Von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome. A phenomenon known as genetic anticipation has been documented in some hereditary cancer syndromes, where it was proved to relate to telomere shortening. Because studies of this phenomenon in VHL disease have been relatively scarce, we investigated anticipation in 18 Chinese VHL disease families. We recruited 34 parent-child patient pairs (57 patients) from 18 families with VHL disease. Onset age was defined as the age when any symptom or sign of VHL disease first appeared. Anticipation of onset age was analyzed by paired t test and the other two special tests (HV and RY2). Relative telomere length of peripheral leukocytes was measured in 29 patients and 325 healthy controls. Onset age was younger in child than in parent in 31 of the 34 parent-child pairs. Patients in the first generation had older onset age with longer age-adjusted relative telomere length, and those in the next generation had younger onset age with shorter age-adjusted relative telomere length (P < 0.001) in the 10 parent-child pairs from eight families with VHL disease. In addition, relative telomere length was shorter in the 29 patients with VHL disease than in the normal controls (P ¼ 0.003). The anticipation may relate to the shortening of telomere length in patients with VHL in successive generations. These findings indicate that anticipation is present in families with VHL disease and may be helpful for genetic counseling for families with VHL disease families and for further understanding the pathogenesis of VHL disease. Cancer Res; 74(14); 3802-9. Ó2014 AACR.

The coiled coil is a superhelical structural protein motif involved in a diverse array of biological functions, and the abnormal expression of the coiled-coil domain containing proteins has a direct link with the phenotype of tumor cell migration, invasion and metastasis. The aim of this study was to investigate the critical role of Coiled-coil domain-containing protein 34 (CCDC34) in bladder carcinogenesis, which has never been reported to date. Here, we found CCDC34 expression was elevated in bladder cancer tissues and cell lines. The knockdown of CCDC34 via lentivirus-mediated siRNA significantly suppressed bladder cancer cells proliferation and migration, and induced cell cycle arrest at G2/M phase and increased apoptosis in vitro. In addition, CCDC34 knockdown suppressed bladder tumor growth in nude mice. Moreover, CCDC34 silencing decreased the phosphorylation of MEK, ERK1/2, JNK, p38 and Akt, and the expressions of c-Raf and c-Jun, indicating MAPK and AKT pathways (ERK/MAPK, p38/MAPK, JNK/MAPK and PI3K/Akt) might be involved in CCDC34 regulation of bladder cancer cell proliferation and migration. Our findings revealed for the first time a potential oncogenic role for CCDC34 in bladder carcinoma pathogenesis and it may serve as a biomarker or even a therapeutic target for bladder cancer.

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BackgroundThe aim of the study is to evaluate the role of cytoreductive nephrectomy (CN) with thrombectomy before targeted molecular therapy (TMT) on survival in metastatic renal cell carcinoma (mRCC) with venous tumor thrombus.MethodsWe performed a retrospective analysis of 47 patients treated in our center from April 2008 to October 2014. In the study, 20 patients underwent CN with thrombectomy followed by targeted therapy (group 1); 15 patients received targeted therapy alone (group 2); and 12 patients underwent CN with thrombectomy alone (group 3). The overall survival (OS) and cancer-specific survival (CSS) were calculated according to the Kaplan-Meier survival curve method, and prognostic variables were assessed by Cox regression analyses.ResultsThe median follow-up times of group 1, group 2, and group 3 were 24.5, 12, and 6.5 months, respectively. During follow-up, in both group 1 and group 3, 12 patients died. In group 2, 14 patients died. The median OS of group 1, group 2, and group 3 was 22, 12, and 6 months, respectively (P < 0.001). Compared with surgery alone and targeted therapy alone, patients with cytoreductive surgery before targeted therapy had statistically better survival benefits (P < 0.001, P = 0.009, respectively). On univariate analysis, the number of metastatic sites (P = 0.004) was a statistically significant prognostic factor influencing OS.ConclusionsOur single-center experience showed that CN with thrombectomy before targeted therapy improved the survival of patients with mRCC with venous tumor thrombus. The number of metastatic sites was an independent prognostic factor influencing OS.

This largest VHL survival analysis indicates that onset age, family history, mutation type and first presenting symptom have an effect on the survival of patients with VHL disease, which is helpful to genetic counselling and clinical decision-making.

BackgroundMetastasis is the primary cause of death in renal cell carcinoma (RCC). Loss of cell-to-cell adhesion, including tight junctions (TJs) is the initial step in the process of metastasis. Claudin-7 (CLDN7) is a major component of TJs. However, the clinical significance and its regulation of kidney tumorigenesis remain poorly understood.MethodsA total of 120 fresh clear cell RCC (ccRCC) specimens and 144 primary RCC and adjacent nonmalignant renal paraffin specimens were obtained from Department of Urology, Peking University First Hospital. Expression of CLDN7 in ccRCC tissues and cell lines were determined using bioinformatic data mining, quantitative real-time PCR (qRT-PCR), Western blotting and immunostaining. The clinical significance of CLDN7 expression and promoter DNA methylation status was analyzed in ccRCC patients from Peking University First Hospital and The Cancer Genome Atlas. Additionally, the methylation specific-PCR, bisulfite genomic sequencing and demethylation analysis of CLDN7 were performed. Biological functions of CLDN7 were investigated by examining cell proliferation using MTS assays and EdU incorporation assays, cell migration by in vitro wound healing assays and transwell migration assays, cell invasion by transwell invasion assays, and cell apoptosis by flow cytometry. Mouse model experiments were performed to confirm the effects of CLDN7 on tumor growth and metastasis in vivo. The molecular mechanism of CLDN7 function was investigated using gene-set enrichment analysis (GSEA) and high-throughput cDNA sequencing (RNA-Seq) and confirmed by qRT-PCR, Western blot and immunostaining in vitro and in vivo.ResultsOur findings revealed that CLDN7 is frequently downregulated via hypermethylation of its promoter in ccRCC. CLDN7 can help predict aggressive tumor status and poor prognosis in ccRCC patients. Interestingly, hypermethylation of the CLDN7 promoter was related to advanced ccRCC status and poor prognosis. Moreover, overexpression of CLDN7 induced cell apoptosis, suppressed proliferation, migration and invasion abilities of ccRCC cells both in vitro and in vivo. Additionally, GSEA and RNA-Seq results showed that CLDN7 had negative effects in cancer-associated signaling pathways and (epithelial-mesenchymal transition) EMT-related pathways. These results were validated by qRT-PCR, Western blot and immunostaining.ConclusionsWe have demonstrated a previously undescribed role of CLDN7 as a ccRCC suppressor and suggest that loss of CLDN7 potentiates EMT and tumor progression. CLDN7 may serve as a functional tumor suppressor in tumor progression and a potential biomarker and target in patients with ccRCC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0924-y) contains supplementary material, which is available to authorized users.

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von Hippel–Lindau (VHL) disease is caused by mutations in the VHL gene and demonstrates marked phenotypic variability. Genotype-phenotype correlations in Chinese VHL patients have been unclear. To establish genotype-phenotype correlations in Chinese VHL patients, we collected VHL mutations and phenotypes of 291 patients with VHL disease from 115 unrelated families. Genotype-phenotype correlations at mutation type level, mutation region level, and mutation codon level were analyzed by Kaplan-Meier curves and Cox regression models. We found missense mutations conferred an increased risk of pheochromocytoma developments, but a decreased risk of central nervous system hemangioblastomas (CHBs) and pancreatic lesions. Patients with VHL deletions were more prone to developing retinal angiomas. Renal cell carcinomas were more frequent in nonsense, frameshift or splice-site mutations. Mutations in Exon 2 conferred a higher risk and earlier diagnostic age of CHBs than mutations in other exons (HR = 1.684, 95% CI 1.082–2.620, p = 0.021; 27.0 ± 9.7 years versus 32.8 ± 11.7 years, p = 0.024), while patients with mutations in Exon 3 were more prone to developing pheochromocytomas (HR = 2.760, 95% CI 1.419–5.370, p = 0.003). Mutations at codon 80 or codon167 conferred significantly higher risks of pheochromocytomas than other mutations (HR = 4.678, 95% CI 1.392–15.724, p = 0.013; HR = 4.683, 95% CI 2.515–8.719, p < 0.001 respectively). In conclusion, VHL mutation types, mutation regions and mutation codons can act as phenotypic predictors of VHL disease. Mutation regions and mutation codons may aid in directed surveillance and monitoring of VHL patients.