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Objective: Recently, recurrent mutations within the core promoter of the human telomerase reverse transcriptase (TERT) gene generating consensus binding sites for ETS transcription factor family members were described in melanomas and other malignancies (e.g. bladder cancer, hepatocellular carcinoma). These mutations were discussed as early drivers for malignant transformation. In prostate cancer (PrCa) TERT expression has been associated with a poor prognosis and higher risk for disease recurrence. The underlying mechanisms for high TERT expression in PrCa have still not been clarified. To date, data on TERT promoter mutation analysis in PrCa are sparse. Therefore, we performed sequence analysis of the core promoter region of the TERT gene in an unselected cohort of prostate tumors., Methods: Sections from 167 formalin-fixed, paraffin-embedded and cryopreserved prostate tumors were microdissected and used for DNA isolation. The mutation hotspot region within the TERT core promoter (-260 to +60) was analyzed by direct Sanger sequencing or SNaPshot analysis., Results: All cases were analyzed successfully. Mutations within the core promoter of the TERT gene were not detected in any of the cases with all tumors exhibiting a wild-type sequence., Conclusion: TERT core promoter mutations reported from several other malignancies were not detected in our unselected cohort of PrCa. These data indicate that alterations within the core promoter of the TERT gene do not play an important role in prostate carcinogenesis.

The FGF/FGFR-system plays an important role in embryogenesis, tissue homeostasis and carcinogenesis. Mutational activation of FGFR2 resulting in aberrant FGFR2 signaling activation is known from both hereditary germ line alterations and somatic mutations in various malignancies (e.g. breast, gastric or ovarian cancer). FGFR2 mutations are mainly located within the hinge between Ig-like domains (exon 7), around the 3rd Ig-like domains and within the kinase domain. For bladder cancer only sparse data on FGFR2 mutations are available. Most interestingly a case of early-onset papillary carcinoma of the bladder showing a FGFR2 p.Pro253Arg mutation in exon 7 in a patient with Apert Syndrome was reported recently. To further evaluate the importance of FGFR2 exon 7 alterations in bladder cancer a cohort of 254 bladder tumors (cohort 1: unselected cases: n=139; cohort 2: early-onset bladder cancer cases (age at time of diagnosis≤45 years): n=115) was analyzed. Sections from formalin-fixed, paraffin-embedded bladder tumors were used for DNA isolation. After precise microdissection exon 7 of the FGFR2 gene was analyzed by direct Sanger sequencing. All cases could be analyzed successfully. Mutations in exon 7 of FGFR2 could not be detected in any of the cases. All tumors showed wild type sequence. Our data demonstrate that the recently reported association between early-onset papillary carcinoma of the bladder with germ line FGFR2 p.Pro253Arg mutation could not be found in our cohorts of sporadic bladder tumors. These results indicate that FGFR2 gene mutations might only play a minor role in bladder carcinogenesis.

Background: The prognosis of metastatic non-small cell lung cancer (NSCLC) is still poor. Activating epithelial growth factor receptor (EGFR) mutations are important genetic alterations with dramatic therapeutical implications. Up to now, in contrast to Asian populations only limited data on the prevalence of those mutations are available from patients with Caucasian and especially European ethnicity., Methods: In this multicentre study, 1201 unselected NSCLC patients from Southern Germany were tested in the daily clinical routine for EGFR mutation status., Results: Activating EGFR mutations were found in 9.8% of all tumours. Mutations in exons 18, 19 and 21 accounted for 4.2%, 61.9% and 33.1% of all mutations, respectively. Non-smokers had a significantly higher rate of EGFR mutations than smokers or ex-smokers (24.4% vs 4.2%; P<0.001). Non-lepidic-non-mucinous adenocarcinomas (G2) accounted for 45.5% of all activating EGFR mutations and 3.5% of all squamous cell carcinomas were tested positive. Thyroid transcription factor 1 protein expression was significantly associated with EGFR mutational status., Conclusion: These comprehensive data from clinical routine in Germany add to the knowledge of clinical and histopathological factors associated with EGFR mutational status in NSCLC.

Recently mutations in the MED12 gene have been reported in 5.4% of prostate tumours from Caucasian patients analysed by exome sequencing (Barbieri CE, Baca SC, Lawrence MS, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nature Genet 2012; 44: 685-689). In more than 70% of prostate tumours with MED12 mutation, a recurrent p.L1224F mutation in exon 26 was found. In order to validate this MED12 p.L1224F mutation, an unselected cohort of prostate tumours from Caucasian patients was analysed by Sanger sequencing. Overall, 223 prostate tumours and three lymph node metastases were analysed. The MED12 p.L1224F mutation could not be detected in any of the cases. So far, the recently reported MED12 p.L1224F mutation could not be validated in our unselected cohort of prostate tumours. Contrary to the findings of Barbieri et al, our data indicate either that the p.L1224F mutation in the MED12 gene plays no role in prostate carcinogenesis or that this alteration is only relevant in a small subgroup of tumours., (Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

BackgroundImmunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined.ObjectiveThis analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors.MethodsClinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed.ResultsWe confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS.ConclusionsPatients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.