Jiangyi Wang

Telomere Shortening Is Associated with Genetic Anticipation in Chinese Von Hippel–Lindau Disease Families

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 = 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.

Genotype-phenotype correlations in Chinese von Hippel–Lindau disease patients

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.

Higher programmed cell death 1 ligand 1 (PD-L1) mRNA level in clear cell renal cell carcinomas is associated with a favorable outcome due to the active immune responses in tumor tissues

Renal cell carcinoma is one of the most common urological tumors. The role of programmed cell death 1 ligand 1 (PD-L1) in renal cell carcinomas in predicting outcome of the patients is yet unclear. We analyzed the clinical and RNA-seq data of 522 kidney clear cell cancer, 259 kidney papillary cell carcinoma and 66 kidney chromophobe patients from The Cancer Genome Atlas (TCGA) database. In kidney clear cell cancer patients with high PD-L1 mRNA level and low PD-L1 mRNA level in tumors, the median overall survival periods were 45.0 and 37.1 months respectively (p=0.002). Multivariate Cox regression tests found that PD-L1 mRNA level in tumor was an independent predictor for overall survival status in kidney clear cell cancer patients (HR=0.7, 95% CI 0.5-0.9, p=0.007). However, no significant difference in overall survival status was found between high and low PD-L1 groups in kidney papillary cell carcinoma and kidney chromophobe cohorts. Gene-set enrichment analysis on the data from databases of TCGA and GSE53757 dataset in Gene Expression Omnibus databases showed that several pathways relating to immunological functions were activated in kidney clear cell cancers with high PD-L1 mRNA expression, and glycolysis and epithelial-mesenchymal transition pathways relating to tumor progression and metastasis were increased in kidney clear cell cancers with low PD-L1 mRNA level. In conclusion, higher PD-L1 mRNA level in kidney clear cell cancer tissues was associated with a favorable outcome due to the higher immunological responses in tumor tissues.

Shorter telomere length increases age‐related tumor risks in von Hippel‐Lindau disease patients

Von Hippel‐Lindau (VHL) disease is a rare autosomal dominant cancer syndrome caused by alterations of VHL gene. Patients are predisposed to develop pheochromocytomas and solid or cystic tumors of the central nervous system, kidney, pancreas, and retina. Remarkable phenotypic heterogeneity exits in organ involvement and tumor onset age between and within VHL families. However, no reliable markers have been found to predict the age‐related tumor risks in VHL patients. A large Chinese cohort composed of 300 VHL patients and 92 healthy family controls was enrolled in our study. Blood relative telomere length was measured in 184 patients and all the controls available for genomic DNA samples. Age‐related risks for the five major VHL‐associated tumors were evaluated using Kaplan–Meier plots and Cox regression analysis. Differences in clinical phenotype were observed between Chinese cohort and the United Kingdom cohort. VHL patients showed significantly shorter telomere length than healthy family controls(P = 0.0183), and a positive correlation was found between telomere length and onset age of the five major tumors, respectively. Moreover, patients in the shorter telomere group (age‐adjusted telomere length ≤ 0.44) suffered higher age‐related risks for VHL‐associated central nervous system hemangioblastomas (HR: 1.879, P = 0.004), renal cell carcinoma (HR: 2.126, P = 0.002) and pancreatic cyst and neuroendocrine tumors (HR: 2.093, P = 0.001). These results indicate that blood shorter telomere length is a new biomarker for age‐related tumor risks in VHL patients, which will be crucial to genetic counseling and future research about the role of telomere shortening in the pathogenesis of VHL‐associated tumors.

Risk factors for survival in patients with von Hippel-Lindau disease

Background Historically, von Hippel-Lindau (VHL) disease is characterised by a poor survival. Although genotype–phenotype correlation has been described in many studies, the risk factors for VHL survival remain unclear. This study aims to evaluate the median survival of Chinese patients with VHL disease and explore whether VHL survival is influenced by genetic and clinical factors. Methods In this retrospective study, we recruited 340 patients from 127 VHL families. Kaplan-Meier plot and Cox regression model were used to evaluate the median survival and assess how survival was influenced by birth year, birth order, sex, family history, mutation type, onset age and first presenting symptom. Results The estimated median life expectancy for Chinese patients with VHL disease was 62 years. Patients with early-onset age, positive family history and truncating mutation types had poorer overall and VHL-related survival. Patients with haemangioblastoma as their first presenting symptom were related to a higher risk of death from central nervous system haemangioblastoma than those with abdominal lesions (HR 8.84, 95% CI 2.04 to 38.37, P=0.004). Conclusions 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.

Genotype and phenotype correlation in von Hippel–Lindau disease based on alteration of the HIF-α binding site in VHL protein

PurposeVon Hippel–Lindau (VHL) disease is a rare hereditary cancer syndrome that reduces life expectancy. We aimed to construct a more valuable genotype–phenotype correlation based on alterations in VHL protein (pVHL).MethodsVHL patients (n = 339) were recruited and grouped based on mutation types: HIF-α binding site missense (HM) mutations, non-HIF-α binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared.ResultsMissense mutations conferred an increased risk of pheochromocytoma (HR = 1.854, p = 0.047) compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group (HR = 0.298, p = 0.003) but was similar between HM and TR groups (HR = 0.901, p = 0.810). Patients in the nHM group had a higher risk of pheochromocytoma (HR = 3.447, p < 0.001) and lower risks of central nervous system hemangioblastoma (CHB) (HR = 0.700, p = 0.045), renal cell carcinoma (HR = 0.610, p = 0.024), and pancreatic tumor (HR = 0.382, p < 0.001) than those in the combined HM and TR (HMTR) group. Moreover, nHM mutations were independently associated with better overall survival (HR = 0.345, p = 0.005) and CHB-specific survival (HR = 0.129, p = 0.005) than HMTR mutations.ConclusionThe modified genotype–phenotype correlation links VHL gene mutation, substrate binding site, and phenotypic diversity (penetrance and survival), and provides more accurate information for genetic counseling and pathogenesis studies.

AB056. Cytoreductive radical prostatectomy for men with oligo-metastatic prostate cancer

Background To present our preliminary surgical experience with cytoreductive radical prostatectomy for patients with oligometastatic prostate cancer. Methods Ten selective cases with oligometastatic prostate cancer diagnosed by bone scan and biopsy of prostate underwent cytoreductive radical prostatectomy. The operating time, estimated blood loss and perioperative complication were recorded and evaluated. Follow up studies were performed with an evaluation for postoperative PSA level and the status of the urinary voiding. Results The mean age was 65.1 years (range, 55–78 years), initial PSA level was 70.27 ng/mL (range, 8.56–280.0 ng/mL), biopsy Gleason score was 8 (range, 6–9), Preoperative clinical stage 1 case T4N0M1, 3 cases T3N1M1, 4 cases T3N0M1, 2 cases T2N0M1. All the operations were successfully performed. The total operative time range was 110–260 min with mean time of 200 min. The blood loss was 85–350 mL with mean 140 mL and no blood transfusion was required. The catheter was removed after a mean [range] of 14 [9–16] days. No intra-operative complications occurred. Eight patients had positive surgical margins. The mean [range] hospital stay was 7 [3–15] days after surgery. All the cases were continent after removal of the catheter. No cases demonstrated vesicourethral stricture. All ten patients had decreased PSA after operation 6 weeks. Conclusions Cytoreductive radical prostatectomy for patients with oligometastatic prostate cancer could be safe, effective, and appropriate. Cytoreductive radical prostatectomy might be a treatment option in the multimodal management of oligo-metastatic prostate cancer.

MP60-05 ERYTHROPOIETIN RECEPTOR MAY BECOME A TARGET FOR RENAL CELL CARCINOMA

paired metastatic tumors, and 8 paired normal kidney samples by immunohistochemistry. RESULTS: NF2 mutations are enriched in higher grade (>pT3, pT4) and metastatic tumors compared to low grade or non-metastatic tumors (20-30% vs. 1.5%), and are associated with a decreased disease-free survival. Cell lines derived from metastatic RCC have lower NF2 expression than cell lines derived from local tumors, more importantly, MERLIN protein levels are decreased or undetectable by Western blot or IHC in metastatic derived cell lines. The metastatic lines Caki1 and ACHN have increased metastatic potential as measured by increased colony formation. MERLIN was absent in a tumor with sarcomatoid differentiation but was present in all 8 metastatic samples. CONCLUSIONS: These results support a potential intriguing role for MERLIN loss of function in the clinically-relevant phenotypic transition from localized to invasive RCC. The model system described here will provide a crucial framework for testing MERLIN0s influence on invasiveness through knockdown and rescue of MERLIN activity in appropriate RCC cell lines.

PD52-10 SHORTER TELOMERE LENGTH INCREASES AGE-RELATED TUMOR RISKS IN CHINESE VON HIPPLE-LINDAU DISEASE

incidents that had occurred up until 2015 were documented. Patient demographics and comorbidities were analyzed for risk factors for VTE. All VTE incidents were documented in adjunct with known risk factors for each patient. RESULTS: Of the 900 patients that were evaluated, 10 were documented to have VTE, making the incidence 1.1%. 40% of these patients had a prior history of VTE. 20% of the patients with a VTE had metastatic disease at time of surgery. 90% of patients were obese with a mean BMI of 32.3. 50% of patients with postoperative VTE had tobacco use. 100% of patients with documented VTE had at least 1 risk factor for VTE while 80% of patients had greater than 2 risk factors. CONCLUSIONS: VTE incident following renal cell carcinoma surgery was found to be 1.1%. All patients had at least one risk factor in addition to surgery. The rate of significant postoperative bleeding following surgical therapy for renal cell carcinoma requiring transfusion is noted to be 3-6%. Risks of postoperative bleeding and other complications outweigh the benefit pharmacological VTE may have with such a low incidence of VTE. Early ambulation and mechanical VTE prophylaxis are warranted following surgery. Although VTE was a rare event, those with multiple risk factors may warrant special consideration and more aggressive VTE prophylaxis following surgery.

MP67-01 TELOMERE LENGTH AND GENETIC ANTICIPATION IN A LARGE COHORT OF CHINESE VON HIPPLE-LINDAU DISEASE

METHODS: This is a single-center, prospective study, conducted at Monash Health, Australia. It includes patients under the age of 18 years who underwent a supine PCNL between April 2007 and June 2015. The Monash Health Human Research Ethics Committee approved this as a Quality and Service improvement activity. Data was collated on patient age, number, size and composition of stones, technique used, equipment used, length of surgery and complications. RESULTS: Thirteen patients (3 girls and 10 boys) with a mean age of 8.2 years were included. Of these, 12 had at least one renal calculus with the largest calculi having a mean size of 15mm and the procedure took 114 minutes. The stone clearance rate was 69%, three patients had residual stones on follow-up imaging. The mean length of stay was 3 days. One patient required ICU post-operatively for sepsis and two patients required blood transfusions. These results are comparable to prone PCNL. CONCLUSIONS: The Modified supine PCNL is a safe and effective and method of retrieving large calculi in the pediatric population and is comparable to the prone PCNL.