胃癌中 ATM 和 ARID1A 的关系

IF 2.9 4区医学 Q2 PATHOLOGY

Pathology, research and practice Pub Date : 2024-10-19 DOI:10.1016/j.prp.2024.155664

Inwoo Hwang , Somin Lee , Yuyeon Kim , Deok Geun Kim , So Young Kang , Soomin Ahn , Jeeyun Lee , Kyoung-Mee Kim

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引用次数: 0

摘要

背景共济失调毛细血管扩张症突变（ATM）基因参与双链DNA断裂的修复，是DNA损伤修复途径的一个组成部分。ARID1A和ATM基因突变或低表达的肿瘤显示肿瘤浸润淋巴细胞数量增加，预后良好。然而，ATM和ARID1A在胃癌（GC）中的关系尚不清楚。方法我们利用亚洲癌症研究小组的mRNA表达数据构建了组织芯片（N = 249）。三星医学中心（SMC）的下一代测序（NGS）数据库（N = 813）用于比较基因改变。组织芯片用于 ATM 和 ARID1A 免疫组化，表达分为 "低 "和 "高"。结果在GCs中，32.1%（80/249）的病例显示ATM蛋白低表达（ATMlow），20.9%（52/249）的病例显示ARID1A低表达（ARID1Alow）。ATMlow与年龄（P <.01）、肿瘤大体类型（P =.02）、组织学（P <.01）、较低的神经周围浸润发生率（P =.04）、较低的疾病分期（P <.01）、微卫星不稳定性高（P <.01）和 ARID1Alow（P <.01）明显相关。此外，SMC NGS 数据库中的 GCs 显示，ATM 突变与 ARID1A 突变显著相关（P <.01），这一发现在 TCGA-STAD 验证队列中仍然显著（P <.01）。ATM突变也与ARID1A突变相关，这突显了ATM和ARID1A在GC中的相互作用，并提示了潜在的治疗靶点。

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Association of ATM and ARID1A in gastric carcinoma

Background

The ataxia telangiectasia mutated (ATM) gene is involved in the repair of double-stranded DNA breaks and a component of the DNA damage repair pathway. Tumors with mutations or low expression of both ARID1A and ATM exhibit increased numbers of tumor-infiltrating lymphocytes and a favorable prognosis. However, the relationship between ATM and ARID1A in gastric carcinoma (GC) is unclear.

Methods

We used the mRNA expression data from the Asian Cancer Research Group to construct tissue microarrays (N = 249). Next-generation sequencing (NGS) databases of Samsung Medical Center (SMC) (N = 813) were used to compare genetic alterations. Tissue microarrays were used for ATM and ARID1A immunohistochemistry, and expressions were categorized as “low” and “high.” NGS data from TCGA-STAD (N = 431) were used as independent cohorts for genetic alterations validation.

Results

In GCs, 32.1 % (80/249) of the cases showed low ATM protein expression (ATM^low) and 20.9 % (52/249) showed low ARID1A expression (ARID1A^low). ATM^low was significantly associated with older age (P <.01), gross type of tumor (P =.02), histology (P <. 01), lower incidence of perineural invasion (P =.04), lower disease stage (P <.01), microsatellite instability-high (P <.01), and ARID1A^low (P <.01). Furthermore, GCs in the SMC NGS database showed that ATM mutations were significantly correlated with ARID1A mutations (P <.01), and this finding remained significant in TCGA-STAD validation cohort (P <.01).

Conclusion

ATM^low in GCs shows a characteristic clinicopathological feature that correlates strongly with ARID1A^low. ATM mutation was also associated with ARID1A mutations, highlighting the interactions between ATM and ARID1A in GC and suggesting a potential therapeutic target.

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来源期刊

Pathology, research and practice 医学-病理学

CiteScore

5.00

自引率

3.60%

发文量

405

审稿时长

24 days

期刊介绍： Pathology, Research and Practice provides accessible coverage of the most recent developments across the entire field of pathology: Reviews focus on recent progress in pathology, while Comments look at interesting current problems and at hypotheses for future developments in pathology. Original Papers present novel findings on all aspects of general, anatomic and molecular pathology. Rapid Communications inform readers on preliminary findings that may be relevant for further studies and need to be communicated quickly. Teaching Cases look at new aspects or special diagnostic problems of diseases and at case reports relevant for the pathologist''s practice.