Very well-differentiated adenocarcinoma of intestinal type is a distinct subtype of gastric cancer characterized by anastomosing glands with a hand-in-hand pattern and low-grade cytologic atypia resembling intestinal metaplasia. This is a slow-growing neoplasm with an indolent clinical course; however, a subset demonstrates transformation into adenocarcinoma with higher-grade histology, typically diffuse-type carcinoma, and behaves aggressively. This study aimed to better characterize the genomic and pathologic features, with a focus on factors associated with diffuse-type transformation. A total of 58 cases with (n=31) and without (n=27) diffuse-type transformation were analyzed for molecular and pathologic features. First, comprehensive deep DNA sequencing was conducted in 18 cases (discovery cohort), followed by a digital droplet polymerase chain reaction of hot spot RHOA mutations in 40 cases (validation cohort). In total, RHOA mutations were the most common alteration (34%), followed by loss of ARID1A (12%), p53 alterations (10%), and CLDN18::ARHGAP26/6 fusions (3.4%). FGFR2 amplification was identified in an advanced case with a p53 alteration. Altered p53 expression was recognized only in higher-grade components and was significantly associated with advanced disease (P=0.0015) and diffuse-type transformation (P=0.026). A mixed mucin phenotype was also strongly correlated with advanced disease (P<0.001) and diffuse-type transformation (P<0.001). Decreased E-cadherin expression was frequently observed (74%) in poorly cohesive components. This study demonstrated that a subset of RHOA-mutant diffuse-type gastric cancers develops through the transformation of very well-differentiated adenocarcinoma of intestinal type. Our observations suggest a mixed mucin phenotype as a risk factor and alterations in p53 and E-cadherin as drivers of diffuse-type transformation.

中文翻译：

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肠型高分化胃腺癌的基因组和病理学分析：重点关注弥漫型转化的研究。


肠型高分化腺癌是胃癌的一种独特亚型，其特征是吻合腺具有手拉手模式和类似于肠上皮化生的低度细胞学异型性。这是一种生长缓慢的肿瘤，具有惰性的临床病程；然而，一部分表现出转化为具有较高组织学级别的腺癌，通常为弥漫型癌，并且表现出侵袭性。本研究旨在更好地表征基因组和病理特征，重点关注与弥漫型转化相关的因素。对总共 58 例有（n = 31）和无（n = 27）弥漫型转化的病例进行了分子和病理特征分析。首先，对 18 例（发现队列）进行了全面的深度 DNA 测序，随后对 40 例（验证队列）进行了热点 RHOA 突变的数字液滴聚合酶链反应。总的来说，RHOA 突变是最常见的改变 (34%)，其次是 ARID1A 缺失 (12%)、p53 改变 (10%) 和 CLDN18::ARHGAP26/6 融合 (3.4%)。在一个具有 p53 改变的晚期病例中发现了 FGFR2 扩增。 p53 表达的改变仅在较高级别的成分中被识别，并且与晚期疾病 (P=0.0015) 和弥漫型转化 (P=0.026) 显着相关。混合粘蛋白表型也与晚期疾病（P<0.001）和弥漫型转化（P<0.001）密切相关。在粘性差的成分中经常观察到 E-钙粘蛋白表达降低 (74%)。这项研究表明，RHOA 突变的弥漫型胃癌的一个亚型是通过肠型高分化腺癌的转化而发展起来的。 我们的观察结果表明，混合粘蛋白表型是一个危险因素，p53 和 E-钙粘蛋白的改变是弥漫型转化的驱动因素。