Analysis of promoter methylation and polymorphic minisatellites of BORIS and lack of association with gastric cancer

BORIS is a member of the cancer-testis gene family that comprises genes normally expressed only in testis but abnormally activated in different malignancies. In this study, we examined the relation between BORIS expression and gastric cancer, which is the most common cancer in Korea. Abnormal BORIS expression in the patient's gastric cancer tissues was observed. We checked the methylation status of the gene in gastric cancer tissue, because the regulation by methylation in its CpG islands is well known for BORIS. However, there was no correlation between the methylation status and gene expression. Then, we focused on the minisatellites (variable number of tandem repeats) of BORIS as another possible regulator for this abnormal expression. Previously, we reported the characterization of BORIS-MS2 and determined the frequency of alleles in cancer patients. A case-control study was performed using DNA from 774 controls and 496 patients with gastric cancer. There was no significant difference observed in the overall distribution of minisatellite alleles. These results suggest that additional different regulators for the abnormal BORIS expression in gastric cancer may exist. Additionally, we performed a segregation analysis of BORIS-MS2 with genomic DNA obtained from two generations of five families and from three generations of two families. BORIS-MS2 alleles were transmitted through meiosis following Mendelian inheritance, which suggests that this polymorphic minisatellite could be a useful marker for paternity mapping and DNA fingerprinting.     

Steroid hormone concentrations in relation to patient prognosis and prostate tumour grade

Survival of patients who received endocrine therapy as first-line treatment for their prostatic cancer was statistically analysed in relation to several parameters, primary tumour stage, metastatic status, age, pretreatment plasma hormone concentrations and Gleason grade. Prognostic indices were derived for both M0 and M1 patients in which Gleason grade and plasma testosterone concentrations were significant prognostic factors. In the M1 patients growth hormone values were also significant and to a lesser degree age. The relationship of Gleason grade to testosterone, growth hormone, prolactin, the gonadotrophins and age was also analysed. No significant differences in any of these hormones was noted with increasing Gleason grade but the age of patients with Grade 5 tumours was significantly lower.     

Gradient of nuclear volume changes in breast cancer and its relation to prognosis

OBJECTIVE: In a study of 112 cases of invasive breast cancer, the prognostic value of the gradient of nuclear volume (NV) changes was examined. STUDY DESIGN: On conventional histologic slides of surgically resected specimens, we studied the nuclear changes from early to advanced. The former was represented by the noninvasive area in the tumor periphery and the latter by the invasive area with true neoplastic stroma. We analyzed the difference in NV between the noninvasive area in the tumor periphery (NVcis) and the invasive area where the nuclei are large (NVlarge), a zone we assessed to have the greatest cancer progression. Based on these measurements, we defined NV gradient index (NVG index) as the ratio of NVlarge to NVcis. RESULTS: The NVG index in cases of cancer death (4.33 +/- 1.70, n = 35) was significantly larger than in relapsing survivors (2.76 +/- 1.31, n = 13, P = .002) and in relapse-free survivors (2.17 +/- 1.60, n = 64, P < .0003). In the group of cancer deaths, the correlation coefficient between NVG index and survival was -0.398 (0 < P < .02). Even in cases of stage I, NVG index in the group of cancer deaths (5.68 +/- 1.4) was significantly larger than in relapsing survivors (2.42 +/- 1.2) or relapse-free survivors (1.74 +/- 0.55). By multivariate analysis, NVG index was independently prognostic for disease-specific survival (P = .0001). CONCLUSION: The NVG index contributes to discrimination between possible survivors and cancer deaths. Though there are exceptions, cases with a small NVG index can be expected to survive for a longer period even after a relapse.     

Circulating levels of 25-hydroxyvitamin D and prostate cancer prognosis

Objectives: Ecological, in vitro, and in vivo studies demonstrate a link between vitamin D and prostate tumor growth and aggressiveness. The goal of this study was to investigate whether plasma concentration of vitamin D is associated with survivorship and disease progression in men diagnosed with prostate cancer. Materials and methods: We conducted a population-based cohort study of 1476 prostate cancer patients to assess disease recurrence/progression and prostate cancer-specific mortality (PCSM) risks associated with serum levels of 25(OH) vitamin D [25(OH)D]. Results: There were 325 recurrence/progression and 95 PCSM events during an average of 10.8 years of follow-up. Serum levels of 25(OH)D were not associated with risk of recurrence/progression or mortality. Clinically deficient vitamin D levels were associated with an increased risk of death from other causes. Conclusions: We did not find evidence that serum vitamin D levels measured after diagnosis affect prostate cancer prognosis. Lower levels of vitamin D were associated with risk of non-prostate cancer mortality.     

Perinatal characteristics in relation to incidence of and mortality from prostate cancer.

OBJECTIVE--To test the hypothesis that factors causing morbidity and mortality from prostate cancer may operate in utero. DESIGN--Matched case-control study of singleton men born between 1874 and 1946 at one hospital. SETTING--Uppsala University Hospital. SUBJECTS--250 patients with prostate cancer and 691 controls, including 80 patients who died from prostate cancer and their 196 matched controls. MAIN OUTCOME MEASURES--Mother''s age at menarche, parity, pre-eclampsia or eclampsia before delivery, age at delivery and socioeconomic status; case or control''s birth length and weight, placental weight, prematurity derived from gestational age, and presence of jaundice. RESULTS--Both pre-eclampsia (odds ratio 0, 95% confidence interval 0 to 0.71) and prematurity (0.31, 0.09 to 1.04) were inversely associated with incidence of prostate cancer. Among subjects born full term, placental weight, birth weight, and ponderal index (weight/height 3) showed non-significant positive associations with prostate cancer incidence, and stronger associations with mortality. CONCLUSION--Prenatal exposures that are likely correlates of pregnancy hormones and other growth factors are important in prostate carcinogenesis and influence the natural course as well as the occurrence of this cancer.     

Comprehensively analysis of splicing factors to construct prognosis prediction classifier in prostate cancer

Splicing factors (SFs) are proteins that control the alternative splicing (AS) of RNAs, which have been recognized as new cancer hallmarks. Their dysregulation has been found to be involved in many biological processes of cancer, such as carcinogenesis, proliferation, metastasis and senescence. Dysregulation of SFs has been demonstrated to contribute to the progression of prostate cancer (PCa). However, a comprehensive analysis of the prognosis value of SFs in PCa is limited. In this work, we systematically analysed 393 SFs to deeply characterize the expression patterns, clinical relevance and biological functions of SFs in PCa. We identified 53 survival-related SFs that can stratify PCa into two de nove molecular subtypes with distinct mRNA expression and AS-event expression patterns and displayed significant differences in pathway activity and clinical outcomes. An SF-based classifier was established using LASSO-COX regression with six key SFs (BCAS1, LSM3, DHX16, NOVA2, RBM47 and SNRPN), which showed promising prognosis-prediction performance with a receiver operating characteristic (ROC) >0.700 in both the training and testing datasets, as well as in three external PCa cohorts (DKFZ, GSE70769 and GSE21035). CRISPR/CAS9 screening data and cell-level functional analysis suggested that LSM3 and DHX16 are essential factors for the proliferation and cell cycle progression in PCa cells. This study proposes that SFs and AS events are potential multidimensional biomarkers for the diagnosis, prognosis and treatment of PCa.     

Diagnosis and prognosis potential of four gene promoter hypermethylation in prostate cancer

The current prostate special antigen (PSA) test causes the overtreatment of indolent prostate cancer (PCa). It also increases the risk of delayed treatment of aggressive PCa. DNA methylation aberrations are important events for gene expression dysregulation during tumorigenesis and have been suggested as novel candidate biomarkers for PCa. This may improve the diagnosis and prognosis of PCa. This study assessed the differential methylation and messenger RNA (mRNA) expression between normal and PCa samples. Correlation between promoter methylation and mRNA expression was estimated using Pearson's correlation coefficients. Moreover, the diagnostic potential of candidate methylation markers was estimated by the receiver operating characteristic (ROC) curve using continuous beta values. Survival and Cox analysis was performed to evaluate the prognostic potential of the candidate methylation markers. A total of 359 hypermethylated sites 3435 hypomethylation sites, 483 upregulated genes, and 1341 downregulated genes were identified from The Cancer Genome Atlas database. Furthermore, 17 hypermethylated sites (covering 13 genes), including known genes associated with hypermethylation in PCa (e.g., AOX1 and C1orf114), showed high discrimination between adjacent normal tissues and PCa samples with the area under the ROC curve from 0.88 to 0.94. Notably, ANXA2, FGFR2, HAAO, and KCNE3 were identified as valuable prognostic markers of PCa through the Kaplan–Meier analysis. Using gene methylation as a continuous variable, four promoter hypermethylation was significantly associated with disease-free survival in univariate Cox regression and multivariate Cox regression. This study identified four novel diagnostic and prognostic markers for PCa. The markers provide important strategies for improving the timely diagnosis and prognosis of PCa.     

Chromosome-specific segment size alterations are determinants of prognosis in prostate cancer

Currently, risk stratification is the most difficult problem in prostate cancer (PCa) management. Gleason grading cannot adequately predict cancer progression. This study aimed to identify chromosome-specific segment size alterations that could aid risk stratification and predict metastasis using a retrospective cohort-study strategy. A binary logistic regression model was generated using 16 chromosome-specific segments with size alterations (deletions and amplifications) that showed associations with disease stage (primary versus metastatic). The regression model was trained with the MSKCC PIK3R1 PCa cohort (n = 1417), and validated with the TCGA Firehose Legacy (n = 500), MSKCC Prostate Oncogenome Project (n = 218), and the SU2C/PCF Dream Team (n = 150) PCa cohorts. Furthermore, the capacity of the model to predict metastasis between primary tumours with metastasis (n = 54) and primary tumours without metastasis (n = 54) was tested. The accuracy, sensitivity, and specificity of the model at disease stage stratification ranged from 69.02% to 88.55%, 72.8% to 86.00% and 66.30% to 89.50%, respectively. The model also showed good performance at metastasis prediction with accuracy, sensitivity, and specificity of 57.41%, 62.96% and 51.85%, respectively. The study conclusion was that chromosome-specific segment size alterations can aid risk stratification and metastasis prediction. The significance of the study findings is that in combinations with clinical, biochemical, and histopathological variables, chromosome-specific alterations could improve current risk stratification and prediction models for PCa.     

LncRNA PVT1 predicts prognosis and regulates tumor growth in prostate cancer

Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1(PVT1) was aberrantly expressed in various cancers and is associated with tumor prognosis. Here, we aim to investigate its function in prostate cancer. Small interfering RNA against PVT1 was transfected into prostate cancer cell lines and cell growth and apoptosis were analyzed. Our results showed that PVT1 was overexpressed in prostate cancer tissues and cells. Higher levels of PVT1 indicated poorer overall survival and disease-free survival. A significant association was found between PVT1 expression and tumor stage. Besides, PVT1 knockdown significantly inhibited prostate cancer growth in vivo and in vitro and promoted cell apoptosis. PVT1 knockdown also significantly upregulated the expression of cleaved caspase-3 and cleaved caspase-9, but downregulated the expression of c-Myc in prostate cancer cell lines. Our results suggest that PVT1 played an oncogenic role in prostate cancer and could be used as a potential biomarker for diagnosis of prostate cancer.     

DNA methylation profiles in African American prostate cancer patients in relation to disease progression

This study examined whether differential DNA methylation is associated with clinical features of more aggressive disease at diagnosis and prostate cancer recurrence in African American men, who are more likely to die from prostate cancer than other populations. Tumor tissues from 76 African Americans diagnosed with prostate cancer who had radical prostatectomy as their primary treatment were profiled for epigenome-wide DNA methylation levels. Long-term follow-up identified 19 patients with prostate cancer recurrence. Twenty-three CpGs were differentially methylated (FDR q ≤ 0.25, mean methylation difference ≥ 0.10) in patients with vs. without recurrence, including CpGs in GCK, CDKL2, PRDM13, and ZFR2. Methylation differences were also observed between men with metastatic-lethal prostate cancer vs. no recurrence (five CpGs), regional vs. local pathological stage (two CpGs), and higher vs. lower tumor aggressiveness (one CpG). These results indicate that differentially methylated CpG sites identified in tumor tissues of African American men may contribute to prostate cancer aggressiveness.     

Presentation of rheumatoid arthritis and its relation to prognosis.

A review of published reports in an attempt to relate the way rheumatoid arthritis presents to its manner of progression and prognosis has provided few positive answers. Certain, but not all, studies indicate that cases with an acute explosive onset do better than those of more insidious onset, but the latter have almost certainly lasted longer by the time they come under medical supervision. Cases of monarthritis and palindromic (remittent) arthritis do better than polyarthritic and persistent cases, but true diagnosis of the former is often uncertain. Undoubtedly persistent high-titre seropositivity and nodule formation are bad prognostic pointers. A plea is made for a more intensive study of the early case: if any therapeutic agent now or in the future can reverse the inflammatory process this is surely the time it is most likely to do so. This is the curable end of what is now an incurable disease.     

Variants in the HEPSIN gene are associated with prostate cancer in men of European origin

There is considerable evidence that genetic factors are involved in prostate cancer susceptibility. We have studied the association of 11 single nucleotide polymorphisms (SNPs) in the HEPSIN gene (HPN) with prostate cancer in men of European ancestry. HPN is a likely candidate in prostate cancer susceptibility, as it encodes a transmembrane cell surface serum protease, which is overexpressed in prostate cancer; HPN is also located on 19q11–q13.2, where linkage is found with prostate cancer susceptibility. In this case-control association study (590 men with histologically verified prostate cancer and 576 unrelated controls, all of European descent), we find significant allele frequency differences between cases and controls at five SNPs that are located contiguously within the gene. A major 11-locus haplotype is significantly associated, which provides further support that HPN is a potentially important candidate gene involved in prostate cancer susceptibility. Association of one of the SNPs with Gleason score is also suggestive of a plausible role of HPN in tumor aggressiveness.     

超声引导下前列腺穿刺联合外周血循环肿瘤细胞检测对前列腺癌预后分析

目的探讨超声引导下前列腺穿刺联合外周血循环肿瘤细胞(CTCs)检测对前列腺癌预后的预测效果。方法选取2011年1月至2017年12月期间于郑州大学第二附属医院收治的83例前列腺癌患者为研究对象,全部患者均根据超声引导下经直肠前列腺穿刺活检术确诊为前列腺癌,检测病理标本中CK34BE12、p63、α-甲酰基辅酶A消旋酶(AMACR)等免疫标志物的表达状况,并采用Cell Search细胞搜索系统检测外周血CTCs的数量,据此分为阳性组(≥5个/7.5 ml)和阴性组(<5个/7.5 ml)。分析穿刺组织中免疫标志物表达状况、外周血CTCs计数与患者临床病理特征、生存状况的相关性。各标志物的阳性例数、Gleason评分>7分的比例、TNM分期等定性资料的比较采用x^2检验或Fisher确切概率法,年龄、血常规、凝血功能、肝功能、PSA水平等定量资料的比较采用t检验。采用Kaplan-Meier法进行生存分析,采用多因素Cox比例风险回归模型分析患者预后的预测因素。结果(1)全部患者中外周血CTCs、穿刺组织中CK34BE12、p63、AMACR的阳性率分别为31.33、3.61、3.61、86.75。CTCs阳性组的AMACR阳性率为100.00,高于CTCs阴性组的80.70,差异有统计学意义(x^2=4.227,P<0.05)。(2)AMACR阳性组患者的血红蛋白(HB)低于AMACR阴性组[(123.66±13.33)g/L比(134.89±20.08)g/L,t=2.420,P=0.018],血小板(PLT)、血清谷丙转氨酶、D-二聚体(DD)、前列腺特异抗原(PSA)水平、Gleason评分>7分的比例均高于AMACR阴性组[(197.23±36.98)×10^9/L比(172.83±33.33)×10^9/L,t=2.062,P=0.042;(38.80±10.03)U/L比(31.46±7.83)U/L,t=2.317,P=0.023;(255.00±38.80)μg/L比(220.81±30.99)μg/L,t=2.785,P=0.007;(26.60±12.23)ng/ml比(17.90±8.88)ng/ml,t=2.263,P=0.026;45.83比9.09,x^2=3.916,P=0.048],差异有统计学意义(P<0.05)。CTCs阳性组患者的HB低于CTCs阴性组[(121.69±15.89)g/L比(132.73±18.85)g/L,t=2.767,P=0.007],血清碱性磷酸酶、DD、PSA水平、Gleason评分>7分、T3~T4期、M1期的比例均高于CTCs阴性组[(105.69±30.56)U/L比(88.89±35.58)U/L,t=2.205,P=0.030;(256.63±35.86)μg/L比(236.98±33.30)μg/L,t=2.368,P=0.020;(30.09±11.89)ng/ml比(23.33±10.99)ng/ml,t=2.533,P=0.013;57.69比33.33,x^2=4.381,P=0.036;30.77比8.77,x^2=4.981,P=0.026;50.00比17.54,x^2=9.390,P=0.002],差异有统计学意义(P<0.05)。(3)全部患者的中位生存时间为58.33个月,1、3、5年的生存率分别为88.95、51.81、30.12。AMACR阳性组、CTCs阳性组患者的中位生存时间为40.93、36.93个月,低于AMACR阴性组、CTCs阴性组的66.66、69.56个月,差异有统计学意义(P<0.05)。多因素Cox比例风险回归模型分析结果表明,Gleason评分>7分、M1期、AMACR阳性、CTCs阳性是患者死亡的独立危险因素(HR=1.883、3.666、2.009、2.923,P<0.05)。结论超声引导下前列腺穿刺联合外周血CTCs检测对前列腺癌患者的预后具有重要的预测价值,临床上可根据穿刺组织中AMACR表达水平和外周血CTCs计数进行预后的综合分析。