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FGFR1 expression in cancer cell lines.

Detailed description of STS Cohort 1 including the clinical data and FGFR1 status.

Soft-tissue sarcoma cohorts.

Detailed description of STS Cohort 2 including the clinical data and FGFR1 status.

Purpose: Altered FGFR1 signaling has emerged as a therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties of FGFR1 and its potential as a drug target in patients with STS.Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by FISH, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis.Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; cohort 1), 13 of 79 (16.5%; cohort 2), and 80 of 254 (31.5%; cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, cohort 2) and 39 of 254 (15.4%; cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK–ERK1/2 axis as critical FGFR1 effector pathway.Conclusions: These data identify FGFR1 as a driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to the FGFR1 expression and monitoring of MAPK–ERK1/2 signaling, as a therapeutic option in this challenging group of diseases. Clin Cancer Res; 23(4); 962–73. ©2016 AACR.

Radiographic assessment of target lesions following BGJ398 treatment.

The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug.We analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers.Among 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3-high, IGF1R-low and KDR-high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p lt; 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib.A score based on the combined expression of NTRK3, IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic.

Background Pancreatoblastoma is a rare malignancy that occurs predominantly in children. Less than 50 adult cases, including 17 patients with metastatic disease, have been published to date. Recent outcome data from children with advanced-stage disease suggest an intensive multimodal treatment approach; however, little is known about the most beneficial therapy in adults. Molecular characterization of pancreatoblastoma is limited to a small number of pediatric cases and revealed few recurrent genetic events without immediate clinical relevance. Methods Patients were treated between 2013 and 2018 at a high-volume German university cancer center. Molecular analyses included whole genome, exome, transcriptome, and fusion gene panel sequencing. Molecularly guided treatment recommendations were discussed within a dedicated molecular tumor board (MTB) embedded in a precision oncology program (NCT MASTER). Results We identified four adult patients with metastatic pancreatoblastoma. In three patients, local approaches were combined with systemic treatment. Oxaliplatin-containing protocols showed an acceptable tumor control as well as an adequate toxicity profile. Overall survival was 15, 17, 18 and 24 months, respectively. Three tumors harbored genetic alterations involving the FGFR pathway that included an oncogenic FGFR2 fusion. Conclusion Oxaliplatin-containing chemotherapy seems to be a reasonable approach in adult patients with advanced pancreatoblastoma, whereas the benefit of intensified treatment including local ablative techniques or surgical resection remains unclear. Our finding of FGFR alterations in three of four cases indicates a potential role of FGFR signaling in adult pancreatoblastoma whose clinical significance warrants further study.

Background Soft-tissue sarcomas (STS) are a heterogeneous group of mesenchymal tumors for which response to immunotherapies is not well established. Therefore, it is important to risk-stratify and identify STS patients who will most likely benefit from these treatments. Results To reveal shared and distinct methylation signatures present in STS, we performed unsupervised deconvolution of DNA methylation data from the TCGA sarcoma and an independent validation cohort. We showed that leiomyosarcoma can be subclassified into three distinct methylation groups. More importantly, we identified a component associated with tumor-infiltrating leukocytes, which suggests varying degrees of immune cell infiltration in STS subtypes and an association with prognosis. We further investigated the genomic alterations that may influence tumor infiltration by leukocytes including RB1 loss in undifferentiated pleomorphic sarcomas and ELK3 amplification in dedifferentiated liposarcomas. Conclusions In summary, we have leveraged unsupervised methylation-based deconvolution to characterize the immune compartment and molecularly stratify subtypes in STS, which may benefit precision medicine in the future.

Purpose: Altered FGFR1 signaling has emerged as a therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties of FGFR1 and its potential as a drug target in patients with STS. Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by FISH, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis. Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; cohort 1), 13 of 79 (16.5%; cohort 2), and 80 of 254 (31.5%; cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, cohort 2) and 39 of 254 (15.4%; cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK–ERK1/2 axis as critical FGFR1 effector pathway. Conclusions: These data identify FGFR1 as a driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to the FGFR1 expression and monitoring of MAPK–ERK1/2 signaling, as a therapeutic option in this challenging group of diseases. Clin Cancer Res; 23(4); 962–73. ©2016 AACR.

The manifestation of brain metastases in patients with advanced melanoma is a common event that limits patient's survival and quality of life. The immunosuppressive properties of the brain parenchyma are very different compared to the rest of the body, making it plausible that the current success of cancer immunotherapies is specifically limited here. In melanoma brain metastases, the reciprocal interplay between immunosuppressive mediators such as indoleamine 2, 3-dioxygenase (IDO) or programmed cell death-ligand 1 (PD-L1) in the context of neoplastic transformation are far from being understood. Therefore, we analyzed the immunoreactive infiltrate (CD45, CD3, CD8, Forkhead box P3 [FoxP3], CD11c, CD23, CD123, CD68, Allograft Inflammatory factor 1[AIF-1]) and PD-L1 with respect to IDO expression and localization in melanoma brain metastases but also in matched metastases at extracranial sites to correlate intra- and interpatient data with therapy response and survival. Comparative tissue analysis identified macrophages/microglia as the major source of IDO expression in melanoma brain metastases. In contrast to the tumor infiltrating lymphocytes, melanoma cells per se exhibited low IDO expression levels paralleled by cell surface presentation of PD-L1 in intracranial metastases. Absolute numbers and pattern of IDO-expressing cells in metastases of the brain correlated with recruitment and localization of CD8+ T cells, implicating dynamic impact on the regulation of T cell function in the brain parenchyma. However, paired analysis of matched intra- and extracranial metastases identified significantly lower fractions of cytotoxic CD8+ T cells in intracranial metastases while all other immune cell populations remain unchanged. In line with the already established clinical benefit for PD-L1 expression in extracranial melanoma metastases, Kaplan-Meier analyses correlated PD-L1 expression in brain metastases with favorable outcome in advanced melanoma patients undergoing immune checkpoint therapy. In summary, our data provide new insights into the landscape of immunosuppressive factors in melanoma brain metastases that may be useful in the implication of novel therapeutic strategies for patients undergoing cancer immunotherapy.

Background Establishment of telomere maintenance mechanisms is a universal step in tumor development to achieve replicative immortality. These processes leave molecular footprints in cancer genomes in the form of altered telomere content and aberrations in telomere composition. To retrieve these telomere characteristics from high-throughput sequencing data the available computational approaches need to be extended and optimized to fully exploit the information provided by large scale cancer genome data sets. Results We here present TelomereHunter, a software for the detailed characterization of telomere maintenance mechanism footprints in the genome. The tool is implemented for the analysis of large cancer genome cohorts and provides a variety of diagnostic diagrams as well as machine-readable output for subsequent analysis. A novel key feature is the extraction of singleton telomere variant repeats, which improves the identification and subclassification of the alternative lengthening of telomeres phenotype. We find that whole genome sequencing-derived telomere content estimates strongly correlate with telomere qPCR measurements (r = 0.94). For the first time, we determine the correlation of in silico telomere content quantification from whole genome sequencing and whole genome bisulfite sequencing data derived from the same tumor sample (r = 0.78). An analogous comparison of whole exome sequencing data and whole genome sequencing data measured slightly lower correlation (r = 0.79). However, this is considerably improved by normalization with matched controls (r = 0.91). Conclusions TelomereHunter provides new functionality for the analysis of the footprints of telomere maintenance mechanisms in cancer genomes. Besides whole genome sequencing, whole exome sequencing and whole genome bisulfite sequencing are suited for in silico telomere content quantification, especially if matched control samples are available. The software runs under a GPL license and is available at https://www.dkfz.de/en/applied-bioinformatics/telomerehunter/telomerehunter.html. Electronic supplementary material The online version of this article (10.1186/s12859-019-2851-0) contains supplementary material, which is available to authorized users.

Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism. Finally, most tumors display hallmarks of “BRCAness”, including alterations in homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells are sensitive towards olaparib and cisplatin. This comprehensive study of LMS genomics has uncovered key biological features that may inform future experimental research and enable the design of novel therapies., The molecular genetic landscape of leiomyosarcoma (LMS) is largely unknown. Here, the authors identify frequent DNA copy number alterations, whole-genome duplication, TP53 and RB1 inactivation, alternative telomere lengthening, and genomic imprints of defective DNA repair via homologous recombination as a potential therapeutic target in LMS patients.

Background The acronym VATER/VACTERL association describes the combination of at least three of the following cardinal features: vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. Although fibroblast growth factor-8 (FGF8) mutations have mainly found in patients with Kallmann syndrome, mice with a hypomorphic Fgf8 allele or complete gene invalidation display, aside from gonadotropin-releasing hormone deficiency, parts or even the entire spectrum of human VATER/VACTERL association. Methods We performed FGF8 gene analysis in 49 patients with VATER/VACTERL association and 27 patients presenting with a VATER/VACTERL-like phenotype (two cardinal features). Results We identified two heterozygous FGF8 mutations in patients displaying either VATER/VACTERL association (p.Gly29_Arg34dup) or a VATER/VACTERL-like phenotype (p.Pro26Leu) without limb anomalies. Whereas the duplication mutation has not been reported before, p.Pro26Leu was once observed in a Kallmann syndrome patient. Both our patients had additional bilateral cryptorchidism, a key phenotypic feature in males with FGF8 associated Kallmann syndrome. Each mutation was paternally inherited. Besides delayed puberty in both and additional unilateral cryptorchidism in one of the fathers, they were otherwise healthy. Serum hormone levels downstream the gonadotropin-releasing hormone in both patients and their fathers were within normal range. Conclusion Our results suggest FGF8 mutations to contribute to the formation of the VATER/VACTERL association. Further studies are needed to support this observation.

Loss of TFAP2C in mouse leads to developmental defects in the extra-embryonic compartment with lethality at embryonic day (E)7.5. To investigate the requirement of TFAP2C in later placental development, deletion of TFAP2C was induced throughout extra-embryonic ectoderm at E6.5, leading to severe placental abnormalities caused by reduced trophoblast population and resulting in embryonic retardation by E8.5. Deletion of TFAP2C in TPBPA(+) progenitors at E8.5 results in growth arrest of the junctional zone. TFAP2C regulates its target genes Cdkn1a (previously p21) and Dusp6, which are involved in repression of MAPK signaling. Loss of TFAP2C reduces activation of ERK1/2 in the placenta. Downregulation of Akt1 and reduced activation of phosphorylated AKT in the mutant placenta are accompanied by impaired glycogen synthesis. Loss of TFAP2C led to upregulation of imprinted gene H19 and downregulation of Slc38a4 and Ascl2. The placental insufficiency post E16.5 causes fetal growth restriction, with 19% lighter mutant pups. Knockdown of TFAP2C in human trophoblast choriocarcinoma JAr cells inhibited MAPK and AKT signaling. Thus, we present a model where TFAP2C in trophoblasts controls proliferation by repressing Cdkn1a and activating the MAPK pathway, further supporting differentiation of glycogen cells by activating the AKT pathway.

The acronym VATER/VACTERL association is used to describe the non-random co-occurrence of vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheo-esophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). We report a familial case of VATER/VACTERL association in which both the index case and her maternal uncle displayed four major component features of the disorder. A systematic literature search identified 12 previously described familial cases. However, on comparison, both members fulfilled the diagnostic criteria for VATER/VACTERL association only in one instance, and ours is the second such report. Although, a SNP array-based analysis identified no causal genomic alteration, the findings in the present family suggest that genetic factors are implicated in the development of the disorder.

Leiomyosarcomas (LMS) are malignant tumors of smooth-muscle origin that occur across age groups. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown, and few therapeutic options exist for LMS patients. To detect somatic mutations, copy number alterations, and structural rearrangements, we performed whole-exome and transcriptome sequencing of 49 and 37 LMS tumors, respectively, and performed integrative analysis. Recurrence analysis identified TP53, RB1, and ATRX as significantly mutated genes and various other cancer-associated genes mutated at low frequency, indicating substantial mutational heterogeneity. Copy number analysis revealed widespread chromosomal gains and losses and highly rearranged genomes in all tumors. Additionally, chromothripsis and whole-genome duplication were detected in 35% and 51% of cases, respectively. Principle component analysis and unsupervised hierarchical clustering of transcriptome data revealed three distinct subgroups of patients. Furthermore, we detected multiple non-recurrent fusion transcripts resulting from chromosomal rearrangements, many of which were predicted to result in loss of TP53 and RB1 function. In-depth analysis of these loci revealed protein-damaging microdeletions, intragenic or distal inversions, and exon skipping events as additional, previously unrecognized mechanisms of TP53 and RB1 disruption. Integration of whole-exome and transcriptome data demonstrated biallelic disruption of TP53 and RB1 in 92% and 94% of cases, respectively, and tumors with wildtype RB1 displayed loss of CDKN2A expression, overexpression of CCND1, or mutation of MAX resulting in CDK4 and CCND2 overexpression as alternative mechanisms of RB1 suppression. We also detected alternative lengthening of telomeres (ALT) in 78% of cases, and identified recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing novel insight into the genetic basis of this mechanism. Finally, most tumors displayed hallmarks of “BRCAness”, including alterations in homologous recombination DNA repair genes and enrichment of specific mutational signatures, and cultured LMS cells were sensitive towards olaparib and cisplatin. This comprehensive genomic and transcriptomic analysis has unveiled that LMS is characterized by mutational heterogeneity, genomic instability, near-universal inactivation of TP53 and RB1, and frequent whole-genome duplication. Furthermore, we have established that most LMS tumors rely on ALT to escape replicative senescence, and identified recurrent alterations in a broad spectrum of telomere maintenance genes. Finally, our findings uncover “BRCAness” as potentially actionable feature of LMS tumors, and provide a rich resource for guiding future investigations into the mechanisms underlying LMS development and the design of novel therapeutic strategies. Citation Format: Priya Chudasama, Sadaf Mughal, Mathijs Sanders, Daniel Hübschmann, Inn Chung, Aurélie Ernst, Bernd Kasper, Hans-Georg Kopp, Sebastian Bauer, Karsten Rippe, Benedikt Brors, Marcus Renner, Peter Hohenberger, Claudia Scholl, Stefan Fröhling. Integrative genomic and transcriptomic analysis of leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4336.

Loss of TFAP2C in mouse leads to developmental defects in the extra-embryonic compartment with lethality at embryonic day (E)7.5. To investigate the requirement of TFAP2C in later placental development, deletion of TFAP2C was induced throughout extra-embryonic ectoderm at E6.5, leading to severe placental abnormalities caused by reduced trophoblast population and resulting in embryonic retardation by E8.5. Deletion of TFAP2C in TPBPA(+) progenitors at E8.5 results in growth arrest of the junctional zone. TFAP2C regulates its target genes Cdkn1a (previously p21) and Dusp6, which are involved in repression of MAPK signaling. Loss of TFAP2C reduces activation of ERK1/2 in the placenta. Downregulation of Akt1 and reduced activation of phosphorylated AKT in the mutant placenta are accompanied by impaired glycogen synthesis. Loss of TFAP2C led to upregulation of imprinted gene H19 and downregulation of Slc38a4 and Ascl2. The placental insufficiency post E16.5 causes fetal growth restriction, with 19% lighter mutant pups. Knockdown of TFAP2C in human trophoblast choriocarcinoma JAr cells inhibited MAPK and AKT signaling. Thus, we present a model where TFAP2C in trophoblasts controls proliferation by repressing Cdkn1a and activating the MAPK pathway, further supporting differentiation of glycogen cells by activating the AKT pathway.

BACKGROUND: The exstrophy-epispadias complex (BEEC) is a urogenital birth defect of varying severity. The causes of the BEEC are likely to be heterogeneous, with individual environmental or genetic risk factors still being largely unknown. In this study, we aimed to identify de novo causative copy number variations (CNVs) that contribute to the BEEC. METHODS: Array-based molecular karyotyping was performed to screen 110 individuals with BEEC. Promising CNVs were tested for de novo occurrence by investigating parental DNAs. Genes located in regions of rearrangements were prioritized through expression analysis in mice to be sequenced in the complete cohort, to identify high-penetrance mutations involving small sequence changes. RESULTS: A de novo 0.9 Mb microduplication involving chromosomal region 19p13.12 was identified in a single patient. This region harbors 20 validated RefSeq genes, and in situ hybridization data showed specific expression of the Wiz gene in regions surrounding the cloaca and the rectum between GD 9.5 and 13.5. Sanger sequencing of the complete cohort did not reveal any pathogenic alterations affecting the coding region of WIZ. CONCLUSIONS: The present study suggests chromosomal region 19p13.12 as possibly involved in the development of CBE, but further studies are needed to prove a causal relation. The spatiotemporal expression patterns determined for the genes encompassed suggest a role for Wiz in the development of the phenotype. Our mutation screening, however, could not confirm that WIZ mutations are a frequent cause of CBE, although rare mutations might be detectable in larger patient samples. 19p13.12, microduplication, bladder exstrophy-epispadias complex, array-based molecular karyotyping, in situ hybridization analysis, copy number variations, WIZ gene Birth Defects Research (Part A) 97:133–139, 2013. 2013 Wiley Periodicals, Inc.

Purpose: Soft-tissue sarcomas (STS) are highly diverse, devastating and clinically challenging malignancies. In advanced-stage STS, conventional chemotherapy provides symptom palliation but not prolonged survival, which typically ranges from 11-15 months after development of distant metastases. Thus, there is an urgent need for more effective, well-tolerated and targeted STS therapies. Alterations of the FGFR1 receptor tyrosine kinase are under investigation as biomarker of FGFR inhibitor sensitivity in several epithelial cancers. Prompted by the detection of high-level FGFR1 amplification in a patient with metastatic leiomyosarcoma through clinical exome sequencing, we investigated the role of FGFR1 as oncogenic driver and potential drug target in STS. Specific aims were to (i) determine the frequency of FGFR1 amplification and overexpression in adult STS, (ii) evaluate the sensitivity of FGFR1-altered STS cells to genetic and pharmacologic FGFR1 inhibition, and (iii) delineate the signaling pathways engaged by FGFR1 in these cells. Experimental design: The frequency of FGFR1 amplification and overexpression was established in a cohort of patients with treatment-näive high-grade STS using array-based comparative genomic hybridization and mRNA expression profiling, respectively, and results were validated using data from The Cancer Genome Atlas (TCGA). FGFR1 dependence was assessed in STS cell lines with and without FGFR1 alteration through RNA interference (RNAi)-mediated knockdown and selective small-molecule FGFR inhibitors. FGFR ligand and pharmacologic inhibitors were employed to dissect FGFR signaling in FGFR1-altered STS cells. Results: FGFR1 amplification and overexpression were present in 31% and 34% of cases in the untreated high-grade STS cohort (n = 176) and in 16% and 15% of cases in the TCGA cohort (n = 256). Interestingly, FGFR1 overexpression was detected in a substantial proportion of cases with no amplification (high-grade sarcoma cohort, 26%; TCGA cohort, 6.6%) comprising seven STS subtypes. Functional studies employing RNAi and different FGFR inhibitors (PD173074, AZD4547, BGJ398) demonstrated that the degree of dependence on FGFR1 for proliferation, survival, and anchorage-independent growth was primarily determined by FGFR1 expression levels. Furthermore, we identified the MAPK-ERK1/2 signaling axis as critical FGFR1 effector pathway whose suppression dictates the sensitivity of FGFR1-driven STS cells to FGFR-targeted therapy. Conclusions: FGFR1 amplification and overexpression are frequent events in multiple STS subtypes, and high FGFR1-expressing STS cells are sensitive to FGFR inhibition. These findings support FGFR1 as novel therapeutic target in STS and point to FGFR1 overexpression as a more reliable biomarker of sensitivity to FGFR pathway inhibition than genomic amplification, which might be of value for enrichment of future clinical trial populations. Citation Format: Priya Chudasama, Marcus Renner, Katja Specht, Sadaf Mughal, Barbara Hutter, Ingo Alldinger, Simon Schimmack, Dirk Jäger, Christof von Kalle, Stefan Gröschel, Stephan Wolf, Benedikt Brors, Wilko Weichert, Hanno Glimm, Gunhild Mechtersheimer, Claudia Scholl, Stefan Fröhling. FGFR1 overexpression is frequent in adult soft tissue sarcoma and predicts sensitivity to FGFR inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 457.

Anorectal malformations (ARMs) comprise a broad spectrum of anomalies, including anal atresia, congenital anal fistula and persistence of the cloaca. Research suggests that genetic factors play an important role in ARM development. However, few genetic variants have been identified. Embryogenesis is orchestrated by crosstalk of the wingless-type MMTV integration site family (WNT) and fibroblast growth factor (FGF) signaling pathways in a process that involves several intracellular cascades. Studies in mice have implicated several genes from these pathways in the etiology of ARMs. We performed sequencing analysis of seven of these previously reported genes in 78 patients with ARMs occurring within the context of at least one additional congenital anomaly. No associations were identified with variants in WNT3A, WNT5A, WNT11, DACT1, FGF10 or the T gene. In the FGFR2 gene, three novel heterozygous nucleotide substitutions were identified. Further investigations, including the study of family members, revealed that these variants were not causally related to the phenotype in the present ARM cohort. Mutations in the seven investigated genes may nonetheless be a cause of ARMs in rare cases. However, further studies should consider genes encoding other proteins in the WNT/FGF signaling pathways as possible candidates.

Severe and reproducible low-renin hypertension responsive to salt restriction and amiloride–thiazide therapy in a 13-year-old otherwise asymptomatic boy suggested Liddle syndrome. This assumption was strengthened by a positive family history of hypertension poorly responsive to conventional treatment or sudden deaths under 40 years of age in four generations. DNA analysis of the beta and gamma subunits of the epithelial sodium channel revealed a heterozygous mutation c.C1852T (p.Pro618Ser) in the SCNN1B gene in the patient and in both his hypertensive mother and uncle. A PubMed search revealed 21 different disease-causing mutations reported to date, all but two clustering in the cytoplasmic C-terminal regions of either beta (16 mutations) or gamma (5) subunit, leading to a three- to eightfold increase in the amiloride-sensitive sodium current. Inter- and intrafamilial variability in both hypertension and hypokalemia were disclosed, which may not be obligatory among the subjects carrying a Liddle mutation. Conclusion: Liddle syndrome should be considered as a cause of hypertension in children or adolescents particularly with suppressed renin activity. Early diagnosis and appropriately tailored treatment avoid complications of long-term unrecognized or inappropriately managed hypertension.