Polymorphisms in DNA repair genes and therapeutic outcomes of AML patients from SWOG clinical trials

Repair of damage to DNA resulting from chemotherapy may influence drug toxicity and survival in response to treatment. We evaluated the role of polymorphisms in DNA repair genes APE1, XRCC1, ERCC1, XPD, and XRCC3 in predicting therapeutic outcomes of older adults with acute myeloid leukemia (AML) from 2 Southwest Oncology Group (SWOG) clinical trials. All patients received standard chemotherapy induction regimens. Using logistic and proportional hazards regression models, relationships between genotypes, haplotypes, and toxicities, response to induction therapy, and overall survival were evaluated. Patients with XPD Gln751C/Asp312G ('D') haplotype were more likely to have complete response (OR = 3.06; 95% CI, 1.44-6.70) and less likely to have resistant disease (OR = 0.32; 95%CI, 0.14-0.72) than patients with other haplotypes. ERCC1 polymorphisms were significantly associated with lung (P = .037) and metabolic (P = .041) toxicities, and patients with the XRCC3 241Met variant had reduced risk of liver toxicity (OR = 0.32; 95%CI, 0.11-0.95). Significant associations with other toxicities were also found for variant XPD genotypes/haplotypes. These data from clinical trials of older patients treated for AML indicate that variants in DNA repair pathways may have an impact on both outcomes of patients and toxicities associated with treatments. With validation of results in larger samples, these findings could lead to optimizing individual chemotherapy options.     

Polymorphisms in the brain-specific thyroid hormone transporter OATP1C1 are associated with fatigue and depression in hypothyroid patients

Introduction Some hypothyroid patients continue to have significant impairments in psychological well‐being, despite adequate treatment with levothyroxine (LT4). T4 transport across the blood–brain barrier is one of the crucial processes for thyroid hormone action in the brain. OATP1C1, a thyroid hormone transporter expressed at the blood–brain barrier, is considered to play a key role in delivering serum T4 to the brain. Objective To examine whether polymorphisms in OATP1C1 are determinants of well‐being, neurocognitive functioning and preference for replacement therapy with a combination of LT4 and liothyronine (LT3). Design and participants We studied 141 patients with primary autoimmune hypothyroidism, adequately treated with LT4 monotherapy and participating in a randomized clinical trial comparing LT4 therapy with LT4–LT3 combination therapy. Outcome measurements Different questionnaires on well‐being and neurocognitive tests were performed at baseline. Serum thyroid parameters, OATP1C1‐intron3C > T, OATP1C1‐Pro143Thr and OATP1C1‐C3035T polymorphisms were determined. Results Allele frequencies of the OATP1C1 polymorphisms in patients with primary hypothyroidism were similar to those of healthy controls. Both the OATP1C1‐intron3C > T and the OATP1C1‐C3035T polymorphism, but not the OATP1C1‐Pro143Thr polymorphism, were associated with symptoms of fatigue and depression. OATP1C1 polymorphisms were not associated with measures of neurocognitive functioning or preference for combined LT4–LT3 therapy. Conclusions OATP1C1 polymorphisms are associated with fatigue and depression, but do not explain differences in neurocognitive functioning or appreciation of LT4–LT3 combination therapy. Future studies are needed to confirm these findings.     

Polymorphisms of TAP1 transporter genes in Chinese patients with systemic lupus erythematosus in Taiwan

The aim of this study was to determine how polymorphisms of transporters associated with transporter and antigen processing 1 (TAP1) alleles contributed to the pathogenesis of systemic lupus erythematosus (SLE) in Taiwan. We collected 88 patients with SLE and 104 healthy people for the control group. The polymorphisms were detected as a result of polymerase chain reaction (PCR)-based restriction analysis. Associations between SLE and TAP1 polymorphisms were evaluated. The results revealed no significant differences between the healthy individuals and SLE patients with TAP1-1 (Dpn II) and TAP1-2 (Acc I) polymorphisms (P=0.10 and 0.36, respectively). However, the G alleles of TAP1-1 and TAP1-2 were significantly more common than the A alleles in serositis of SLE patients (²=11.16 and P=0.004, ²=8.10 and P=0.02, respectively).     

Clinical outcomes of lung metastasectomy in patients with colorectal cancer

AIM: To investigate prognostic factors of survival following curative, non-palliative surgical removal of lung metastases secondary to colorectal cancer (CRC).METHODS: Between 1999 and 2009, a radical metastasectomy with curative intent was performed on lung metastases in 21 patients with CRC (15 male and 6 female; mean age: 57.4 ± 11.8 years; age range: 29-74 years) who had already undergone primary tumour resection.RESULTS: The mean number of lung metastases ranged from one to five. The mean overall survival was 71 ± 35 mo (median: 25 mo). After adjusting for potential confounders, multivariable Cox regression analyses predicted only the number of lung metastases (1 vs ≥ 2; hazard ratio: 7.60, 95% confidence interval: 1.18-17.2, P = 0.03) as an independent predictor of poor survival following lung resection for metastatic CRC.CONCLUSION: Resection of lung metastases is a safe and effective treatment in selected CRC patients with single lung metastases.     

Polymorphisms of the TLR2 and TLR4 genes are associated with risk of gastric cancer in a Brazilian population

AIM: To investigate toll-like receptor 2 (TLR2) -196 to -174 del, and TLR4 (+896A/G rs4986790 and +1196C/T rs4986791) polymorphisms at risk of chronic gastritis and gastric cancer in a Brazilian population and association of gastric lesions with risk factors such as smoking, alcohol intake and Helicobacter pylori infection.METHODS: In this case-control study, polymorphism at TLR2 -196 to -174 del was investigated by using the allele-specific polymerase chain reaction (PCR) method, while the PCR-restriction fragment length polymorphism technique was carried out to identify the TLR4 (rs4986790 and rs4986791) genotypes in 607 Brazilian individuals (208 with chronic gastritis-CG, 174 with gastric cancer-GC and 225 controls -C).RESULTS: The single nucleotide polymorphisms TLR4+1196C/T was not associated with risk of chronic gastritis or gastric cancer and the homozygous genotypes TLR4+896GG and TLR4+1196TT were absent in the studied population. However, the frequency of TLR2 -196 to -174 ins/del + del/del and TLR4+896AG genotypes was significantly higher (P < 0.01 and P = 0.01, respectively) in the cancer group (33.4% and 11.5%, respectively) than in the control group (16.9% and 4.5%, respectively). It was also observed that the G-C haplotype of the TLR4+896A/G+1196C/T (P = 0.02) and the combination of variant alleles of the TLR2/TLR4+896G (P = 0.02) are associated with susceptibility to gastric cancer. In addition, the multiple logistic regression showed that male gender [odds ratio (OR) = 2.70; 95% CI: 1.66-4.41; P < 0.01], alcohol intake (OR = 2.93; 95% CI: 1.76-4.87; P < 0.01), TLR2 -196 to -174 del (OR = 2.64; 95% CI: 1.56-4.44; P < 0.01) and TLR4+896G (OR = 3.19; 95% CI: 1.34- 7.61; P < 0.01) polymorphisms were associated with a higher susceptibility to developing this neoplasm.CONCLUSION: Our data indicate that TLR2 -196 to -174 del and TLR4+896G may increase the risk of gastric cancer in a Brazilian population.     

Polymorphisms in Nef associated with different clinical outcomes in HIV type 1 subtype C-infected children

The human immunodeficiency virus type 1 (HIV-1) negative factor, or Nef, has a variety of functions that are important in viral pathogenesis. Sequence analysis has identified nef mutations that are linked to the rate of disease progression in adults and children infected with HIV-1 subtype B. Here we have sequenced and analyzed HIV-1 subtype C nef sequences from 34 children with rapid (RP) or slow progressing (SP) disease and identified polymorphisms associated with disease stage including motifs involved in specific pathogenic functions. Unlike subtype B, insertions and deletions in the N-terminal variable region were observed exclusively in SP children (8 out of 25). Strong positive selection pressures were found in sites of known functional importance among SP sequences, whereas RP had strong negative selection across the gene. A lineage analysis of selection pressures indicated weaker pressure across the nef gene in SP sequences bearing a deletion in region 8-12, suggesting this deletion has functional importance in vivo. Together these results suggest a differential adaptation of certain Nef functions related to disease progression, some of which may be attributable to immune-imposed pressures. These data broadly reflect previous studies on subtype B, corroborate the decreased cytopathicity of SP viruses, but also highlight potential subtype differences that require further investigation.     

Chemotherapy options and outcomes in older adult patients with colorectal cancer

The majority of patients with colorectal cancer (CRC) are ≥65 years of age, yet older patients with CRC remain under-represented in clinical trials. Older adult patients may be more likely than younger patients to experience chemotherapy-related toxicities due to factors such as existing comorbidities, incompatibility of chemotherapy with other medications, and age-related reduction in the detoxification and elimination potential of the liver and kidneys. However, the older patient group are a heterogeneous population. The available data on treatment of older patients with CRC indicate that fit older adult patients have the potential to derive the same benefit as do younger patients. A comprehensive geriatric assessment can help to identify patients most likely to benefit from standard treatment. In this review, we will evaluate the chemotherapy regimens investigated in older adult patients with CRC, and how the safety profiles and efficacy of chemotherapy in the older adult compare with those observed in younger patients.     

年龄对老年人结直肠癌手术后临床预后的影响

目的 探讨年龄对老年人结直肠癌手术治疗后临床结局的影响.方法 回顾性总结我院1999年1月至2007年12月结直肠癌手术患者的临床资料1249例,根据年龄分为研究组(≥75岁,312例)和对照组(<75岁,937例).结果 (1)研究组的平均年龄明显高于对照组(t=33.09,P<0.05),具有营养不良风险的比例、并存其他疾病的比例、近端结肠肿瘤的比例、区域淋巴结转移的比例明显高于对照组(χ2值分别为47.33、130.75、21.24、45.33,均P<0.05);(2)研究组术前外科并发症的发生率、肠梗阻的发生率、急诊手术的比例明显高于对照组(χ2值分别为26.81、34.14、10.72,均P<0.05),研究组的手术切除率明显低于对照组(χ2=9.732,P<0.05);(3)研究组术后总并发症的发生率、一般并发症的发牛率和围手术期病死率明显高于对照组(χ2值分别为19.38、20.75、10.11,均P<0.05);(4)研究组2年生存率和5年生存率明显低于对照组(χ2值分别为11.91、27.17,均P<0.05);但研究组2年肿瘤特异生存率和5年瘤特异生存率与对照组的差异无统计学意义.结论 术前并存疾病、术前外科并发症、肿瘤的局部转移和术后非外科并发症影响老年人结直肠癌术后的临床结局.     

Temporal increases in subclinical levels of inflammation are associated with adverse clinical outcomes in patients with left ventricular dysfunction

BackgroundThe implication of various cytokines in a subclinical inflammatory process has been documented in heart failure (HF). The role of temporal changes of more conventional markers of inflammation, such as the white blood cell (WBC) count, on clinical outcomes remains largely unknown.Methods and ResultsWe performed a retrospective analysis of patients included in the Studies Of Left Ventricular Dysfunction that had documented eligibility at the baseline visit, a documented WBC count at baseline and at least 1 measurement during follow-up. We evaluated the association between variations in WBC count, WBC subfractions and mortality and non-fatal events. An increase in WBC count during follow-up compared with baseline was associated with a significantly higher risk of all-cause and cardiovascular (CV) mortality, HF mortality and arrhythmic death (all P < .05). A relative increase in the neutrophil count was associated with higher risk of all-cause and CV mortality, HF mortality and cardiac ischemic events (all P < .05). No significant interaction was present in regards to the etiology of HF.ConclusionsTemporal increases in WBC and neutrophil counts are associated with increased risks of death and CV events. This relationship appears to be independent of HF etiology.     

Polymorphisms of interleukin-10 promoter are not associated with prognosis of advanced gastric cancer

AIM: To evaluate the association between of the interleukin-10 (IL-10) promoter polymorphisms and survival of advanced gastric cancer (GC) patients. METHODS: The IL-10 (-1082, rs1800896; -819, rs1800871; and-592, rs1800896) genotypes in 234 patients with advanced gastric cancer and in 243 healthy controls were determined by polymerase chain reaction-restriction fragment length polymorphism assay. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by unconditional logistic regression for the ...     

Exon 3 beta-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome

BACKGROUND AND AIMS: Activating beta-catenin mutations in exon 3 have been implicated in colorectal tumorigenesis. Although reports to the contrary exist, it has been suggested that beta-catenin mutations occur more often in microsatellite unstable (MSI+) colorectal carcinomas, including hereditary non-polyposis colorectal cancer (HNPCC), as a consequence of defective DNA mismatch repair. We have analysed 337 colorectal carcinomas and adenomas, from both sporadic cases and HNPCC families, to provide an accurate assessment of beta-catenin mutation frequency in each tumour type. METHODS: Direct sequencing of exon 3 of beta-catenin. RESULTS: Mutations were rare in sporadic (1/83, 1.2%) and HNPCC adenomas (1/37, 2.7%). Most of the sporadic adenomas analysed (80%) were small (<1 cm), and our data therefore differ from a previous report of a much higher mutation frequency in small adenomas. No oncogenic beta-catenin mutations were identified in 34 MSI+ and 78 microsatellite stable (MSI-) sporadic colorectal cancers but a raised mutation frequency (8/44, 18.2%) was found in HNPCC cancers; this frequency was significantly higher than that in HNPCC adenomas (p=0.035) and in both MSI- (p<0.0001) and MSI+ (p=0.008) sporadic cancers. Mutations were more common in higher stage (Dukes' stages C and D) cancers (p=0.001). CONCLUSION: Exon 3 beta-catenin mutations are associated specifically with malignant colorectal tumours in HNPCC; mutations appear not to result directly from deficient mismatch repair. Our data provide evidence that the genetic pathways of sporadic MSI+ and HNPCC cancers may be divergent, and indicate that mutations in the HNPCC pathway of colorectal tumorigenesis may be determined by selection, not simply by hypermutation.     

Polymorphisms of peroxiredoxin 1, 2 and 6 are not associated with esophageal cancer

Purpose  

Peroxiredoxins, which reduced intracellular peroxides as a noval kind of antioxidant protein, were extensively expressed in various types of cancers and were thought as a biomarker of cancer cells. In this work, we performed genotyping analyses for tag SNP of Prdx 1, 2 and 6, and then evaluated the association with susceptibility and clinic stage of esophageal squamous cell carcinoma (ESCC) in a case–control study.     

Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects

Single nucleotide polymorphisms (SNPs) in genes involved in thyroid hormone metabolism may affect thyroid hormone bioactivity. We investigated the occurrence and possible effects of SNPs in the deiodinases (D1-D3), the TSH receptor (TSHR), and the T(3) receptor beta (TR beta) genes. SNPs were identified in public databases or by sequencing of genomic DNA from 15 randomly selected subjects (30 alleles). Genotypes for the identified SNPs were determined in 156 healthy blood donors and related to plasma T(4), free T(4), T(3), rT(3), and TSH levels. Eight SNPs of interest were identified, four of which had not yet been published. Three are located in the 3'-untranslated region: D1a-C/T (allele frequencies, C = 66%, T = 34%), D1b-A/G (A = 89.7%, G = 10.3%), and D3-T/G (T = 85.5%, G = 14.2%). Four are missense SNPs: D2-A/G (Thr92Ala, Thr = 61.2%, Ala = 38.8%), TSHRa-G/C (Asp36His, Asp = 99.4%, His = 0.6%), TSHRb-C/A (Pro52Thr, Pro = 94.2%, Thr = 5.8%), and TSHRc-C/G (Asp727Glu, Asp = 90.7%, Glu = 9.3%). One is a silent SNP: TR beta-T/C (T = 96.8%, C = 3.2%). D1a-T was associated in a dose-dependent manner with a higher plasma rT(3) [CC, 0.29 +/- 0.01; CT, 0.32 +/- 0.01; and TT, 0.34 +/- 0.02 nmol/liter (mean +/- SE); P = 0.017], a higher plasma rT(3)/T(4) (P = 0.01), and a lower T(3)/rT(3) (P = 0.003) ratio. The D1b-G allele was associated with lower plasma rT(3)/T(4) (P = 0.024) and with higher T(3)/rT(3) (P = 0.08) ratios. TSHRc-G was associated with a lower plasma TSH (CC, 1.38 +/- 0.07, vs. GC, 1.06 +/- 0.14 mU/liter; P = 0.04), and with lower plasma TSH/free T(4) (P = 0.06), TSH/T(3) (P = 0.06), and TSH/T(4) (P = 0.08) ratios. No associations with TSH and iodothyronine levels were found for the other SNPs. We have analyzed eight SNPs in five thyroid hormone pathway genes and found significant associations of three SNPs in two genes (D1, TSHR) with plasma TSH or iodothyronine levels in a normal population.     

Polymorphisms of the macrophage inflammatory protein 1 alpha and ApoE genes are associated with ulcerative colitis

Background and aims  An increased production of macrophage inflammatory proteins 1 alpha (MIP-1α) has been reported to be associated with ulcerative colitis (UC). We investigated whether a polymorphism site in MIP-1α was associated with UC in a Chinese population. Additionally, considering the abnormal lipoprotein metabolism in subjects with UC, we also sought to determine whether genetic variation in the apolipoprotein E (ApoE) gene may play a role in the development of UC. Materials and methods  We examined the MIP-1α −906 (TA)₄/(TA)₆ polymorphism and the ApoE polymorphism in a cohort of 162 unrelated UC patients and 220 healthy controls by using restriction fragment length polymorphism assay. Results  A significantly increased frequency of the MIP-1α −906 (TA)₆/(TA)₆ genotype (P = 0.0031, odds ratio [OR] = 1.851, 95% confidence interval [CI] 1.228–2.791), as well as of the ApoE ε4+ genotype (P < 0.001, OR = 2.869, 95% CI 1.768–4.657), in patients with UC was proven. Moreover, the carriage of both MIP-1α −906 (TA)₆/(TA)₆ genotype and ApoE ε4+ genotype confers greater risk for the development of UC (P < 0.001, OR = 5.432, 95% CI 2.761–10.689). Conclusion  These findings suggest that variation in the MIP-1α and ApoE genes and their interaction may increase susceptibility to UC. Identifying these novel susceptibility genes, as well as their interactions, will help our understanding of the disease mechanisms of UC and may identify targets for developing novel treatment measures.