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Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing.

病例报告: 一个同义VHL突变 (c.414A  > g,p.Pro138Pro) 通过调节失调的剪接引起致病性家族性血管母细胞瘤。

  • 影响因子:1.91
  • DOI:10.1186/s12881-020-0976-7
  • 作者列表:"Liu F","Calhoun B","Alam MS","Sun M","Wang X","Zhang C","Haldar K","Lu X
  • 发表时间:2020-02-27

BACKGROUND:von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations. Synonymous mutations are expected to be phenotypically silent and their role in VHL disease remains poorly understood. CASE PRESENTATION:We report a Caucasian male with a family history of pheochromocytoma and the synonymous VHL mutation c.414A > G (p.Pro138Pro). At 47-years, MRI revealed pheochromocytoma in the left adrenal gland and hemangioblastomas in the spine and brain. Pheochromocytoma was treated by adrenalectomy. Radiotherapy, followed by craniotomy and resection were needed to reduce hemangioblastomas to residual lesions. Two of three of the proband's children inherited the mutation and both presented with retinal hemangioblastomas without pheochromocytoma at age 7: one twin needed four laser treatments. Primary skin fibroblasts carrying the heterozygous mutation or wild type VHL were established from the family. Mutant fibroblasts downregulated full-length VHL mRNA and protein, and upregulated the short VHL mRNA isoform (a result of exon 2 skipping in splicing) at the mRNA level but not at the protein level. CONCLUSIONS:Our study shows that the synonymous VHL mutation c.414A > G can within 7 years induce pediatric retinal hemangioblastoma in absence of pheochromocytoma. This highlights the need to include splicing-altering synonymous mutations into the screening for VHL disease. This is also the first report on detecting and validating a synonymous VHL mutation using patient-derived fibroblasts. The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2. The reduced but not completely abolished pVHL protein in a loss-of-heterozygosity genetic backdrop may underlie the etiology of VHL disease.


背景: von Hippel-Lindau (VHL) 病是由VHL种系突变引起的家族性肿瘤综合征。致病性VHL突变包括缺失、移码、无义和错义突变。同义突变预计为表型沉默,其在VHL疾病中的作用仍知之甚少。 病例报告: 我们报告了 1 例有嗜铬细胞瘤家族史和同义VHL突变c.414A> g (p.Pro138Pro) 的高加索男性。47 年时,MRI显示左侧肾上腺嗜铬细胞瘤,脊柱和脑部血管母细胞瘤。肾上腺切除术治疗嗜铬细胞瘤。需要放疗,然后开颅手术和切除,以减少血管母细胞瘤至残留病灶。3 例先证者患儿中有 2 例遗传了该突变,7 岁时均出现无嗜铬细胞瘤的视网膜血管母细胞瘤: 1 例双胞胎需要 4 次激光治疗。从该家系中建立携带杂合突变或野生型VHL的原代皮肤成纤维细胞。突变成纤维细胞在mRNA水平下调全长VHL mRNA和蛋白,在蛋白水平上调短VHL mRNA亚型 (外显子 2 剪接跳跃的结果)。 结论: 我们的研究表明,同义VHL突变c.414A> g可在 7 年内诱发无嗜铬细胞瘤的儿童视网膜血管母细胞瘤。这突出了将剪接改变同义突变纳入VHL病筛查的必要性。这也是首次使用患者来源的成纤维细胞检测和验证同义VHL突变的报告。突变c.414A  > g翻译为p。pro138Pro,但它在功能上不是沉默的,因为它通过跳过外显子 2 引起异常剪接。在杂合性缺失遗传背景下,pVHL蛋白减少但未完全消失可能是VHL病病因的基础。



作者列表:["Tran S","Puric E","Walser M","Poel R","Datta NR","Heuberger J","Pica A","Marder D","Lomax N","Bolsi A","Morach P","Bachtiary B","Seddon BM","Schneider R","Bodis S","Weber DC"]

METHODS:OBJECTIVE:Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT). METHODS: :Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed. RESULTS: :Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369-1142). All patients completed PT and received a median of 5 HT sessions (range, 2-6). Median follow-up was 18 months (range, 9-26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9-72). All patients experienced acute Grade 2-3 local pain. One patient presented with a late Grade 3 iliac fracture. CONCLUSION:Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial. ADVANCES IN KNOWLEDGE: :This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma.

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翻译标题与摘要 下载文献
作者列表:["Gyori DJ","Bullington SM","Crawford BS","Vernon VP"]

METHODS:BACKGROUND:National guidelines recommend screening and treatment for cancer-related bone disease and continued monitoring of bone-modifying agents. It is unclear whether a standardized screening tool is utilized to identify eligible patients and ensure appropriate supportive care is implemented. The purpose of this study was to evaluate current prescribing practices and optimize management of bone-modifying agents. METHODS:A retrospective chart review was performed to identify patients who received hormone deprivation therapy or had bone metastases through Hematology/Oncology or Urology clinics from 1 November 2016 to 31 October 2017. The primary endpoints of this study were the incidence of completed baseline dual-energy X-ray absorptiometry (DEXA) scan for patients on hormone deprivation therapy and percent of patients started on a bone-modifying agent for the prevention of skeletal-related events secondary to bone metastasis. Secondary endpoints included percent of patients with dental examinations prior to initiation, adequate calcium and vitamin D supplementation, incidence of osteonecrosis of the jaw or flu-like symptoms and education, and percent of bisphosphonate doses appropriately adjusted based on renal function. RESULTS:A total of 375 patients were assessed for baseline DEXA scans and bone-modifying therapy. Of the 226 patients on hormone deprivation therapy, 111 (49%) patients were appropriately screened with a DEXA scan prior to initiation of hormone deprivation therapy. Among the 149 patients with bone metastases, only 94 (63.1%) patients were started on a bone-modifying agent. CONCLUSIONS:Opportunities have been identified to optimize management of patients with cancer-related bone disease. Implementation of standardized tools may increase the rate of appropriate screening and initiation of bone-modifying therapy when warranted.

翻译标题与摘要 下载文献
作者列表:["Dohzono S","Sasaoka R","Takamatsu K","Hoshino M","Nakamura H"]

METHODS:PURPOSE:Low skeletal muscle mass has been associated with poor prognosis in patients with advanced lung cancer. However, little is known about the relationship between skeletal muscle mass and overall survival in patients with bone metastases from lung cancer. The objective of the present study was to evaluate the prognostic value of low trunk muscle mass in predicting overall survival in these patients. METHODS:The data from 198 patients who were diagnosed with bone metastases from lung cancer from April 2009 to May 2017 were retrospectively reviewed. The areas of the psoas and paravertebral muscles were measured at the level of the third lumbar vertebra on computed tomography scans taken at the time nearest to the diagnosis of bone metastasis. Muscle area was evaluated for male and female cohorts separately using different cutoff points. Cox proportional hazards analysis was performed to evaluate the factors independently associated with overall survival. RESULTS:The overall survival of patients in the lowest quartile for psoas muscle area or paravertebral muscle area was significantly shorter than that of patients above the 25th percentile for muscle area (p < 0.001). Multivariate analyses showed that paravertebral muscle mass (hazard ratio, 1.73; 95% confidence interval, 1.17-2.56; p = 0.006), epidermal growth factor receptor-targeted therapy, and performance status were independent prognostic factors. CONCLUSIONS:Low paravertebral muscle mass was associated with shorter survival, independently of known prognostic factors.

翻译标题与摘要 下载文献