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The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients with urothelial cell carcinoma of bladder. The somatic mutations, mainly at positions −124 and −146 bp from ATG start site that create binding motifs for E-twenty six/ternary complex factors (Ets/TCF), affected 65.4% of the tumors, with even distribution across different stages and grades. Our data showed that a common polymorphism rs2853669, within a preexisting Ets2 binding site in the TERT promoter, acts as a modifier of the effect of the mutations on survival and tumor recurrence. The patients with the mutations showed poor survival in the absence [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.02-4.70] but not in the presence (HR 0.42, 95% CI 0.18-1.01) of the variant allele of the polymorphism. The mutations in the absence of the variant allele were highly associated with the disease recurrence in patients with Tis, Ta, and T1 tumors (HR 1.85, 95% CI 1.11-3.08). The TERT promoter mutations are the most common somatic lesions in bladder cancer with clinical implications. The association of the mutations with patient survival and disease recurrence, subject to modification by a common polymorphism, can be a unique putative marker with individualized prognostic potential.TERT mutations | cancer genetics | transcription factors | noncoding mutations | reporter assays T he human telomerase reverse transcriptase (TERT) gene encodes the catalytic reverse transcriptase subunit of telomerase that maintains telomere length (1). Increased telomerase activity is perceived to be one of the hallmarks of human cancers, and the transcriptional regulation of the TERT gene is the major cause of its cancer-specific activation (2, 3). The TERT promoter has been shown to be the most important element of telomerase expression because it harbors binding sites for numerous cellular transcriptional activators and repressors that directly or indirectly regulate the gene expression (4). In addition, the high GC content around the transcription start site of the TERT promoter confers epigenetic regulation through methylation and chromatin remodeling (5, 6).We previously described a high-penetrant disease segregating single-nucleotide germ-line mutation in the TERT promoter in a large melanoma family (7). The A > C (T > G) mutation at position −57 bp (from the ATG start site; Chr 5:1295161 hg19 coordinate) resulted in creation of a new binding motif GGAA/T for E-twenty six (Ets) transcription factors and a general binding CCGGAA/T motif for ternary complex factors (TCF) (8). Simultaneous screening of the TERT promoter for somatic mutations...

Summary Purpose:  Glutamic acid decarboxylase antibodies (GADAs) have been detected in patients with epilepsy, but the clinical determinants of epilepsy associated with GADA have not been defined. Methods:  We analyzed GADA with a radioimmunoassay in sera of 253 well‐characterized patients with epilepsy and 200 control subjects. The positive samples were confirmed by immunohistochemistry and western blotting (WB). Sera were screened for other autoantibodies. Results:  GADA were detected in 15 patients (5.9%) and in three control subjects (1.5%) (p = 0.026). Seven patients (2.8%) had high GADA titers [≥1,000 relative units (RUs)/ml], six of whom had temporal lobe epilepsy (TLE). All three GADA‐positive control subjects had low titers. Two of the five patients with high GADA titers and available cerebrospinal fluid (CSF) samples had intrathecal synthesis (IS) of GADA; one patient had CSF oligoclonal bands. The prevalence of increased levels of GADA tended to be higher in patients with TLE than in patients with extra‐TLE [odds ratio (OR) 1.32, 95% confidence interval (CI) 0.39–4.42; p = 0.657]. The patients with high GADA titers had significantly higher number of other autoantibodies compared to the patients with low GADA titers (p = 0.001) and the patients with normal GADA (p < 0.001). Discussion:  High GADA titers were present in a subgroup of patients; close to 90% had TLE. The immunologic profile of these patients suggests that the most probable origin of their epilepsy is autoimmune. A positive IS of GADA may be a marker of an ongoing immune response that could identify those patients in whom a trial with immunosuppressive therapy might be warranted.

Many of 33 studied ADs (except for ankylosing spondylitis, diabetes type I graves/hyperthyroidism, multiple sclerosis, chorea minor, and pernicious anemia), especially when diagnosed at younger ages, were associated with higher risk of NHL. However, the absolute risk of NHL in many ADs is still small.

Previous studies have reported activation of inflammatory cytokines in seizures, but clinical characteristics of epilepsy associated with cytokine activation have not been well established. In this study, serum levels of interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1RA) were measured, and clinical characteristics of epilepsy were assessed in 86 well-evaluated patients with refractory focal epilepsy and in 5 patients with controlled focal epilepsy. Epilepsy was evaluated based on patient histories, electroclinical findings, and high-resolution brain MRI scans. Sixty-three healthy blood donors served as controls. IL-6 concentrations were chronically increased in epilepsy patients (11%) compared with healthy controls (0%) (P = 0.007). Increased levels of IL-6 were more prevalent in patients with temporal lobe epilepsy (TLE) compared to patients with extra-TLE (P = 0.028). Also the mean and the median serum levels of IL-6 were higher in patients with TLE than in patients with extra-TLE (P = 0.042). Concentrations of IL-1RA were not significantly different in patients compared with controls. Indicated by increased levels of IL-6 in TLE, epilepsy type is important in determining chronic overproduction of cytokines in refractory focal epilepsy. The results may reflect a chronic immunological process in the brain in patients with refractory epilepsy.

Public perception and anxiety of familial cancer have increased demands for clinical counseling, which may be well equipped for gene testing but less prepared for counseling of the large domain of familial cancer with unknown genetic background. The aim of the present study was to highlight the full scope of familial cancer and the variable levels of risk that need to be considered. Data on the 25 most common cancers were obtained from the Swedish Family Cancer Database and a Poisson regression model was applied to estimate relative risks (RR) distinguishing between family histories of single or multiple affected first-degree relatives and their diagnostic ages. For all cancers, individual risks were significantly increased if a parent or a sibling had a concordant cancer. While the RRs were around 2.00 for most cancers, risks were up to 10-fold increased for some cancers. Familial risks were even higher when multiple relatives were affected. Although familial risks were highest at ages below 60 years, most familial cases were diagnosed at older ages. The results emphasized the value of a detailed family history as a readily available tool for individualized counseling and its preventive potential for a large domain of non-syndromatic familial cancers.

Telomere repeats at chromosomal ends, critical for genomic integrity, undergo age-dependent attrition and telomere length has been associated with different disorders including cancers. In this study, based on 1469 patients and 1158 healthy controls, we show a statistically significant (P = 6 × 10 ) association between increased telomere length and melanoma risk. Mendelian randomization, using 5 telomere length-associated polymorphisms, ruled out confounding factors or reverse causality and showed association between increased telomere length and melanoma risk with odds ratio of 2.66 (95% confidence interval: 2.07-3.25). Age-dependent telomere attrition was faster in melanoma cases than controls (P = .01). The carriers of a highly penetrant germline -57A>C TERT promoter mutation, in a previously reported melanoma family, had longer telomeres than the noncarriers. The mutation causes increased TERT and telomerase levels through creation of a binding motif for E-twenty six (ETS) transcription factors and the carriers develop melanoma with an early age of onset and rapid progression to metastasis. In analogy, we hypothesize that increased telomere length in melanoma patients reflects stochastic increased telomerase levels due to common genetic variation. Paradoxically, we observed shorter telomeres (P = 1 × 10 ) in primary tumors from unrelated melanoma patients with (121) than without (170) somatic TERT promoter mutations that similar to the germline mutation, also create binding motifs for ETS transcription factors. However, the age-dependent telomere attrition was faster in tumors with the TERT promoter mutations than in those without such mutations. Besides a robust association between increased telomere length and risk, our data show a perturbed telomere homeostasis in melanoma.

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