The biological basis and function of GNAS mutation in pseudomyxoma peritonei: a review.

腹膜假性粘液瘤中GNAS突变的生物学基础和功能: 综述。

  • 影响因子:3.23
  • DOI:10.1007/s00432-020-03321-8
  • 作者列表:"Lin YL","Ma R","Li Y
  • 发表时间:2020-09-01

PURPOSE:Pseudomyxoma peritonei (PMP) is a rare clinical malignancy syndrome characterized by the uncontrollable accumulation of copious mucinous ascites in the peritoneal cavity, resulting in "jelly belly". The mechanism of tumor progression and mucin hypersecretion remains largely unknown, but GNAS mutation is a promising contributor. This review is to systemically summarize the biological background and variant features of GNAS, as well as the impacts of GNAS mutations on mucin expression, tumor cell proliferation, clinical-pathological characteristics, and prognosis of PMP. METHODS:NCBI PubMed database (in English) and WAN FANG DATA (in Chinese) were used for literature search. And NCBI Gene and Protein databases, Ensembl Genome Browser, COSMIC, UniProt, and RCSB PDB database were used for gene and protein review. RESULTS:GNAS encodes guanine nucleotide-binding protein α subunit (Gsα). The mutation sites of GNAS mutation in PMP are relatively stable, usually at Chr20: 57,484,420 (base pair: C-G) and Chr20: 57,484,421 (base pair: G-C). Typical GNAS mutation results in the reduction of GTP enzyme activity in Gsα, causing failure to hydrolyze GTP and release phosphoric acid, and eventually the continuous binding of GTP to Gsα. The activated Gsα could thus continuously promote mucin secretion through stimulating the cAMP-PKA signaling pathway, which is a possible mechanism leading to elevated mucin secretion in PMP. CONCLUSION:GNAS mutation is one of the most important molecular biological features in PMP, with major functions to promote mucin hypersecretion.


目的: 腹膜假性粘液瘤 (PMP) 是一种临床罕见的恶性肿瘤综合征,其特征是腹腔内大量粘液性腹水难以控制地积聚,形成 “果冻腹”。肿瘤进展和粘蛋白分泌过多的机制在很大程度上仍然是未知的,但GNAS突变是一个有希望的贡献者。本文就GNAS的生物学背景、变异特征以及GNAS突变对PMP黏蛋白表达、肿瘤细胞增殖、临床病理特征及预后的影响作一综述。 方法: 采用NCBI PubMed数据库 (英文) 和万方数据 (中文) 进行文献检索。和NCBI基因和蛋白质数据库,Ensembl基因组浏览器,COSMIC,UniProt和RCSB PDB数据库用于基因和蛋白质审查。 结果: GNAS编码鸟嘌呤核苷酸结合蛋白 α 亚基 (gs α)。PMP中GNAS突变的突变位点相对稳定,通常在Chr20: 57,484,420 (碱基对: C-G) 和Chr20: 57,484,421 (碱基对: G-C)。典型的GNAS突变导致gs α 中GTP酶活性降低,导致GTP不能水解并释放磷酸,最终GTP与gs α 持续结合。因此,活化的gs α 可以通过刺激cAMP-PKA信号通路持续促进粘蛋白分泌,这是导致PMP中粘蛋白分泌升高的可能机制。 结论: GNAS突变是PMP最重要的分子生物学特征之一,其主要功能是促进黏蛋白分泌过多。



作者列表:["Letica-Kriegel AS","Leinwand JC","Sonett JR","Gorenstein LA","Taub RN","Chabot JA","Kluger MD"]

METHODS:BACKGROUND:The most common sites of malignant mesothelioma are the pleura and peritoneum, but little is known about the incidence, prognosis, or treatment of patients with disease in both cavities. Previous series suggest that multimodality treatment improves overall survival for pleural or peritoneal disease, but studies typically exclude patients with disease in both cavities. Despite limitations, this investigation is the only study to broadly examine outcomes for patients with malignant mesothelioma in both the pleural and peritoneal cavities. METHODS:This study retrospectively examined 50 patients with both pleural and peritoneal mesothelioma treated with the intent to prolong survival. The primary end point was overall survival from the initial operative intervention. RESULTS:The median overall survival was 33.9 months from the initial intervention. Female gender and intraperitoneal dwell chemotherapy were independent predictors of overall survival. Within 1 year after the initial diagnosis, second-cavity disease was diagnosed in 52% of the patients. The median time to the second-cavity diagnosis for those with a diagnosis 1 year after the initial diagnosis was 30 months. CONCLUSIONS:Well-selected patients with both pleural and peritoneal mesothelioma have a survival benefit over palliative treatment that is comparable with that seen in single-cavity disease. The presence of disease in both cavities is not a contraindication to multimodality treatment aimed at prolonging survival, whether the disease is diagnosed synchronously or metachronously. Patients with an initial diagnosis of single cavity disease are at the highest risk for identification of second-cavity disease within the first year after diagnosis.

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作者列表:["Ali YM","Sweeney J","Shen P","Votanopoulos KI","McQuellon R","Duckworth K","Perry KC","Russell G","Levine EA"]

METHODS:INTRODUCTION:Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is an accepted treatment for peritoneal mesothelioma. In this study, we evaluated QOL after HIPEC for peritoneal mesothelioma. METHODS:This was a prospective study performed after HIPEC for peritoneal mesothelioma between 2002 and 2015. Patients completed QOL surveys, including the Short Form-36 (SF-36), Functional Assessment of Cancer Therapy + Colon (FACT-C), Brief Pain Inventory (BPI), and Center for Epidemiologic Studies Depression Scale (CES-D) preoperatively and at 3, 6, 12, and 24 months postoperatively. RESULTS:Overall, 46 patients underwent HIPEC for peritoneal mesothelioma and completed QOL surveys. Mean age was 52.8 ± 13.8 years and 52% were male. Good preoperative functional status was 70%. Median survival was 3.4 years, and 1, 3, and 5-year survivals were 77.4, 55.2, and 36.5%, respectively. CES-D score decreased at 3 months postoperatively, but increased at 24 months (p = 0.014); SF-36 physical functioning scale decreased at 3 months but returned to baseline at 12 months (p = 0.0045); and the general health scale decreased at 3 months, then improved by 6 months (p = 0.0034). Emotional well-being (p = 0.0051), role limitations due to emotional problems (p = 0.0006), social functioning (p = 0.0022), BPI (p = 0.025), least pain (p = 0.045), and worst pain (p < 0.0001) improved. FACT-C physical well-being decreased at 3 months but returned to baseline at 6 months (p = 0.020), and total FACT-C score improved at 6 months (p = 0.052). CONCLUSION:QOL returned to baseline or improved from baseline between 3 months and 1 year following surgery. Despite the risks associated with this operation, patients may tolerate HIPEC well and have good overall QOL postoperatively.

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作者列表:["Bayat Z","Taylor EL","Bischof DA","McCart JA","Govindarajan A"]

METHODS:BACKGROUND:Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) can be associated with decreases in quality of life (QOL). Bowel-related QOL (BR-QOL) after CRS-HIPEC has not been previously studied. The objectives of the current study were to examine the effect of different types of bowel resection during CRS-HIPEC on overall QOL and BR-QOL. METHODS:A prospective cohort study was performed. QOL data were collected using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and CR-29 questionnaires at 3, 6, and 12 months after CRS-HIPEC. Patients were divided into groups that underwent no bowel resection, non-low anterior resection (LAR) bowel resection, LAR, and LAR with stoma. Primary outcomes were global QOL and BR-QOL. RESULTS:Overall, 158 patients were included in this study. Bowel resections were performed in 77% of patients, with 31% undergoing LAR. Global QOL was not significantly different between groups. LAR patients (with and without stoma) had significantly worse BR-QOL, embarrassment, and altered body image, with LAR + stoma patients having the largest impairments in these domains. Trends toward higher levels of impotence and anxiety were also seen in LAR patients. Although global QOL improved over time, impairments in BR-QOL and sexual and social function did not significantly improve over time. CONCLUSIONS:Although global QOL after CRS-HIPEC was not affected by the type of bowel resection, the use of LAR and ostomies was associated with clinically meaningful and persistent impairments in BR-QOL and related functional domains. Generic QOL questionnaires may not adequately capture these domains; however, targeted questionnaires in these patients may help improve QOL after CRS-HIPEC.

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