Micro-environmental changes indicate potential for subclinical intestinal tissue damage in early-age-onset colorectal cancer patients.

IF 3.8 3区医学 Q2 GASTROENTEROLOGY & HEPATOLOGY

Gastroenterology Report Pub Date : 2025-02-20 eCollection Date: 2025-01-01 DOI:10.1093/gastro/goaf015

Sean G Kraus, Katherine A Johnson, Philip B Emmerich, Linda Clipson, Cheri A Pasch, Wei Zhang, Kristina A Matkowskyj, Dustin A Deming

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引用次数: 0

Abstract

Background: While improved screening rates have contributed to an overall decrease in the incidence of colorectal cancer (CRC), the incidence of early-age-onset CRC (EAO CRC; age <50 years) has increased. Here, we characterize the genetic alterations and tumor microenvironment (TME) for EAO and later-age-onset (LAO) CRCs to identify relevant biological differences that might point to etiologic factors.

Methods: A cohort of EAO (n = 60) and LAO (n = 93) CRC patients were evaluated for mutations by using targeted DNA sequencing and for TME differences by using immunohistochemistry and immunofluorescence. The Cancer Genome Atlas (TCGA) PanCancer Atlas colorectal adenocarcinoma cohort was evaluated for transcriptional changes between EAO (n = 82) and LAO (n = 510) patients.

Results: KRAS and BRAF mutations were less frequent in EAO CRCs. Gene-set enrichment analysis of TCGA data revealed the downregulation of immune-related pathways in EAO CRCs. Both age cohorts had similar numbers of CD8⁺ tumor-infiltrating lymphocytes (TILs), although LAO patients had more CD4⁺ TILs and Th1-polarized CD4s. While significant associations between immune subsets and versican (VCAN), versikine, and alpha-smooth muscle actin (αSMA) were found, none of these trends differed between age cohorts. EAO patients trended towards greater VCAN accumulation in adjacent normal tissue, lower rates of VCAN proteolysis, and decreased αSMA accumulation vs LAO patients.

Conclusions: Overall, established EAO cancers are similar to LAO cancers in mutational profile and key TME features. High VCAN and αSMA expression in adjacent normal colon indicates a presence of factors that are associated with increased intestinal subclinical inflammation. Future mechanistic studies will be conducted to better understand the importance of these findings and related processes should be prioritized as potential etiologic factors for EAO tumorigenesis.

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微环境变化提示早发性结直肠癌患者亚临床肠组织损伤的可能性。

背景：虽然提高筛查率有助于总体降低结直肠癌（CRC）的发病率，但早发性CRC (EAO CRC；方法：通过靶向DNA测序评估EAO（60例）和LAO（93例）CRC患者的突变，通过免疫组织化学和免疫荧光评估TME差异。癌症基因组图谱（TCGA）胰腺癌图谱结直肠癌队列评估了EAO （n = 82）和LAO （n = 510）患者之间的转录变化。结果：KRAS和BRAF突变在EAO crc中较少发生。TCGA数据的基因集富集分析揭示了EAO crc中免疫相关通路的下调。两个年龄组的CD8+肿瘤浸润淋巴细胞（TILs）数量相似，尽管LAO患者有更多的CD4+ TILs和th1极化CD4s。虽然免疫亚群与versican （VCAN）、verskine和α -平滑肌肌动蛋白（αSMA）之间存在显著关联，但这些趋势在年龄队列之间没有差异。与LAO患者相比，EAO患者在邻近正常组织中有较大的VCAN蓄积，VCAN蛋白水解率较低，αSMA蓄积减少。结论：总体而言，已建立的EAO癌在突变谱和关键TME特征上与LAO癌相似。邻近正常结肠中VCAN和αSMA的高表达表明存在与肠道亚临床炎症增加相关的因素。未来将进行机制研究，以更好地了解这些发现的重要性，并优先考虑相关过程作为EAO肿瘤发生的潜在病因。

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

Gastroenterology Report Medicine-Gastroenterology

CiteScore

4.60

自引率

2.80%

发文量

审稿时长

8 weeks

期刊介绍： Gastroenterology Report is an international fully open access (OA) online only journal, covering all areas related to gastrointestinal sciences, including studies of the alimentary tract, liver, biliary, pancreas, enteral nutrition and related fields. The journal aims to publish high quality research articles on both basic and clinical gastroenterology, authoritative reviews that bring together new advances in the field, as well as commentaries and highlight pieces that provide expert analysis of topical issues.