Association of pre- and postoperative αKlotho levels with long-term remission after pituitary surgery for acromegaly

Soluble αKlotho (sKl) is a disease-specific biomarker that is elevated in patients with acromegaly and declines after surgery for pituitary adenoma. Approximately 25% of patients do not achieve remission after surgery, therefore a risk stratification for patients early in the course of their disease may allow for the identification of patients requiring adjuvant treatment. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have been assessed as biomarker for disease activity, however the value of sKl as a predictive biomarker of surgical success has not been evaluated yet. In this study, we measured serum biomarkers before and after transsphenoidal pituitary surgery in 55 treatment-naïve patients. Based on biochemical findings at follow-up (7-16 years), we divided patients into three groups: (A) long-term cure (defined by normal IGF-1 and random low GH (< 1 μg/l) or a suppressed GH nadir (< 0.4/μg/l) on oral glucose testing); (B) initial remission with later disease activity; (C) persistent clinical and/or biochemical disease activity. sKl levels positively related to GH, IGF-1 levels and tumor volume. Interestingly, there was a statistically significant difference in pre- and postoperative levels of sKl between the long-term cure group and the group with persistent disease activity. This study provides first evidence that sKl may serve as an additional marker for surgical success, decreasing substantially in all patients with initial clinical remission while remaining high after surgery in patients with persistent disease activity

MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value

Treatment with the alkylating agent temozolomide is known to be prognostically beneficial in a subset of glioblastoma patients. Response to such chemotherapeutic treatment and the prognostic benefit have been linked to the methylation status of O$^{6}$-methylguanine-DNA methyltransferase (MGMT). To date, it has not been entirely resolved which methylation pattern of MGMT is most relevant to predict response to temozolomide treatment and outcome. In this retrospective study, we compared the methylation patterns, analyzed by Sanger sequencing, of 27 isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients that survived more than 3 years (long-term survivors) with those of 24 patients who survived less than a year after initial surgery (short-term survivors). Random Forest-, Correlation-, and ROC-curve analyses were performed. The data showed that MGMT is typically methylated in long-term survivors, whereas no prominent methylation is observed in short-term survivors. The methylation status of CpGs, especially in the promoter and exon1/enhancer region correlated highly with outcome. In addition, age and temozolomide treatment were strongly associated with overall survival. Some CpGs in the enhancer region, in particular CpG 86 (bp + 154), demonstrated high values associated with overall survival in the Random Forest analysis. Our data confirm previously published prognostic factors in IDH-wildtype glioblastoma patients, including age and temozolomide treatment as well as the global MGMT methylation status. The area frequently used for decision making to administer temozolomide at the end of exon1 of MGMT, was associated with outcome. However, our data also suggest that the enhancer region, especially CpG 86 (bp + 154) is of strong prognostic value. Therefore, we propose further investigation of the enhancer region in a large prospective study in order to confirm our findings, which might result in an optimized prediction of survival in glioblastoma patients, likely linked to response to temozolomide treatment

MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value

Abstract Treatment with the alkylating agent temozolomide is known to be prognostically beneficial in a subset of glioblastoma patients. Response to such chemotherapeutic treatment and the prognostic benefit have been linked to the methylation status of O 6 -methylguanine-DNA methyltransferase (MGMT). To date, it has not been entirely resolved which methylation pattern of MGMT is most relevant to predict response to temozolomide treatment and outcome. In this retrospective study, we compared the methylation patterns, analyzed by Sanger sequencing, of 27 isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients that survived more than 3 years (long-term survivors) with those of 24 patients who survived less than a year after initial surgery (short-term survivors). Random Forest-, Correlation-, and ROC-curve analyses were performed. The data showed that MGMT is typically methylated in long-term survivors, whereas no prominent methylation is observed in short-term survivors. The methylation status of CpGs, especially in the promoter and exon1/enhancer region correlated highly with outcome. In addition, age and temozolomide treatment were strongly associated with overall survival. Some CpGs in the enhancer region, in particular CpG 86 (bp + 154), demonstrated high values associated with overall survival in the Random Forest analysis. Our data confirm previously published prognostic factors in IDH-wildtype glioblastoma patients, including age and temozolomide treatment as well as the global MGMT methylation status. The area frequently used for decision making to administer temozolomide at the end of exon1 of MGMT, was associated with outcome. However, our data also suggest that the enhancer region, especially CpG 86 (bp + 154) is of strong prognostic value. Therefore, we propose further investigation of the enhancer region in a large prospective study in order to confirm our findings, which might result in an optimized prediction of survival in glioblastoma patients, likely linked to response to temozolomide treatment

A common classification framework for histone sequence alterations in tumours: an expert consensus proposal

The description of genetic alterations in tumours is of increasing importance. In human genetics, and in pathology reports, sequence alterations are given using the human genome variation society (HGVS) guidelines for the description of such variants. However, there is less adherence to these guidelines for sequence variations in histone genes. Due to early cleavage of the N-terminal methionine in most histones, the description of histone sequence alterations follows their own nomenclature and differs from the HGVS-compliant numbering by omitting this first amino acid. Next generation sequencing reports, however, follow the HGVS guidelines and as a result, an unambiguous description of sequence variants in histones cannot be provided. The coexistence of these two nomenclatures leads to confusions for pathologists, oncologists, and researchers. This review provides an overview of tumour entities with sequence alterations of the H3-3A gene (HGNC ID = HGNC:4764), highlights the problems associated with the coexistence of these two nomenclatures, and proposes a standard for the reporting of histone sequence variants that allows an unambiguous description of these variants according to HGVS principles. We hope that scientific journals will adopt the new notation, and that both geneticists and pathologists will include it in their reports