四川大学华西医院 泌尿外科
四川大学华西医院 泌尿外科 4+2+3本硕博连读项目博士生
多次获得国家级奖学金及四川大学优秀毕业生称号
Netherlands Cancer Institute联合培养博士
主要从事泌尿系统肿瘤（前列腺癌、肾癌、膀胱癌）的基础和临床转化研究
Journal of Clinical Medicine特刊编辑及许多知名杂志审稿人
中华人民共和国翻译专业资格（水平）证书 三级笔译（中华人民共和国人力资源部）
至今已发表SCI学术论文60余篇，其中第一/共同第一作者18篇，IF>10分累计20篇，包括Genome Medicine、BMC Medicine、Clin Cancer Res 等杂志，近五年第一/共同第一作者文章累计总影响因子94，总被引次数612，引用文章作者遍布全球各地，H指数15
研究多次受邀参加美国临床肿瘤学会（ASCO）、欧洲肿瘤内科学会（ESMO）、欧洲泌尿外科学会（EAU）、美国泌尿外科学会（AUA）等国际学术会议并作多次大会发言及壁报交流
前列腺导管内癌（IDC-P）是前列腺癌的一种高度侵袭性亚型，其特征是肿瘤细胞在前列腺导管和腺泡内生长并保留基底细胞层。该亚型在2016年被世界卫生组织正式列为前列腺癌的一种病理亚型[1]，通常与浸润性前列腺腺泡腺癌（PAC）同时存在[2]，并已被证实与不良预后密切相关，成为识别高风险致命病例的重要表型标志。随着对癌症认识的不断深入，我们越来越意识到理解每个病理亚型背后的分子机制的重要性。尤其对于IDC-P，这一点尤为突出，因为其侵袭性特点与患者不良预后密切相关。因此，深入了解IDC-P发展和进展的分子途径和遗传改变变得至关重要，以制定更有效的诊断、预后和治疗策略来应对这种致命的前列腺癌亚型。
本综述旨在探讨IDC-P的临床特点和分子特征方面的重要研究发现，重点突出其与PAC相比的相似性和差异性。我们相信，IDC-P的临床行为最终源于其独特的分子特征。目前的证据表明，在IDC-P中存在多个异常基因和途径，包括癌基因和肿瘤抑制基因/抑癌基因（如TP53、RB1、PTEN、MYC和ERG）的失调、DNA损伤和修复机制、特殊的雄激素受体（AR）通路突变模式，以及转录因子MED12和非编码RNA SChLAP1的参与。这些分子异常可能在一定程度上对目前临床观察到的IDC-P的生物学行为有所贡献，但仍需要更全面的研究设计来解决一些基本问题，例如IDC-P的起源、推动其进展和侵袭性的因素，以及潜在的治疗靶点。
通过对IDC-P分子特征的深入研究，我们可以为改进这种侵袭性前列腺癌的诊断、预后和个体化治疗策略铺平道路。此外，我们还将探讨新的治疗策略和可能的治疗靶点，以期为患有IDC-P的患者提供更好的治疗选择。这项综述旨在为医生和研究人员提供全面了解IDC-P的临床和分子特征的综合资源，以便更好地理解和管理这一具有挑战性的前列腺癌亚型。
1. IDC-P的临床特征
1.1. IDC-P的检出率
IDC-P的检出率在不同的前列腺癌疾病阶段会有所差异[3]。与转移性和去势抵抗性前列腺癌相比，局限性前列腺癌患者中IDC-P的患病率相对较低[4]，约为2.1%左右。然而，随着疾病的进展，IDC-P的检出率开始逐渐增加。在中风险和高风险疾病分类中，检出率分别达到23.1%和36.7%。而在晚期阶段，IDC-P的检出率显著增加至56.0%[3]。前列腺癌的系统治疗本身似乎也与IDC-P的检出率有关，一项研究显示接受过治疗的人群中IDC-P的检出率也明显增加[3]。由于不同医疗中心在临床实践中对IDC-P的诊断标准和定义存在差异[5-7]，IDC-P的发病率呈现出明显的差异[4,8-10]。局限性前列腺癌的复发风险不同也是影响IDC-P检出率差异的另一个因素。例如，有报道称局限性前列腺癌（前瞻性收集的前列腺活检样本）中IDC-P的发病率仅为2.8%[10]，而在本团队的前期研究中，高复发风险患者中IDC-P的检出率增加至8.6%[11]。此外，IDC-P的确诊依赖于所用组织的质量，且需要结合组织形态学、免疫组化染色结果来综合判定，由于部分地区并为将其纳入常规诊疗流程，研究团队认为目前所报道的IDC-P检出率事实上偏低。
1.2. IDC-P的病理报道争议
两个前列腺癌病理领域著名机构，即国际泌尿病理学会（ISUP）和泌尿生殖道病理学会（GUPS），近年分别对前列腺癌分级进行了更新。然而，它们对于报告IDC-P存在冲突的建议。虽然两者都建议不对孤立的IDC-P进行分级，但是ISUP建议将IDCP组分纳入Gleason分级中，而GUPS则建议将IDCP作为注释单独报告，而不进行Gleason评分。因此，争论的焦点是IDC-P是否应该纳入Gleason分级。
具体而言，GUPS和ISUP就孤立IDC-P的报告达成一致意见，两者都建议不对这种情况下的IDC-P进行分级，而应进行免疫组化检测以确认是否存在伴随的腺癌。事实上，关于与侵袭性腺癌伴随存在的IDC-P的临床意义，ISUP和GUPS之间并没有根本性分歧。双方都认为IDC-P组分的存在是不利的预后因素，但主要的分歧在于如何向治疗临床医生传达这一信息。GUPS的立场是，将IDCP纳入Gleason分级中会增加过度分级的风险。因此，GUPS建议在病理报告中清楚记录IDCP的存在。与之对应的ISUP的立场是，将IDCP排除在Gleason分级之外会增加低估肿瘤分级的风险。双方的观点均有一定的理论依据，然而目前的现状可能会让临床医生感到困惑，因此在这个问题上需要达成国际共识[12]。
1.3. IDC-P的预后及预测价值
在局限性前列腺癌中，前列腺穿刺活检及切除样本中检测到IDC-P与不良的临床病理特征密切相关，如更高的Gleason评分、更高的病理分级、前列腺外侵犯、精囊浸润、高T分期和区域淋巴结侵及等[2,10,13-19]。其次，无论其接受术后辅助治疗与否，IDC-P的检出率直接与根治性手术或放疗后的早期生化复发有关，同时与早期转移、发展为去势抵抗性前列腺癌（CRPC）密切相关[4,5,9,11,13,15,16,20-23]。许多研究证实了IDC-P与生存期缩短的紧密联系[4,11,24-27]。因此，目前普遍认为在局限性疾病中只要有IDC-P的存在，均不推荐患者进行主动监测[28]，而是应该尽早采取根治性治疗并积极结合术后辅助治疗[1,2,26,29]。在晚期前列腺癌中，无论是激素敏感性还是去势抵抗阶段前列腺癌，IDC-P同样具有显著的不良预后提示作用[19,30,31]。且在转移性前列腺癌患者中，除了IDC-P本身的存在与否，IDC-P的比例和组织结构模式也是预后不良的指标。具体而言，IDC-P比例大于或等于10%以及致密筛状和实体状形态模式的肿瘤具有更差的预后[32]。总的来说，这些证据表明IDC-P的预后价值似乎独立于疾病阶段。
除预后价值之外，IDC-P的存在也对治疗方案选择具有一定的提示作用。本团队的前期研究提示，初诊转移性前列腺肿瘤中的IDC-P成分似乎并不随激素治疗的进行而减少，反而观察到部分IDC-P成分在治疗过程中出现面积扩大或免疫组化标记表达增强的情况[19]。此外，阿比特龙在含有IDC-P的转移性去势抵抗性前列腺癌（mCRPC）患者中显示出比多西他赛更好的治疗效果[31]。同样对于mCRPC患者，不同IDC-P亚型对阿比特龙和多西他赛治疗的反应存在差异，IDC-P比例大于或等于10%以及致密筛状和实体状形态模式的肿瘤对阿比特龙和多西他赛治疗的反应均不理想，需要进一步探索新的治疗策略[33]。
2. IDC-P的分子特征
2.1. 癌基因与抑癌基因
在IDC-P中普遍存在等位基因丢失，这很可能归因于其广泛的基因组不稳定性[34,35]。这种现象导致了重要的抑癌基因（包括TP53、RB1和PTEN）的丢失，同时也导致了MYC等癌基因的过度表达[35-42]。
TP53和RB1在控制细胞周期进程中起着关键作用，其中TP53是DNA损伤应答途径的中心枢纽[43]。RB1主要调节细胞周期的G1到S转变[44]，通过结合并抑制E2F转录因子家族的活性来实现。因此，不出所料，IDC-P表现出与E2F靶点相关的富集途径[41]。此外，TP53、RB1和MYC与神经内分泌前列腺癌（NEPC）的发展也有关联，后者是一种具有不良预后和对标准治疗抵抗性的亚型[45,46]。TP53和RB1已被证实在调节前列腺上皮细胞分化方面发挥作用，它们的丧失可能通过激活神经嵴干细胞程序而导致NEPC的发展[46,47]。MYC是一种转录因子，参与细胞生长、增殖、基因组不稳定性和分化的调节，其过度表达已被证明在小鼠模型中促进NEPC的发展[39,48,49]。与被认为是前列腺癌前病变的高级前列腺上皮内瘤变（HGPIN）[50]相比，IDC-P中观察到涉及TP53和RB1基因的等位基因丧失（LOH）更为常见[35]。此外，尽管TP53和RB1的丧失在原发性前列腺癌中不常见，但在mCRPC中更为普遍（分别为53.3%和21%）[51]。Mateo等人的研究[52]对61名前列腺癌患者进行了治疗前和去势抵抗性样本的临床可操作基因变异评估。分析显示，同一患者的两次活检存在显著差异，mCRPC中观察到了增加的TP53、RB1和PI3K/AKT通路变异。此外，RB1的丧失与原发性前列腺癌的预后较差有关，另一项研究报告了其与向去势抵抗状态转变和更差临床结果的相关性[53]。有趣的是，我们的分析还表明，TP53突变与较短的去势抵抗无进展生存期相关（中位数分别为10.9个月和28.9个月，P = 0.026）[54]。TP53和RB1基因组异常与抗雄激素治疗抵抗性有关[55]，并且几乎所有NEPC肿瘤中常见检测到这些基因的变异[56]。因此，与NEPC的演化类似，TP53和RB1具有在IDC-P中产生治疗抵抗性和促进疾病进展的潜力，这是由于治疗选择压力所致。
PTEN失活代表着前列腺癌中的另一个普遍事件，在具有IDC-P特征的肿瘤中发生率甚至更高[35,36,38,42,57]。PTEN作为脂质和蛋白磷酸酶的多功能角色对细胞过程产生广泛影响，包括细胞极性、运动性、衰老、肿瘤微环境和免疫应答[58]。此外，除了PTEN外，缺乏侵袭性癌变的独立IDC-P病例中显示了其他MAPK/PI3K基因的驱动突变富集，而这在传统前列腺癌中很少见[59]。这表明在IDC-P中存在一个失调的激酶和磷酸酶网络，为治疗干预提供了众多潜在的靶点。值得注意的是，在局限性前列腺癌中PTEN基因组缺失与较高的Gleason评分和前列腺外扩的可能性增加等不良临床病理特征相关[60]。多项广泛的研究一致表明，PTEN丧失与前列腺切除术后生化复发的风险增加之间存在明确的关联[61-63]。此外，PTEN已成为转移、CRPC发展和前列腺癌特异性死亡的独立预测因子[64-66]。在一项使用免疫组织化学检测PTEN丧失的研究中，明确发现PTEN丧失与IDC-P之间存在显著相关性。具体而言，相比PTEN完整样本的仅12%，总体上69%的IDC-P样本显示了PTEN丧失[38]。此外，IDC-P显示出PTEN丧失的最高相对风险（4.99）。
因此，这些与癌症相关的关键基因在IDC-P中的频繁功能失调可能引起细胞周期进程的紊乱、基因组不稳定性以及其他尚未被发现的功能异常，从而推动肿瘤的侵袭性生长。这些基因的异常活动可能导致细胞无法准确调控其生命周期，进而促使肿瘤细胞的异常增殖和分化。此外，由于这些基因在调控细胞内多个关键途径和信号转导网络中发挥重要作用，它们的失调可能对细胞的正常功能产生广泛的影响。这些功能异常可能包括细胞的运动性、增殖能力、基因表达调控以及与肿瘤侵袭和转移相关的分子过程。因此，这些基因的频繁功能失调可能是IDC-P肿瘤侵袭性增强的重要驱动因素之一。进一步研究这些基因的具体功能异常及其对肿瘤生物学行为的影响，有助于我们深入了解IDC-P的发展机制，并为开发针对这些异常的精确治疗策略提供基础。
2.2. DNA损伤修复通路
在IDC-P中，基因组不稳定性不仅源于细胞周期检查点的失调，还源于DNA损伤和修复机制（DDR）的破坏。大量证据将IDC-P与DNA损伤和修复途径的紊乱联系起来。
IDC-P与胚系BRCA2变异之间的关联最初是通过PDX模型发现的[67]，随后对复发性或转移性前列腺癌患者进行的胚系遗传测试进一步揭示了IDC-P中DNA修复基因（BRCA2、BRCA1、MSH6、PALB2、NBN）和DNA损伤感应基因（ATM、CHEK2、CDH1）的失调[37,68]。此外，尽管在前列腺癌中这类异常很少见，但IDC-P肿瘤表现出更高的错配修复基因（MMR）异常发生率（MSH2、MSH6、MLH1和PMS2）[69]。携带胚系BRCA2突变的前列腺癌患者，不论是否接受手术或放疗作为根治治疗，其临床预后均较差[3,67]。Risbridger等人[67]发现，与散发性前列腺癌相比，BRCA2肿瘤的PDXs在IDC-P中的发生率显著增加。携带IDC-P的BRCA2携带者与不携带IDC-P的BRCA2携带者相比，整体存活率和前列腺癌特异性存活率均显著较差。我们之前的研究[54]的数据还显示，在具有IDC-P的患者中，胚系BRCA2突变的患病率明显高于前列腺腺癌患者（分别为8.7%和0%）。此外，在接受一线阿比特龙治疗的具有IDC-P成分的mCRPC患者中，BRCA2突变与较短的前列腺特异性抗原无进展生存期（PSA-PFS）相关（中位数分别为9.1个月和11.9个月，P = 0.036）。
我们的研究结果表明，IDC-P与DDR突变的关联也适用于中国患者队列，并且中国IDC-P患者中似乎更常见CDK12突变[54]。尽管CDK12在传统上不被视为典型的DDR基因，但已知其影响同源重组修复基因的表达[70-72]。因此，许多研究在DDR基因测试中没有将其纳入检测列表。然而，携带CDK12突变的患者往往具有明显更差的生存预后，并对标准治疗显示出较差的反应[73]。鉴于其在调节DDR基因表达和随之增加的新抗原负荷方面的生物学作用，携带CDK12突变的患者理论上可能从PARP抑制剂和免疫治疗中受益[74,75]。然而，目前有关此方面的证据仍不确定[76-78]。因此，探究IDC-P与CDK12功能失调之间是否存在关联具有一定的研究意义。
2.3. 特殊AR通路突变模式
报道称，带有IDC-P组分的患者对ADT治疗不敏感[19,22,79]。这一现象的潜在原因仍然不太清楚。在我们之前的研究中，我们观察到雄激素受体（AR）的突变率在具有和不具有IDC-P的肿瘤之间没有显著差异[54]。然而，一个值得注意的发现是在具有IDC-P的肿瘤中富集了核受体共抑制因子2（NCOR2）组蛋白去乙酰化酶[54]。虽然NCOR2最初被认为是AR的负调节因子[80]，但新出现的证据表明它与AR信号通路之间存在更为复杂的相互作用，影响经典雄激素调控和增强子区域的表观遗传控制，这可能有助于系谱可塑性的改变[81]。NCOR2表达的降低与前列腺癌的疾病侵袭性相关，并且在细胞系模型中敲除NCOR2会导致NEPC基因特征[81]。这些发现加强了IDC-P和NEPC之间的潜在关联。
除了在AR信号通路中的作用外，NCOR2还涉及到细胞毒性应激响应和抗肿瘤免疫，这两个方面与乳腺癌的治疗抵抗性和患者预后相关[82]。失去NCOR2转录抑制功能会导致DUB3的过度表达，从而对溴域和额外末端（BET）抑制剂产生抵抗性[83]。BET抑制剂由于对MYC表达和雄激素受体（AR）产生潜在影响，正在成为晚期前列腺癌的潜在治疗方法[84]。
值得注意的是，AR信号通路和DNA损伤应答（DDR）途径之间存在着正反馈环，可以影响肿瘤的进展和治疗反应。因此，虽然我们观察到IDC-P肿瘤中存在这些异常，但要解开IDC-P的疾病侵袭性的驱动因素或找到打破这一恶性循环的关键仍然是一个重大挑战。这种复杂性与“nimbosus”的概念相吻合，这表明虽然我们认识到IDC-P中存在这些异常，但理解它们的精确作用和相互作用仍然存在困难[85]。
2.4. 转录因子MED12
RNA聚合酶II（RNA Pol II）负责转录人类基因组的大部分区域，这一过程由一个复杂的多蛋白组装体——调节因子复合物的紧密调控[86]。在这个复合物中，MED12（调节因子复合物亚单位12）是激酶模块的一部分，在多个生物学过程中扮演着关键角色。破坏MED12功能与恶性肿瘤的发生有关[87]。
值得注意的是，MED12突变在依赖激素的癌症，如乳腺癌、前列腺癌和卵巢癌中频繁发现[88]，在前列腺癌中的错义突变率为5.4%[89,90]。一项针对BRCA2突变型前列腺癌的研究中观察到，具有IDC-P的肿瘤表现出对MED12基因组和表观基因组的异常调控更为普遍[40]。
从生物学角度来看，MED12在Wnt通路中起着重要的调控作用，包括经典Wnt信号通路和Wnt/PCP信号通路[91]。有趣的是，Wnt通路的失调与NEPC的发展密切相关[92,93]。此外，一项研究表明，IDC-P病变中APC基因的甲基化水平增加，进一步促进了Wnt通路的激活[94]。虽然一些研究已经指出，IDC-P在某种程度上具有NEPC样的形态学和免疫组化标记[95,96]，但尚未确立IDC-P与NEPC之间的明确关联。
此外，已发现MED12与TP53、TGFβ信号通路以及AR/雌激素受体α（ERα）信号通路的转录程序相互作用，表明基因组完整性、细胞周期调控和上皮-间质转化（EMT）在激素驱动的癌症（在这种情况下特指前列腺癌）中存在潜在的相互作用[86,89]。这一观察结果也与“nimbosus”的概念相吻合[85]，该概念强调了具有IDC-P的肿瘤中各种不良临床、病理和分子因素的汇聚。
有趣的是，MED12突变的患病率在不同的前列腺癌研究群体中存在显著差异[97-99]。除了患者种族和样本类型的差异外，我们推测作为一种特定的病理亚型，IDC-P的存在也可能对这种变异性有所贡献。不过现有研究尚未提供有关这一方面的数据，因此需要进一步的研究来解决这个问题。此外，关于MED12突变在前列腺癌中的功能后果存在相互矛盾的观点[97-99]。一项研究表明，与MED12突变相关的致瘤机制可能是癌症种类特异性的[97]。因此，揭示该网络在前列腺癌中的精确作用机制可能是开发针对这些肿瘤有效治疗方法的关键。
2.5. TMPRSS2-ERG fusion
TMPRSS2-ERG是一种常见于前列腺癌中的基因融合事件，其中雄激素调控基因TMPRSS2的调控区域与癌基因ERG的编码区域融合在一起。这一融合事件导致ERG转录因子的过度表达[100]，被认为与前列腺癌的发展和进展有关，并经常被用作该疾病的生物标志物。
据报道，与前列腺上皮内瘤变（PIN）相比，IDC-P显示出更高的TMPRSS2-ERG融合发生率[101,102]，但在IDC-P和同时存在的浸润性癌之间，融合发生率似乎相似[103-105]，因此一些研究根据这种相似的TMPRSS2-ERG发生率推断了IDC-P和前列腺之间的克隆关系。然而，TMPRSS2-ERG融合是前列腺癌中常见的事件，可在多达50%的病例中发现[100,106-108]。因此，IDC-P和前列腺腺癌中都存在TMPRSS2-ERG可能只是巧合，而不是克隆关系存在的有力证据。要建立明确的克隆关系，需要进行额外的分子和遗传分析。这些分析应包括全基因组测序、拷贝数变异分析以及评估IDC-P和前列腺腺癌中可能存在的其他遗传和表观遗传改变。目前尚不确定TMPRSS2-ERG融合与更具侵袭性的肿瘤特征之间的关系。一些研究表明TMPRSS2-ERG的状态与Gleason分级、生化复发和生存等因素之间存在显著关联[106,109,110]。然而，其他研究发现基因融合的存在与这些因素之间没有显著差异[107,111,112]。有趣的是，PTEN和TP53突变状态与通过TMPRSS2-ERG融合过度表达的ERG的组合在生化复发和生存方面显示出预测价值[113]。
2.6. 非编码RNA SChLAP1
第二染色体与前列腺关联-1（SChLAP1）是一种长链非编码RNA，在先前的研究中被确认为不利的肿瘤学预后的独立预测因子，并作为一种潜在的疾病检测工具[114,115]。据报道，SChLAP1通过调控SWI/SNF复合物在转录后水平上调控基因表达，干扰了该复合物的肿瘤抑制功能[116]。
IDC-P中的一项奠基性研究发现，肿瘤中存在许多不良的分子事件，包括基因组不稳定性、SChLAP1的失调和缺氧，这些事件共同导致了多参数磁共振成像的可见性和更差的预后[117,118]。在超过25,000个基因中，SChLAP1是在IDC-P中表达水平增加了三倍的唯一基因[117]。然而，正如作者们所指出，SChLAP1失调（以及基因组不稳定性）的存在不一定是IDC-P发展的驱动因素[117]。因此，解决这些分子事件的时间顺序仍然至关重要。
3. 结论与展望
含有IDC-P的肿瘤已表现出多种失调的信号通路和基因表达，表现出侵袭性的生物学行为，成为不良预后和治疗反应差的独立风险因素。此外，普通前列腺腺癌通常需要经过长期雄激素抑制治疗才会有极小概率出现神经内分泌分化，而IDC-P则在无或相对短期的雄激素抑制治疗后，分子特征上已经显示出与神经内分泌前列腺癌具有一定相似性。这些发现凸显了IDC-P作为一种独特前列腺癌病理亚型的重要性。
为了揭示IDC-P的分子特征，学术界已经进行了广泛的研究。然而，对于IDC-P的分子机制目前仍知之甚少。未来的研究方向应包括利用显微切割技术分离IDC-P组分，以减少来自同时存在的前列腺腺癌的混淆因素，并提供更准确的IDC-P分子特征洞察。通过这样的方法，我们可以更好地理解IDC-P的病理生理机制、分子变化及其与预后的关联。
此外，随着技术的不断进步，将进一步探索IDC-P与 DNA损伤修复、激酶与磷酸酶网络、肿瘤微环境和治疗反应之间的关系也是未来研究的重要方向。了解这些方面将有助于制定更加个体化的治疗策略，提高IDC-P患者的预后和生存质量。
综上所述，IDC-P作为一种特殊的前列腺癌亚型，具有独特的临床病理特征和预后意义。尽管已进行广泛的研究以揭示其分子特征，但我们仍需要深入了解其分子机制。通过利用显微切割技术分离IDC-P组分以及探索其与免疫应答和肿瘤微环境的关系，我们有望获得更全面、准确的IDC-P分子特征洞察。这些研究将为发展个体化治疗策略和改善IDC-P患者的预后提供重要的指导。
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