Institute of Pathology, University of Würzburg, Würzburg, Germany.
Comprehensive Cancer Center Mainfranken, University of Würzburg Medical Centre, Würzburg, Germany.
Genes Chromosomes Cancer. 2024 Oct;63(10):e23270. doi: 10.1002/gcc.23270.
Low-grade appendiceal mucinous neoplasia (LAMN) represents a relatively rare tumor of the appendix typically diagnosed incidentally through appendectomy for acute appendicitis. In cases where perforation occurs, mucinous content may disseminate into the abdominal cavity, leading to the development of pseudomyxoma peritonei (PMP). The primary objective of this study was to elucidate the molecular characteristics associated with various stages of LAMN and PMP. DNA was extracted from LAMN, primary PMPs, recurrent PMPs, and adenocarcinomas originating from LAMN. The subsequent analysis involved the examination of mutational hotspot regions within 50 cancer-related genes, covering over 2800 COSMIC mutations, utilizing amplicon-based next-generation sequencing (NGS). Our findings revealed activating somatic mutations within the MAPK-signaling pathway across all tumors examined. Specifically, 98.1% of cases showed mutations in KRAS, while one tumor harbored a BRAF mutation. Additionally, GNAS mutations were identified in 55.8% of tumors, with no significant difference observed between LAMN and PMP. While LAMN rarely displayed additional mutations, 42% of primary PMPs and 60% of recurrent PMPs showed additional mutations. Notably, both adenocarcinomas originating from LAMN showed mutations within TP53. Furthermore, 7.7% (4/52) of cases exhibited a potentially targetable KRAS G12C mutation. In four patients, NGS analysis was performed on both primary PMP and recurrent PMP/adenocarcinoma samples. While mutations in KRAS and GNAS were detected in almost all samples, 50% of recurrent cases displayed an additional SMAD4 mutation, suggesting a notable alteration during disease progression. Our findings indicate two key points: First, mutations within the MAPK pathway, particularly in KRAS, are evident across all tumors, along with a high frequency of GNAS mutations. Second, progression toward PMP or adenocarcinoma is associated with an accumulation of additional mutations within common oncogenic pathways.
低级别阑尾黏液性肿瘤 (LAMN) 是一种相对罕见的阑尾肿瘤，通常在因急性阑尾炎行阑尾切除术时偶然诊断。如果发生穿孔，黏液内容物可能会扩散到腹腔，导致假性黏液瘤腹膜（PMP）的发生。本研究的主要目的是阐明与 LAMN 和 PMP 各阶段相关的分子特征。从 LAMN、原发性 PMP、复发性 PMP 和源自 LAMN 的腺癌中提取 DNA。随后，使用基于扩增子的下一代测序（NGS）对 50 个癌症相关基因中的突变热点区域进行了检查，这些基因涵盖了超过 2800 个 COSMIC 突变。我们的研究结果显示，在所有检查的肿瘤中，MAPK 信号通路中存在激活的体细胞突变。具体来说，98.1%的病例显示 KRAS 突变，而一个肿瘤存在 BRAF 突变。此外，55.8%的肿瘤中存在 GNAS 突变，LAMN 和 PMP 之间无显著差异。虽然 LAMN 很少显示其他突变，但 42%的原发性 PMP 和 60%的复发性 PMP 显示了其他突变。值得注意的是，源自 LAMN 的两种腺癌均显示 TP53 内的突变。此外，7.7%（4/52）的病例存在潜在可靶向的 KRAS G12C 突变。在四名患者中，对原发性 PMP 和复发性 PMP/腺癌样本进行了 NGS 分析。虽然几乎所有样本中均检测到 KRAS 和 GNAS 突变，但 50%的复发性病例显示出额外的 SMAD4 突变，表明在疾病进展过程中发生了显著改变。我们的研究结果表明两点：第一，MAPK 通路中的突变，特别是 KRAS 突变，在所有肿瘤中均可见，同时 GNAS 突变的频率也很高。第二，向 PMP 或腺癌进展与常见致癌通路中额外突变的积累有关。
