Sánchez-Ramón Silvia, Fuentes-Antrás Jesús, Rider Nicholas L, Pérez-Segura Pedro, de la Fuente-Muñoz Eduardo, Fernández-Arquero Miguel, Neves Esmeralda, Pérez de Diego Rebeca, Ocaña Alberto, Guevara-Hoyer Kissy
Cancer Immunomonitoring and Immune-Mediated Diseases Research Unit, San Carlos Health Research Institute (IdSSC), Department of Clinical Immunology, San Carlos University Hospital, Madrid, Spain.
Department of Clinical Immunology, Instituto de médicina de laboratorio (IML) and IdSSC, San Carlos University Hospital, Madrid, Spain.
J Allergy Clin Immunol Glob. 2023 Dec 23;3(2):100203. doi: 10.1016/j.jacig.2023.100203. eCollection 2024 May.
Gastric cancer (GC) stands as a prominent cause of cancer-related mortality and ranks second among the most frequently diagnosed malignancies in individuals with common variable immunodeficiency (CVID).
We sought to conduct a comprehensive, large-scale genetic analysis to explore the CVID-associated germline variant landscape within gastric adenocarcinoma samples and to seek to delineate the transcriptomic similarities between GC and CVID.
We investigated the presence of CVID-associated germline variants in 1591 GC samples and assessed their impact on tumor mutational load. The progression of GC was evaluated in patients with and without these variants. Transcriptomic similarities were explored by matching differentially expressed genes in GC to healthy gastric tissue with a CVID transcriptomic signature.
CVID-associated germline variants were found in 60% of GC samples. Our analysis revealed a significant association between the presence of CVID-related genetic variants and higher tumor mutational load in GC ( < .0001); high GC mutational load seems to be linked to immunotherapy response and worse prognosis. Transcriptomic similarities unveiled key genes and pathways implicated in innate immune responses and tumorigenesis. We identified upregulated genes related to oncogene drivers, inflammation, tumor suppression, DNA repair, and downregulated immunomodulatory genes shared between GC and CVID.
Our findings contribute to a deeper understanding of potential molecular modulators of GC and shed light on the intricate interplay between immunodeficiency and cancer. This study underscores the clinical relevance of CVID-related variants in influencing GC progression and opens avenues for further exploration into novel therapeutic approaches.
胃癌（GC）是癌症相关死亡的一个主要原因，在常见可变免疫缺陷（CVID）个体中最常诊断的恶性肿瘤中排名第二。
我们试图进行一项全面、大规模的基因分析，以探索胃腺癌样本中与CVID相关的种系变异情况，并试图描绘GC和CVID之间的转录组相似性。
我们调查了1591份GC样本中与CVID相关的种系变异的存在情况，并评估了它们对肿瘤突变负荷的影响。对有和没有这些变异的患者的GC进展情况进行了评估。通过将GC中差异表达的基因与具有CVID转录组特征的健康胃组织进行匹配，探索转录组相似性。
在60%的GC样本中发现了与CVID相关的种系变异。我们的分析揭示了GC中与CVID相关的基因变异的存在与更高的肿瘤突变负荷之间存在显著关联（<0.0001）；高GC突变负荷似乎与免疫治疗反应和更差的预后有关。转录组相似性揭示了与先天免疫反应和肿瘤发生相关的关键基因和途径。我们确定了GC和CVID之间共同上调的与癌基因驱动、炎症、肿瘤抑制、DNA修复相关的基因，以及下调的免疫调节基因。
我们的发现有助于更深入地了解GC的潜在分子调节因子，并揭示免疫缺陷与癌症之间的复杂相互作用。这项研究强调了与CVID相关的变异在影响GC进展方面的临床相关性，并为进一步探索新的治疗方法开辟了道路。
