpression, hormonal receptors, p53, and Ki‐67).

Conclusion

Although this polymorphism did not demonstrate potential as a prognostic marker, it may be a suitable susceptibility marker for BC.

     

p53 codon72基因多态性与人乳头瘤病毒相关食管鳞癌遗传易感性研究的Meta分析

目的运用Meta分析的方法综合评价p53 codon72基因多态性与人乳头瘤病毒(HPV)相关食管鳞癌的关系。方法系统检索Pub Med、中国期刊网全文数据库和万方数据知识服务平台文献,并辅以文献追溯等方法,收集截至2016年3月国内外公开发表的关于p53 codon72基因多态性与HPV相关食管鳞癌研究的文献。采用Stata 11.0软件进行统计分析,对各项研究结果进行异质性检验,以合并OR值及95%可信区间(95%CI)为效应指标,同时进行敏感性分析。结果共纳入8篇文献,其中6篇病例对照研究,2篇单纯病例研究,纳入研究的病例553例,对照354名。HPV感染阳性人群患食管鳞癌的风险是HPV感染阴性人群的15.35倍[95%CI(2.33,101.23),P<0.05];p53 codon72基因多态性与食管鳞癌发生的易感性有一定的相关性[OR=1.38,95%CI(1.09,1.77),P<0.05],Arg/Arg基因型可增加患HPV相关食管鳞癌的风险[OR=1.82,95%CI(1.28,2.59),P<0.05];在食管鳞癌患者中,Arg等位基因携带者感染HPV的风险是Pro等位基因携带者的1.97倍[95%CI(1.49,2.61),P<0.05]。结论 p53 Arg72Pro基因多态性与HPV相关食管鳞癌的发生相关,携带等位基因Arg或Arg/Arg纯合基因型是HPV相关食管鳞癌的高危因素。在食管鳞癌患者中,p53codon72Arg等位基因和HPV感染具有共存性。     

A case-control study of the HER2 Ile655Val polymorphism and risk of breast cancer in Taiwan

OBJECTIVES: To investigate the HER2 Ile655Val polymorphism in relation to risk of breast cancer in a case-control study in Taiwan. DESIGN AND METHODS: The HER2 polymorphism at codon 655 was analyzed in 424 patients with breast cancer and 318 controls by using the polymerase chain reaction methodology, followed by the restriction fragment-length polymorphism (PCR-RFLP) analysis. RESULTS: There was a 1.48-fold (95% CI=1.00-2.24) increase in the risk of patients with breast cancer who are Val carrier (Ile/Val and Val/Val genotypes). Furthermore, for the early onset (less than 45 years old) breast cancers with Val carrier, there was a 2.24-fold (95% CI=1.17-4.34) increase in the risk of breast cancer. CONCLUSIONS: Our results indicate that the Val carrier was associated with increased risks in patients with breast cancer in Taiwan. The association was more apparent in patients who were younger than or equal to 45 years of age.     

Correlation of p21 gene codon 31 polymorphism and TNF-alpha gene polymorphism with nasopharyngeal carcinoma

Background p21 (WAF1/CIP1) is a downstream protein from p53 and can arrest the cell cycle at the G1/S phase in response to signal from p53. The most frequently seen polymorphic site is at codon 31, where a base change from AGC to AGA causes an amino acid change from serine to arginine. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that is secreted from macrophages, and is related to a sequence of events in the response to inflammation and cancer formation. The TNF-alpha gene promoter -308 G/A polymorphism has been reported to be associated with some cancers. In this study, these polymorphisms were proposed to be a candidate genetic marker of nasopharyngeal carcinoma (NPC). The distribution was analyzed in 47 NPC patients and a control group of 119 healthy people. The association of the p21 codon 31 polymorphism with NPC was detected by polymerase chain reaction (PCR) and restriction analysis by Blp I endonuclease, and calculated by the chi-square test. The TNF-alpha gene promoter -308 G/A polymorphism was identified by Nco I endonuclease. The distribution of the gene p21 codon 31 polymorphisms showed no significant difference between the two groups. The serine form of p21 codon 31 was more prominent in smokers than nonsmokers among the NPC patients (P < 0.05). There was no significant difference in the distribution of TNF-alpha gene promoter -308 G/A polymorphism between control and cancer patients. The results indicate that the gene p21 codon 31 polymorphism and TNF-alpha promoter -308 polymorphism are not correlated with NPC. However, the difference between smokers and nonsmokers suggests that an environmental factor may be involved in association with the p21 gene in the formation of NPC.     

A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease

Although Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens, the influence of polymorphisms in this gene family on human susceptibility to infection is poorly understood. We demonstrated recently that TLR5 recognizes flagellin, a potent inflammatory stimulus present in the flagellar structure of many bacteria. Here, we show that a common stop codon polymorphism in the ligand-binding domain of TLR5 (TLR5392STOP) is unable to mediate flagellin signaling, acts in a dominant fashion, and is associated with susceptibility to pneumonia caused by Legionella pneumophila, a flagellated bacterium. We also show that flagellin is a principal stimulant of proinflammatory cytokine production in lung epithelial cells. Together, these observations suggest that TLR5392STOP increases human susceptibility to infection through an unusual dominant mechanism that compromises TLR5's essential role as a regulator of the lung epithelial innate immune response.     

IL-2 gene C/T polymorphism is associated with prostate cancer

Cytokines are reported to be associated with the formation of prostate cancer. Our aim was to investigate whether C/T polymorphisms of the interleukin-2 (IL-2) gene and IL-2 receptor beta (IL-2RB) gene are associated with prostate cancer. We compared the frequency of the polymorphisms of the IL-2 gene and the IL-2RB gene between 96 patients with prostate cancer and 105 healthy male volunteers from the same area (age >60 years). They were followed for at least 5 years. There was a significant difference in distribution of the genotype of the IL-2 gene polymorphism between the prostate cancer group and the control group (P = 0.017). The distribution of the TT homozygote of the IL-2 gene was significantly higher in the cancer group (32.3%) than in the control group (16.2%). However, no significant statistical difference was found between the polymorphism of the IL-2 gene and prostate cancer in survival analysis during a 5-year follow up period (log rank test; P = 0.19). There was no significant difference in the distribution of the genotype of the IL-2RB gene polymorphism between controls and cancer patients (P = 0.388). This study suggests that the IL-2 gene may be associated with susceptibility to prostate cancer in the Taiwan population.     

Deep-vein thrombosis is associated with large uterine fibroids

Pulmonary thromboembolism (PE) may occur upon a patient's first postoperative attempt of ambulation. PE is a serious complication, often leading to shock or sudden death. Reported rates of PE following gynecologic surgery are between 0.3% and 0.8%, while the incidence of postoperative deep-vein thrombosis (DVT), the major cause of PE, is between 17% and 20%. Therefore, effective preventive measures, such as preoperative assessment for asymptomatic DVT, should be considered. It is well known that DVT and/or PE are associated with large uterine fibroids, the common, benign tumor of myometrium. Here, to establish the statistical relationship between DVT risk and uterine fibroid size/weight, we assessed the preoperative DVT rate with respect to three possible risk factors: age, obesity level, and uterine size/weight. A total of 361 patients with uterine fibroids undergoing hysterectomy between July, 2003 and December, 2009 were enrolled. All patients were evaluated for preoperative DVT; the results were stratified for statistical comparison by patient age, BMI, and uterine weight. There was no statistical difference in the DVT rate for patients stratified by age (below age 45 years or older) or BMI (below 25 or higher). By contrast, the rate of DVT was significantly higher for patients with uterine weights of 1,000 gm or more (11.5% [7/61]) compared with weights below 1,000 gm (3.0% [9/300]). None of the patients studied developed PE. In conclusion, the incidence of DVT is significantly higher in cases where uterine weight is 1,000 gm or more (ie, adult head size on pelvic examination).     

A CXCL2 polymorphism is associated with better outcomes in patients with severe sepsis

OBJECTIVE: Several studies have implicated the CXCL2 chemokine as a mediator in the development of sepsis. We hypothesized that a tandem repeat polymorphism (AC)n in the CXCL2 gene, previously associated with susceptibility to severe sepsis, contributes to morbidity and mortality in severe sepsis. DESIGN: Prospective, observational, genetic study of septic patients. SETTING: A network of Spanish postsurgical and critical care units. PATIENTS: A total of 183 critically ill patients fulfilling the International Sepsis Criteria for severe sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were classified into three groups according to the presence of compound 24 +/- 1 (AC) repeat genotypes: homozygote 24 +/- 1 carriers (HC group), heterozygote 24 +/- 1 carriers (HTC), and non 24 +/- 1 carriers (NC group). Mortality, development of acute respiratory distress syndrome, and number of failing organs were determined for each group. Overall mortality was 46.4%. HC patients had a lower mortality (39.9%) than HTC (52.2%) and NC (72.7%) patients (trend test p = .018). This difference remained significant when using a multiple logistic regression analysis (p = .035). The presence of population stratification was ruled out, since 20 independent genomic control markers demonstrated homogeneity among groups. An exploratory analysis of the effect of acute respiratory distress syndrome on mortality showed a relative risk of 2.60 in the HC group (p = .0004), while in the nonhomozygote carriers (NHC) group the relative risk was 3.34 (p = .0001). CONCLUSIONS: Our data suggest that a tandem repeat polymorphism (AC)n at position -665 in the CXCL2 gene may be an independent predictor of mortality for severe sepsis. Additional studies are needed to confirm these results.     

FASL -844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer

The FAS receptor-ligand system plays a key role in regulating apoptotic cell death, and corruption of this signaling pathway has been shown to participate in tumor-immune escape and carcinogenesis. We have recently demonstrated (Sun, T., X. Miao, X. Zhang, W. Tan, P. Xiong, and D. Lin. 2004. J. Natl. Cancer Inst. 96:1030-1036; Zhang, X., X. Miao, T. Sun, W. Tan, S. Qu, P. Xiong, Y. Zhou, and D. Lin. 2005. J. Med. Genet. 42:479-484) that functional polymorphisms in FAS and FAS ligand (FASL) are associated with susceptibility to lung cancer and esophageal cancer; however, the mechanisms underlying this association have not been elucidated. We show that the FAS -1377G, FAS -670A, and FASL -844T variants are expressed more highly on ex vivo-stimulated T cells than the FAS -1377A, FAS -670G, and FASL -844C variants. Moreover, activation-induced cell death (AICD) of T cells carrying the FASL -844C allele was increased. We also found a threefold increased risk of cervical cancer among subjects with the FASL -844CC genotype compared with those with the -844TT genotype in a case-control study in Chinese women. Together, these observations suggest that genetic polymorphisms in the FAS-FASL pathway confer host susceptibility to cervical cancers, which might be caused by immune escape of tumor cells because of enhanced AICD of tumor-specific T cells.     

GNAS1 T393C polymorphism is associated with migraine

Migraineurs have an interictal sympathetic nervous system (SNS) hypofunctionality and hypersensitivity to adrenergic amines. The GNAS1 T393C polymorphism has been associated with a distinct SNS sensitivity in healthy subjects. We tested GNAS1 T393C variant in two independent sets of subjects. In the case-control subset, 365 migraine patients [194 with aura (MA)] vs. 347 healthy controls were studied. A significant excess of the CC genotype was found in migraneurs (31.2%) as opposed to controls (20.2%; P=0.003). Using a logistic regression model corrected for sex, the CC genotype conferred a general risk for migraine twice [odds ratio (OR) 1.79, 95% confidence interval (CI) 1.27-2.53; P=0.001] higher than CT/TT genotypes. Using parents from 117 migraine families, a marginally significant trend for association could be observed (P=0.025), but the transmission disequilibrium test for alleles maternally transmitted failed to demonstrate familial association. In this subgroup, CC genotype conferred a risk for migraine over twice (OR 2.20; 95% CI 1.14-4.40; P=0.019) higher than TT/TC genotypes. In conclusion, the GNAS1 T393C variant is associated with migraine, which suggests a genetic basis for its higher SNS sensitivity.     

BDNF Val66Met polymorphism is associated with unstable angina

BackgroundBrain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of coronary artery disease (CAD). The human BDNF Val66Met polymorphism has been shown to be associated with altered susceptibility to neuropsychiatric disorders. However it is unknown whether this polymorphism plays a role in cardiovascular disease.MethodsGenotyping of BDNF Val66Met polymorphism was carried out in 513 controls, 628 unstable angina pectoris (UAP) and 276 stable angina pectoris (SAP) patients. The plasma concentrations of BDNF and high-sensitivity C-reactive protein (hsCRP) were measured by ELISA. The general clinical data in patients and controls were obtained.ResultsThere was a significant association between genotype and allele frequency of the BDNF Val66Met polymorphism and UAP (all P < 0.05). Multivariate logistic regression analysis revealed that the BDNF_Met/Met genotype had a protective effect on the occurrence of UAP after controlling for known risk factors of CAD (OR 0.53, P = 0.005). Subjects with BDNF_Met/Met genotype also had decreased plasma hsCRP levels compared with the Val carriers (P < 0.01).ConclusionThe BDNF_Met/Met genotype has a protective effect on the occurrence of UAP, which might in part be due to the decreased plasma hsCRP level in BDNF_Met/Met carriers. To our knowledge, this is the first study that demonstrates the link between BDNF Val66Met polymorphism and CAD.     

Cardiotoxicity associated with trastuzumab treatment of HER2+ breast cancer

Introduction

Although having high clinical efficacy in the treatment of human epidermal growth factor receptor-2 (HER2+) metastatic breast cancer, trastuzumab has been associated with cardiotoxicity, and the etiology and pathogenesis of this condition is currently under investigation.

Methods

This paper reviews the cardiotoxicity, associated with trastuzumab use and discusses the risk assessment and management of cardiac dysfunction.

Results

The increased risk of cardiotoxicity is lower when trastuzumab is given as monotherapy (3%–7%) compared with anthracyclines + trastuzumab therapy (27%). Type II cardiac changes occur in trastuzumab-treated patients, which do not appear to be dose-related, are not associated with histological changes, and are generally reversible. Several risk factors for cardiac events have been identified and assessing levels of troponin I and N-terminal pro-brain B-type natriuretic peptide before and after treatment with trastuzumab may allow early detection of cardiotoxicity. A symptomatic and functional evaluation scheme for patients indicated for treatment with trastuzumab has also been proposed to work alongside therapeutic options for the treatment of heart failure.

Conclusion

The risk of cardiac dysfunction associated with trastuzumab can be justified given the increase in overall survival. This risk is lower when trastuzumab is given as monotherapy. The paradigm for cardiologists remains the same: treat the cancer effectively whilst preventing cardiotoxicity.

     

The paraoxonase-1 codon 192 polymorphism is associated with fasting total cholesterol and LDL-cholesterol concentrations only in postmenopausal women. The REGICOR study.

Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-linked enzyme which appears to protect low-density lipoproteins (LDL) from oxidation. PON1 activity is associated with variation at the PON1 gene locus, specifically the common amino acid polymorphism at codon 192, for which the Q192 allele specifies low activity and the R192 allele specifies high activity. We investigated the association between the PON1 codon 192 polymorphism and fasting concentrations of glucose, lipids, lipoproteins and PON1 activity in 1380 subjects (724 men and 656 women). Several anthropometric and environmental factors were assessed in the present study. The PON1 Q192 allele frequency was 0.70 and 0.68 in men and women, respectively. In women, but not in men, significant associations were found between the PON1 codon 192 genotype and both total and LDL-cholesterol (p=0.004 and p=0.008, respectively), and subgroup analysis indicated that this relationship was predominant in postmenopausal women. Specifically, the Q192 allele was associated with increased total and LDL-cholesterol concentrations. Furthermore, these lipoprotein variables were higher among postmenopausal women with Q192/Q192 and Q192/R192 genotypes than in premenopausal women with the same genotypes (p<0.001). The findings suggest a gender-specific lipoprotein-genotype association with PON1 codon 192 genotypes in this study sample.