The Clinicopathological and Molecular Characteristics of Endocervical Gastric-Type Adenocarcinoma and the Use of Claudin18.2 as a Potential Therapeutic Target

IF 7.1 1区 医学 Q1 PATHOLOGY
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Abstract

Endocervical gastric-type adenocarcinoma (GAS) is an aggressive type of endocervical mucinous adenocarcinoma characterized as being unrelated to human papillomavirus (HPV) and resistant to chemo/radiotherapy. In this study, we investigated the histology, immunohistochemistry patterns, and molecular characteristics in a large cohort of GAS (n = 62). Histologically, the majority of GAS cases exhibited a distinct morphology resembling gastric glands, although 2 exceptional cases exhibited HPV-associated adenocarcinoma morphology while retaining the characteristic histology of GAS at the invasive front. By immunohistochemistry, Claudin18.2 emerged as a highly sensitive and specific marker for GAS. Additionally, the strong expression of Claudin18.2 in patients with GAS indicated the potential of anti-Claudin18.2 therapy in the treatment of GAS. Other immunohistochemistry markers, including Muc6, p16, p53, Pax8, ER, and PR, may provide additional diagnostic clues for GAS. Quantitative methylation analysis revealed that the overexpression of Claudin18.2 in GAS was governed by the hypomethylation of the CLDN18.2 promoter CpG islands. To further elucidate the pathogenic mechanisms of GAS and its relationship with gastric adenocarcinoma, we performed whole exome sequencing on 11 GAS and 9 gastric adenocarcinomas. TP53, CDKN2A, STK11, and TTN emerged as the most frequently mutated genes in GAS. Mutations in these genes primarily affected cell growth, cell cycle regulation, senescence, and apoptosis. Intriguingly, these top mutated genes in GAS were also commonly mutated in gastric and pancreaticobiliary adenocarcinomas. Regarding germline variants, we identified a probably pathogenic variant in SPINK1, a gene linked to hereditary pancreatic cancer syndrome, in one GAS sample. This finding suggests a potential pathogenic link between pancreatic cancers and GAS. Overall, GAS exhibits molecular characteristics that resemble those observed in gastric and pancreaticobiliary adenocarcinomas, thereby lending support to the aggressive nature of GAS compared with HPV-associated adenocarcinoma.

宫颈内膜胃型腺癌的临床病理和分子特征以及将Claudin18.2作为潜在的治疗靶点。
宫颈内膜胃型腺癌(GAS)是一种侵袭性宫颈内膜粘液腺癌,其特点是与人类乳头状瘤病毒(HPV)无关,且对化疗/放疗具有抗药性。在这项研究中,我们调查了一大批 GAS(62 例)患者的组织学、免疫组化模式和分子特征。从组织学角度看,大多数 GAS 病例表现出类似胃腺体的独特形态,但也有两例特殊病例表现出 HPV 相关腺癌(HPVA)形态,同时在浸润前沿保留了 GAS 的特征性组织学。通过免疫组化,Claudin18.2 成为 GAS 的高灵敏度和特异性标记物。此外,Claudin18.2在GAS患者中的强表达表明,抗Claudin18.2疗法具有治疗GAS的潜力。其他免疫组化标记物,包括 Muc6、p16、p53、Pax8、ER 和 PR,可能会为 GAS 的诊断提供更多线索。定量甲基化分析表明,Claudin18.2在GAS中的过度表达是由CLDN18.2启动子CpG岛的低甲基化决定的。为了进一步阐明GAS的致病机制及其与胃腺癌的关系,我们对11例GAS和9例胃腺癌进行了全外显子组测序(WES)。TP53、CDKN2A、STK11和TTN是GAS中最常见的突变基因。这些基因的突变主要影响细胞生长、细胞周期调控、衰老和凋亡。耐人寻味的是,在胃癌和胰胆管腺癌中,这些在GAS中突变最多的基因也经常发生突变。在种系变异方面,我们在一个 GAS 样本中发现了 SPINK1(一种与遗传性胰腺癌综合征相关的基因)的可能致病变异。这一发现表明,胰腺癌与GAS之间存在潜在的致病联系。总体而言,GAS 的分子特征与胃癌和胰胆管腺癌中观察到的特征相似,因此与 HPVA 相比,GAS 的侵袭性更强。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Modern Pathology
Modern Pathology 医学-病理学
CiteScore
14.30
自引率
2.70%
发文量
174
审稿时长
18 days
期刊介绍: Modern Pathology, an international journal under the ownership of The United States & Canadian Academy of Pathology (USCAP), serves as an authoritative platform for publishing top-tier clinical and translational research studies in pathology. Original manuscripts are the primary focus of Modern Pathology, complemented by impactful editorials, reviews, and practice guidelines covering all facets of precision diagnostics in human pathology. The journal's scope includes advancements in molecular diagnostics and genomic classifications of diseases, breakthroughs in immune-oncology, computational science, applied bioinformatics, and digital pathology.
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