RAD51C – a new human cancer susceptibility gene for sporadic squamous cell carcinoma of the head and neck (HNSCC)

INTRODUCTION: Head and neck squamous cell carcinomas (HNSSCs) are one of the leading causes of cancer-associated death worldwide. Although certain behavioral risk factors are well recognized as tumor promoting, there is very little known about the presence of predisposing germline mutations in HNSCC patients. METHODS: In this study, we analyzed 121 individuals with HNSCCs collected at our institution for germline alterations in the newly identified cancer susceptibility gene RAD51C. RESULTS: Sequencing of all exons and the adjacent introns revealed five distinct heterozygous sequence deviations in RAD51C in seven patients (5.8%). A female patient without any other risk factors carried a germline mutation that disrupted the canonical splice acceptor site of exon 5 (c.706-2A>G). CONCLUSIONS: As there are only a few publications in the literature identifying germline mutations in head and neck cancer patients, our results provide the first indication that paralogs of RAD51, recently described as mutated in breast and ovarian cancer patients, might also be candidates for genetic risk factors in sporadic squamous cell carcinomas of the head and neck

An intronic alteration of the fibroblast growth factor 10 gene causing ALSG-(aplasia of lacrimal and salivary glands) syndrome

<p>Abstract</p> <p>Background</p> <p>A combined aplasia, hypoplasia or atresia of lacrimal points and salivary glands is rarely diagnosed. Those patients suffer from epiphora, xerostomia and severe dental caries. This phenotype represents the autosomal-dominant aplasia of lacrimal and salivary glands syndrome (ALSG). Recently, aberrations of the <it>Fibroblast Growth Factor 10 </it>(<it>FGF10</it>) gene have been identified to be causative for this disorder.</p> <p>Methods</p> <p>We performed a sequence analysis of the <it>FGF10 </it>gene of a patient with ALSG-syndrome and his also affected brother as well as 193 controls. The FGF10 transcript was analyzed using RNA extracted from primary fibroblasts of the patient's mucosa.</p> <p>Results</p> <p>We detected a novel heterozygous sequence variation in intron 2 (c.430-1, G > A) causing the ALSG syndrome. The alteration derogates the regular splice acceptor site and leads to the use of a new splice acceptor site 127 bp upstream of exon 3. The aberration was detected in the genomic DNA derived from two affected brothers, but not in 193 control individuals. Furthermore, no diseased member of the family displayed additional abnormalities that are indicative for the clinically overlapping lacrimo-auriculo-dento-digital syndrome (LADD).</p> <p>Conclusion</p> <p>This family-based approach revealed an intronic variation of the <it>FGF10 </it>gene causing ALSG-syndrome. Our results expand the mutational and clinical spectrum of the ALSG syndrome.</p

AluY-mediated germline deletion, duplication and somatic stem cell reversion in <i>UBE2T</i> defines a new subtype of Fanconi anemia

Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2-6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2-6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2-6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene.</p

Diagnostic and prognostic value of long noncoding RNAs as biomarkers in urothelial carcinoma

Many long noncoding RNAs (lncRNAs) are deregulated in cancer and contribute to oncogenesis. In urothelial carcinoma (UC), several lncRNAs have been reported to be overexpressed and proposed as biomarkers. As most reports have not been confirmed independently in large tissue sets, we aimed to validate the diagnostic and prognostic value of lncRNA upregulation in independent cohorts of UC patients. Thus, expression of seven lncRNA candidates (GAS5, H19, linc-UBC1, MALAT1, ncRAN, TUG1, UCA1) was measured by RT-qPCR in cell lines and tissues and correlated to clinicopathological parameters including follow-up data (set 1: N n = 10; T n = 106). Additionally, publicly available TCGA data was investigated for differential expression in UC tissues (set 2: N n = 19; T n = 252,) and correlation to overall survival (OS). All proposed candidates tended to be upregulated in tumour tissues, with the exception of MALAT1, which was rather diminished in cancer tissues of both data sets. However, strong overexpression was generally limited to individual tumour tissues and statistically significant overexpression was only observed for UCA1, TUG1, ncRAN and linc-UBC1 in tissue set 2, but for no candidate in set 1. Altered expression of individual lncRNAs was associated with overall survival, but not consistently between both patient cohorts. Interestingly, lower expression of TUG1 in a subset of UC patients with muscle-invasive tumours was significantly correlated with worse OS in both cohorts. Further analysis revealed that tumours with low TUG1 expression are characterized by a basal-squamous-like subtype signature accounting for the association with poor outcome. In conclusion, our study demonstrates that overexpression of the candidate lncRNAs is found in many UC cases, but does not occur consistently and strongly enough to provide reliable diagnostic or prognostic value as an individual biomarker. Subtype-dependent expression patterns of lncRNAs like TUG1 could become useful to stratify patients by molecular subtype, thus aiding personalized treatments

Akustikusneurinom-Segmentierung: Anwendung der Radial-Strahl-basierten 3D-Methodik

Einleitung: Akustikusneurinome sind benigne Tumore des N. vestibularis im Bereich des Kleinhirnbrückenwinkels oder des inneren Gehörgangs. Bei langsamem Wachstum ist neben der operativen Entfernung oder der Strahlentherapie eine ,wait and scan"-Strategie unter regelmäßigen MRT-Kontrollen möglich. Objektivierbare Tumorvolumenbestimmungen können mittels zeitaufwendiger Segmentierungen durchgeführt werden. Durch eine Automatisierung des Segmentierungsvorganges wird diese Methode schnell, genau und objektiv einsetzbar. Methode: Die Radial-Strahl-basierte 3D-Segmentierung sendet ausgehend von einem manuell vorgegebenen Saatpunktes, Strahlen radial in alle Richtungen und erzeugt unter Einbeziehung von Bildinformation und lokalem Formwissen eine Segmentierung. Innerhalb weniger Sekunden werden die Achsen und das Volumen des Tumors angezeigt. Innerhalb eines Projektes wurde die Methode spezifisch für Akustikusneurinome entwickelt und an unserem Patientengut validiert. Es wurden Messungen bei manueller und automatisierter Segmentierung durch verschiedene Untersucher durchgeführt, um die Reliabilität, Geschwindigkeit und Alltagstauglichkeit der Methode zu evaluieren. Ergebnisse: Das Volumen von Akustikusneurinomen kann auch durch unterschiedliche Untersucher reproduzierbar mit hoher Genauigkeit innerhalb weniger Sekunden automatisiert und somit schneller als manuell segmentiert werden. Schlussfolgerung: Die automatisierte Radial-Strahl-basierte 3D-Segmentierung ist eine gut geeignete Methode zur objektiven Volumenbestimmung von Akustikusneurinomen. Sie mindert die Inter-Observer-Variabilität und reduziert den Zeitaufwand der Bildbeurteilung. Insofern hat diese Methode ein gutes Potential, um v.a. bei der ,.wait and scan"-Methode in den klinischen Alltag eingeführt zu werden

Visual analytics for radiomics: Combining medical imaging with patient data for clinical research

The visualization and analysis of electronic health records (EHRs) are becoming increasingly relevant for clinical researchers. While the digitization of medical images is general practice today, many clinics are just starting to build up database with the related patient data, patient histories, and treatment outcomes. This paper reports on a project with a medical group of ear, nose, and throat (ENT) specialists. It combines medical image analysis and Radiomics with visual analytics of patient data to build, analyze, and evaluate patient cohorts. The combined visual interface for both browsing and analyzing patient data was developed in collaboration with the medical researchers. In addition to offering a new way of cohort building, our approach also provides a first comprehensive view on the EHR, including the relevant anatomy of patients. This project triggered a new effort to extend the digitized patient database from around 100 patients to the entire patient population at our partner’s clinic