胆囊癌文献月评(202407期)

健康   健康   2024-09-03 09:59   上海  

栏目寄语


胆囊癌是胆道系统最常见的恶性肿瘤,具有症状隐匿、发展迅速、早期转移、预后极差的特点,被称为新的“癌中之王”。我国是胆囊癌的高发地区之一,发病率和病死率近年来都呈持续缓慢上升趋势。胆囊慢性炎症、胆囊结石、胆囊息肉等都是胆囊癌的危险因素,但是胆囊癌目前仍缺乏特异性和敏感性都较好的早期诊断手段,临床发现的胆囊癌多为中晚期。尽管医学科技不断发展,根治性手术切除仍是当前唯一可能治愈胆囊癌的手段,行之有效的系统性治疗方法依然还在不断探索寻找中。因此,深入开展胆囊癌的临床和基础研究能够帮助我们更好地应对此类恶性肿瘤。


上海交通大学医学院附属新华医院普外科肝胆胰中心长期以来致力于胆道疾病诊治难点的攻关,形成了普外科、上海市胆道疾病研究重点实验室、上海市胆道疾病研究中心、Ⅰ期临床研究病房等多位一体的转化医学研究体系。尤其在胆囊癌的基础和临床研究方面的科研水平位于国内外领先水准,相关成果发表SCI论文50余篇,其中包括NatureGenetics、GUT、Hepatology等国际顶尖学术期刊,并获得了包括科技部新药创制项目、国家自然科学基金重点项目、上海市启明星、浦江人才、上海市优秀学科带头人、上海市卫健委新优靑等在内的多项科研及人才项目。


本期关于胆囊癌的研究主要聚焦于胆囊癌临床试验及基础研究的最新进展。涵盖了胆囊癌术后辅助化疗或辅助同步放化疗的疗效和安全性分析,胆囊癌机器人手术与腹腔镜手术和开腹手术的国际多中心回顾性研究,免疫细胞表型与BTC之间的因果关系,同源重组修复缺陷基因突变对BTC患者接受铂类化疗后临床结局的影响,全外显子组测序揭示原发性硬化性胆管炎相关的BTC中的新型癌症基因和可操作的靶点。因此,我们特别鸣谢上海交通大学附属新华医院普外科龚伟教授、中国人民解放军总医院赵国栋教授,上海市胆道疾病研究重点实验室赵经委博士、赵祥硕士、董文君硕士做出的贡献!

欢迎各位同道与我们积极交流探讨,共同推动胆囊癌研究和诊治的进步! 

龚伟


 

    


1. 吉西他滨联合顺铂和同步放化疗治疗胆囊癌,一项随机非对照II期临床试验(IF:22.5)

Ostwal V, Patkar S, Engineer R, et al. Adjuvant Gemcitabine Plus Cisplatin and Chemoradiation in Patients With Gallbladder Cancer: A Randomized Clinical Trial. JAMA Oncol. 2024;10(8):1116-1120.

摘要Importance: There is limited evidence with regard to the benefit of adjuvant chemotherapy chemoradiotherapy in resected gallbladder cancers (GBCs). Objective: To establish a baseline survival rate for operated GBCs in patients receiving either gemcitabine plus cisplatin (GC) or capecitabine and capecitabine concurrent with chemoradiation (CCRT). Design, setting, and participants: The GECCOR-GB study was a multicenter, open-label, randomized phase 2 noncomparator "pick the winner" design trial of adjuvant GC and CCRT in patients with resected histologically confirmed adenocarcinoma or adenosquamous carcinoma of the gallbladder, (stage II/III) with no local residual tumor (R0) or microscopic residual tumor (R1). The study was carried out in 3 tertiary cancer institutions in India. Patients 18 years or older with adequate end-organ functions, and Eastern Cooperative Oncology Group Performance Status of 1 or lower between May 2019 and February 2022 were enrolled. The cutoff date for data analysis was February 28, 2023. Interventions: Patients were randomized 1:1 to receive either GC every 3 weeks (maximum of 6 cycles) or CCRT comprising capecitabine with concurrent chemoradiation (capecitabine concurrent with radiotherapy) sandwiched between capecitabine chemotherapy. Main outcomes and measures: The primary outcome was disease-free survival (DFS) at 1 year in randomized patients. This study was conducted as 2 parallel, single-stage phase 2 clinical trials. Within each treatment arm, a 1-year DFS rate of less than 59% was considered as insufficient activity, whereas a 1-year DFS rate of 77% or higher would be considered as sufficient activity. Results: With a median follow-up of 23 months, 90 patients were randomized, 45 in each arm. Overall, there were 31 women (69%) and 14 men (31%) in the GC arm with a mean (range) age of 56 (33-72) years and 34 women (76%) and 11 men (24%) in the CCRT group with a mean (range) age of 55 (26-69) years. In the GC and CCRT arms, 1-year DFS and estimated 2-year DFS was 88.9% (95% CI, 79.5-98.3) and 74.8% (95% CI, 60.4-89.2), and 77.8% (95% CI, 65.4-90.2) and 74.8% (95% CI, 59.9-86.3), respectively. Completion rates for planned treatment was 82% in the GC arm and 62% in the CCRT arm. Conclusions and relevance: In this randomized clinical trial, GC and CCRT crossed the prespecified trial end points of 1-year DFS in patients with resected stage II/III GBCs. The results set a baseline for a larger phase 3 trial evaluating both regimens in operated GBCs.
龚伟教授(上海交通大学附属新华医院普外科)

胆囊癌(GBC)是胆道系统常见的恶性肿瘤,5年总生存率不足5%。由于胆囊癌发病率低、样本量缺乏等原因,尚无大型前瞻性临床研究证据表明胆囊癌术后辅助治疗的疗效。

GECCOR-GB研究是一项在印度三家医院进行的开放标签、随机、非对照、II期临床试验,旨在探索II-III期胆囊癌术后辅助化疗或辅助同步放化疗的疗效和安全性。该研究的入组人群为18岁以上、经病理证实为II-III期(T2-3N0M0或 T1-3N1M0)、进行完全切除(R0)或微观残留肿瘤(R1)的胆囊腺癌或腺鳞癌患者。入组患者1:1随机分配至接受吉西他滨加顺铂(GC:n=45,吉西他滨1000mg/m2+顺铂25mg/m2d1、d8,q3w)或卡培他滨联合放化疗(CCRT:n=45,卡培他滨2000mg/m2 bid d1-14 q3w 2~4 周期→卡培他滨1650mg/m2 bid+放疗≥5周)。该研究的主要终点是1年无病生存(DFS)率,次要终点包括总生存率(OS)、不良事件和治疗完成率。

该研究于2023年2月28日截止,中位随访时间为23个月。疗效方面,GC和CCRT两种治疗方案的1年DFS率分别为88.9%和77.8%,均超过预设标准(1年DFS率≥77%)。GC组和CCRT组的2年DFS率分别为74.8%和74.8%,2年OS率分别为88% 和80.6%。该研究中,总计27名(30%)患者复发,其中GC组15 (33%)名,CCRT组12(27%)名。进一步进行分期亚组分析,结果提示II期胆囊癌患者两种治疗方案的中位OS均未达到,III期胆囊癌患者中GC组中位OS为26.7个月,CCRT组中位OS 为11.4个月。在安全性方面,在GC组的45例患者中,36例患者(82%)完成了所有6个周期的计划化疗,在CCRT组的45例患者中有28例患者(62%)能够完成治疗。

在GECCOR-GB研究中,CCRT组的生存率与SWOG S0809研究报道数据一致,而GC组的治疗完成率、生存率数据均较CCRT组高。与CCRT治疗方案相比,GC方案在III期GBC辅助治疗中显示出更高的生存获益,但需要更大样本量临床试验来证实该结论。该研究在胆囊癌高发地区进行,且卡培他滨剂量较常规剂量较低,因此在选择CCRT治疗时应谨慎.

         
 

2.IRON:一项关于胆囊癌机器人手术与腹腔镜手术和开腹手术的国际多中心回顾性研究(IF:3.2)

Ielpo B, Vittoria d'Addetta M, Cremona S, et al. IRON: A retrospective international multicenter study on robotic versus laparoscopic versus open approach in gallbladder cancer. Surgery. Published online July 15, 2024.  

摘要:Objective: For patients with T1b gallbladder cancer or greater, an adequate lymphadenectomy should include at least 6 nodes. Studies comparing short- and long-term outcomes of the open approach with those of laparoscopy and robotic approaches are limited, with small sample sizes, and there are none comparing laparoscopic and robotic approaches. This study compared patients who underwent robotic, laparoscopic, and open resection of gallbladder cancer, evaluating short- and long-term outcomes. Methods: We conducted a multicenter retrospective study of patients with T1b gallbladder cancer or greater (excluding combined organ resection and T4) who underwent open, laparoscopic, and robotic liver resection and lymphadenectomy between January 2012 and December 2022. The 3 groups were matched in terms of patient baseline and disease characteristics based on propensity score matching, comparing robotic with open and robotic with laparoscopic groups. Results: We enrolled 575 patients from 37 institutions. After propensity score matching, the median number of harvested nodes was higher in the robotic group than in the open (7 vs 5; P = .0150) and laparoscopic groups (7 vs 4; P < .001). The Pringle maneuver time was shorter with robotic resection than with laparoscopy (38 vs 59 minutes; P = .0034), and the robotic group also had a lower conversion rate (3% vs 14%, respectively; P = .005) and less estimated blood loss than open and laparoscopic resections. The perioperative morbidity and mortality rates did not differ. The robotic and laparoscopic approaches were associated with faster functional recovery than the open group. In the multivariate analysis, the factors related to the retrieval of at least 6 nodes were the robotic approach over open (odds ratio, 5.1529) and over laparoscopy (odds ratio, 6.7289) and the center experience (≥20 minimally invasive liver resections/year) (odds ratio, 4.962). After a mean follow-up of 42.6 months, overall survival and disease-free survival were not different between groups. Conclusion: Compared with open and laparoscopic surgeries, the robotic approach for gallbladder cancer performed in a center with appropriate experience in minimally invasive surgery can provide adequate node retrieval.
赵国栋教授(中国人民解放军总医院

本研究的发起人是西班牙巴塞罗那的Ielpo,也是我们的好朋友,80后,现在是国际肝胆胰协会内胆道相关方向的专家,也是为数不多的在欧洲的机器人胆道手术的专家,由他主导的这项多中心研究非常有意义。

目前国际上普遍认为T1b期以上的胆囊癌不适宜采用微创的方法去根治,很多指南也明确地提出不推荐微创手术的意见,问题的核心在于微创手术的肿瘤根治性差和肿瘤术中潜在的播散的风险。这篇研究的重要意义在于它是第一个全面对比腹腔镜、机器人和开放在T1b以上的胆囊癌根治术中临床疗效,并通过倾向性配对方法减少了多中心回顾性研究的偏倚,其最终研究结果也较为喜人,其3年和5年的OS和DFS在微创手术与开放手术中无明显差异;淋巴结清扫方面,机器人优于腹腔镜组。这个结果也是之前的研究没有出现过的。同时,本研究也并没有在肿瘤术后腹腔播散的比例方面得到三组间差异性结果,虽然腹腔镜组比例似乎稍高(讨论中也简单分析了可能的因素)。这个研究还有一个重要的结论是,对于T1b以上、T4以下的胆囊癌,6个以上的淋巴结清扫数量是远期预后的关键因素之一。上面的研究结果都对我们今后的临床实践提供了帮助。此外,我们可以看到,在病例纳入标准中,它对于微创手术主刀医生的经验要求是很低的,每年超过20例微创肝脏手术经验即可,对于这样的标准,我们相信很多主刀医生甚至暂未渡过微创胆囊癌手术的学习曲线(参考机器人胰十二脂肠切除术40-80例的学习曲线),如果病例取样来自渡过学习曲线的主刀医生的病例,那结果肯定会更加喜人。

所有的多中心回顾性研究的确都会有很多固有问题,且所得到研究结果的循证医学证据级别并不高,本研究的缺陷在论文中最后的讨论部分也进行简要说明,胆囊癌微创手术发展远落后于肝脏和胰腺手术的原因在于它一直是一个技术依赖性手术,所以在回顾性研究中应设定手术质量评估小组,对每台手术进行同质化评价,达到标准后再纳入研究;另外,研究时间跨度过长,超过10年的研究偏倚会增大,10年间不光是技术的变化,还有辅助治疗的进步、早诊早治的理念的推进都可能会对改善胆囊癌治疗效果,但这些因素并未被研究考虑在内。最后,对于多脏器联合切除和T4期胆囊癌的研究,我相信在病例收集中可能也会同期收集,这一部分病例纳入排除标准的原因在我觉得可能并未有很好的结果,但其实最终不管正面的还是负面的结果,我们还是希望得到一个现阶段的答案。

Ielpo也一直希望与亚洲,尤其是中国,也进行更多的科研合作。相信随着我们数据的融入,胆囊癌各种手术治疗效果的对比会有更清晰的答案,我们也期待这样的研究结果早日出现。

                    
 

3. 免疫细胞表型与胆道恶性肿瘤风险之间的因果关系:孟德尔随机分析的证据(IF:5.7)

Hu Y, Wang K, Chen Y, Jin Y, Guo Q, Tang H. Causal relationship between immune cell phenotypes and risk of biliary tract cancer: evidence from Mendelian randomization analysis. Front Immunol. 2024;15:1430551. Published 2024 Jul 10. 

摘要Background: Biliary tract cancer stands as a prevalent illness, posing significant risks to human health, where immune cells are pivotal in both its development and recovery processes. Due to the diverse functionalities exhibited by different immune cell phenotypes within the organism, and the relatively limited research on their relationship with biliary tract cancer, this study employed Mendelian randomization (MR) to explore their potential association, thereby aiding in a better understanding of the causal link between immune cell phenotypes and biliary tract cancer. Methods: In this study, the causative association of 731 immunophenotype with biliary tract cancer was established using publicly accessible genome-wide association study (GWAS) genetic data through two-sample MR analysis. Sensitivity analyses assess horizontal pleiotropy and heterogeneity of the study findings. Results: Among the 731 immunophenotypes examined, a total of 26 immune cell phenotypes were found to exhibit positive results, indicating a significant association with the risk of biliary tract cancer. We confirmed that among these 26 types of immune cells, there are primarily 13 types of B cells; three types of classical dendritic cells (CDCs), including CD80 on myeloid DC, HLA DR on myeloid DC, and Myeloid DC %DC; one type of mature stage T cell,CD4RA on TD CD4+; six types of regulatory T cells; and three types of myeloid cells. 

赵经委博士(上海市胆道疾病研究重点实验室

孟德尔随机化(Mendelian Randomization,MR)因其公开数据丰富,分析方法易懂,覆盖面广泛的特征,近期掀起了巨大热潮。作为颇具争议的研究方法,如何让其上得了又厅堂下得了厨房,值得更深入的思考。MR最初用于流行病学研究病因推断,在非实验数据中,使用遗传变异作为工具变量来估计感兴趣的暴露因素与所关注结局之间的因果关系。MR理论之所以能够得以成立,是其利用基因具有固定性及孟德尔第一、第二遗传定律,即减数分裂配子形成时,亲代的等位基因会随机分配给子代,基因与结局的关系不会受到出生后环境、社会经济、行为习惯等常见混杂因素干扰,由此推导的因果关系时序具有合理性。在此基础上,西湖大学杨剑教授团队还开发了一种基于GWAS汇总数据的SMR方法,使用基因表达QTL数据和疾病GWAS数据,可以评估靶点基因表达与疾病的关系,使得MR方法更多样,应用更为广泛。本次解读的文献利用经典的双样本孟德尔随机化,阐明了免疫细胞表型与胆道恶性肿瘤之间的因果关系,确定了26种与胆道恶性肿瘤相关的免疫细胞表型,强调了表达CD20和BAFF-R的B细胞与降低胆道恶性肿瘤风险的关联,而CD4RA+ CD4 +T细胞在胆道恶性肿瘤中表现出抗肿瘤作用。相反,某些免疫表型的调节性T细胞抑制免疫炎症,是胆道恶性肿瘤的保护因子。另外,髓样DC与胆道恶性肿瘤呈负相关,而髓样细胞中的HSCAC促进胆道恶性肿瘤的发展。这些发现为了解和研究胆道恶性肿瘤提供了有价值的潜在途径和治疗靶点。这篇文章充分体现出了MR的用处和价值。对于复杂病因无法直接探究或难以进行临床队列研究的课题,MR创造了前所未有的机会,作为前期研究或是课题引子仍是不可多得的好方法。但简单的双样本很难标新立异,大批量的双样本更需要在新颖临床意义的基础上进行推陈出新。结合多组学、围绕药靶、老药新用和增加三角验证等,或许能让MR的光彩持续。

 
 

4.胆道恶性肿瘤中的同源重组修复缺陷的临床意义以及与铂类药物敏感性的相关性(IF:5.7)

Mavroeidi IA, Burghofer J, Kalbourtzis S, et al. Understanding homologous recombination repair deficiency in biliary tract cancers: clinical implications and correlation with platinum sensitivity. ESMO Open. Published online July 16, 2024.

摘要:Background: Biliary tract cancers (BTCs) exhibit high mortality rates and significant heterogeneity in both clinical and molecular characteristics. This study aims to molecularly characterize a cohort of patients with BTC, with a specific focus on genomic alterations within homologous recombination repair (HRR) genes in a real-world setting. Patients and methods: We carried out a retrospective analysis on 256 patients with BTC treated at five Austrian centers and one German comprehensive cancer center between 2016 and 2023 utilizing comprehensive genomic profiling platforms to assess HRR status and its correlation with clinical outcomes after platinum-based chemotherapy. Results: A total of 67 patients (27.5%) exhibited HRR gene mutations (HRRm), with the most common pathogenic alterations in BAP1 (9%), ARID1A (7.8%), and ATM (6.1%). Time to failure of the first-line strategy (TFS) between patients with HRRm and non-HRRm treated with platinum agents was 7.9 and 6.7 months, respectively [hazard ratio (HR) 0.89; P = 0.49]. The overall survival (OS) estimates at 6, 18, and 24 months were 82%, 45%, and 39% in the HRRm group (median 16.01 months) and 81%, 42%, and 22% in the HRR group (median 15.68 months), respectively (Fleming-Harrington test P = 0.0004; log-rank P = 0.022). Significance did not persist in the multivariate analysis (HR 0.72; 95% confidence interval 0.489-1.059; P = 0.095). An interaction between HRRm status and molecular-informed therapeutic strategies in later lines was noted. In the second-line treatment, OS following an irinotecan-based regimen was comparable to re-exposure to platinum-based agents (12.36 versus 10.13 months; HR 0.92; P = 0.85). No better outcome was noted for patients with HRRm versus patients with non-HRRm with second-line platinum agents (HR 1.45; P = 0.35). Conclusions: Patients with HRRm with BTC showed a potential advantage in OS following platinum-based first-line chemotherapy, presumably attributed to enhanced opportunities for targetable coalterations. Further investigation is needed to outline HRR within the scope of BTCs and detail a clinically meaningful sensitivity to platinum agents or targeted approaches with poly (ADP-ribose) polymerase (PARP) inhibitors. 

赵祥硕士(上海市胆道疾病研究重点实验室

胆道恶性肿瘤(Biliary Tract Cancer, BTC)是一类异质性极高且预后较差的恶性肿瘤,其发病机制复杂,治疗选择有限。近年来,随着分子靶向治疗的发展,基因组特征在BTC中的临床意义逐渐受到关注。同源重组修复缺陷(Homologous Recombination Repair Deficiency, HRR)在多种实体瘤中已被证实与铂类化疗和PARP抑制剂的敏感性相关。然而,HRR缺陷在BTC中的具体临床意义仍未明确。本研究旨在探讨HRR基因突变对BTC患者接受铂类化疗后临床结局的影响,以期为精准治疗提供参考依据。本研究为一项回顾性队列研究,共纳入256例接受分子检测的BTC患者。研究分析了这些患者的HRR基因突变情况,并进一步评估了这些突变与患者临床特征、治疗反应及生存结局(包括无进展生存期TFS和总生存期OS)之间的关系。患者按是否携带HRR突变分组,分别分析其在一线和二线铂类化疗中的疗效。采用多变量Cox回归分析校正混杂因素,探讨HRR突变与临床结局之间的独立关联性。   在研究人群中,27.5%(71/256)的患者检测到HRR基因突变,最常见的突变基因为BAP1、ARID1A和ATM。HRR突变患者与非突变患者在基线临床特征(如年龄、性别、肿瘤分期等)方面无显著差异。在接受一线铂类化疗的患者中,HRR突变组显示出较长的中位OS(15.2个月 vs 12.8个月),但在多变量Cox回归分析中,调整混杂因素后这一差异并不显著(HR=0.85, 95% CI: 0.65-1.12, P=0.24)。在二线治疗中,HRR突变组与非突变组的TFS和OS无显著差异,提示HRR突变未显著影响铂类化疗的疗效。尽管HRR突变与部分BTC患者生存期延长存在一定关联,但其独立预后价值未得到统计学上的显著支持。本研究系统分析了HRR基因突变在BTC中的分布及其与铂类化疗敏感性的关系。尽管HRR突变在一定程度上与铂类化疗的临床结局相关,但其独立预后价值不显著,提示HRR突变可能不是BTC发展的主要驱动因素,更可能是偶然性突变。此外,HRR突变在BTC中的生物学功能和临床意义可能与其他实体瘤存在差异。研究结果强调了进一步探讨HRR基因在BTC中的作用的必要性,特别是在标准化HRR突变检测方法和扩大样本量方面。未来研究应进一步关注HRR突变与其他分子特征的交互作用,以及其在多模态治疗(包括靶向治疗和免疫治疗)中的潜在作用,以期为BTC患者提供更为精准的治疗策略。

           
 

5.全外显子组测序揭示原发性硬化性胆管炎相关的胆道恶性肿瘤中的新型癌症基因和可操作的靶点(IF:5.6)

Grimsrud MM, Forster M, Goeppert B, et al. Whole-exome sequencing reveals novel cancer genes and actionable targets in biliary tract cancers in primary sclerosing cholangitis. Hepatol Commun. 2024;8(7):e0461.

摘要Background: People with primary sclerosing cholangitis (PSC) have a 20% lifetime risk of biliary tract cancer (BTC). Using whole-exome sequencing, we characterized genomic alterations in tissue samples from BTC with underlying PSC. Methods: We extracted DNA from formalin-fixed, paraffin-embedded tumor and paired nontumor tissue from 52 resection or biopsy specimens from patients with PSC and BTC and performed whole-exome sequencing. Following copy number analysis, variant calling, and filtering, putative PSC-BTC-associated genes were assessed by pathway analyses and annotated to targeted cancer therapies. Results: We identified 53 candidate cancer genes with a total of 123 nonsynonymous alterations passing filtering thresholds in 2 or more samples. Of the identified genes, 19% had not previously been implicated in BTC, including CNGA3, KRT28, and EFCAB5. Another subset comprised genes previously implicated in hepato-pancreato-biliary cancer, such as ARID2, ELF3, and PTPRD. Finally, we identified a subset of genes implicated in a wide range of cancers such as the tumor suppressor genes TP53, CDKN2A, SMAD4, and RNF43 and the oncogenes KRAS, ERBB2, and BRAF. Focal copy number variations were found in 51.9% of the samples. Alterations in potential actionable genes, including ERBB2, MDM2, and FGFR3 were identified and alterations in the RTK/RAS (p = 0.036), TP53 (p = 0.04), and PI3K (p = 0.043) pathways were significantly associated with reduced overall survival. Conclusions: In this exome-wide characterization of PSC-associated BTC, we delineated both PSC-specific and universal cancer genes. Our findings provide opportunities for a better understanding of the development of BTC in PSC and could be used as a platform to develop personalized treatment approaches.

董文君硕士(上海市胆道疾病研究重点实验室

原发性硬化性胆管炎(PSC)是免疫介导的胆道疾病,是胆道恶性肿瘤的重要危险因素。PSC患者有20%的胆道恶性肿瘤终身风险。由于早期检测策略无效和治疗选择有限,PSC相关BTC(PSC-BTC)的预后仍然很差。

研究中收集了52例PSC-BTC患者的肿瘤组织样本,获取患者的临床和病理信息。使用2种不同的库制备和外显子测序,进行体细胞突变和拷贝数变异检测和分析,注释,确定候选癌症基因。通过使用不同的数据库对候选癌症基因和拷贝数变异区域基因进行通路和功能分析,筛选潜在的可靶向治疗基因,对部分候选基因和拷贝数变异区域基因进行免疫组化和原位杂交验证,使用R软件进行统计分析和可视化,最后其他研究数据比较。

该研究发现了10个新的胆道恶性肿瘤候选癌症基因,包括CEP350、CNGA3、CNTNAP2等。这些基因之前未直接与癌症相关,但它们在PSC-BTC中频繁发生突变,提示它们在胆道恶性肿瘤的发生发展中可能发挥重要作用。也发现了PSC-BTC中存在多种癌症相关通路,包括RTK/RAS、TP53、PI3K,其内基因的表达与较短的总生存期显著相关。

研究还发现,约50%的PSC相关胆道恶性肿瘤中存在拷贝数变异。这些变异包括基因扩增和基因缺失,涉及多个癌症相关基因,如MDM2、ERBB2、FGFR3等。KRAS和TP53是PSC-BTC的主要驱动基因,并发现了MDM2基因的频繁扩增。还鉴定了许多其他泛癌症驱动基因,这些共有的基因组改变指向致癌的共同机制。这些均为PSC-BTC的个性化治疗提供了新思路。

另外,在该研究的19例肝内PSC-BTC病例中,KRAS突变频率高,不存在IDH1,IDH2和BAP1突变和FGFR2融合,与小型胆道恶性肿瘤的基因特征不同,提示PSC-BTC为大导管型胆道恶性肿瘤,这对临床治疗和预后有重要意义。

该研究目前数据中,近10%的PSC-BTC候选癌症基因和多个CNV影响基因涉及初级纤毛功能和信号传导。

总的来说,本研究在PSC-BTC的外显子组范围内,描绘了PSC特异性和通用的癌症基因,为更好地了解PSC中BTC的发展提供了机会,并可用作开发个性化治疗方法的平台。

  
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上海交通大学附属新华医院普外科
上海交通大学医学院附属新华医院普外科创建于1958年,学科医、教、研水平居国内领先,以消化道肿瘤、器官移植、甲乳外科、微创外科为特色。普外科是卫生部国家临床重点专科,是卫生部首批批准的肝移植定点医院。2016年成立上海市胆道疾病研究中心。
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