在原发性肿瘤形态学定义区域中寻找与转移性结直肠癌抗表皮生长因子受体治疗无反应相关的突变。

Search for Mutations Connected With Non-Response to Anti-EGFR Therapy in mCRC in the Morphologically Defined Regions of Primary Tumours.

作者信息

Čarnogurská Martina, Vasylieva Valeriia Serhiivna, Macháčková Táňa, Boudná Marie, Pifková Lucie, Orlíčková Jana, Ivkovic Tina Catela, Slabý Ondrej, Bencsiková Beatrix, Popovici Vlad, Budinská Eva

机构信息

RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic.

Central European Institute of Technology, Masaryk University, Brno, Czech Republic.

出版信息

Cancer Med. 2025 May;14(9):e70910. doi: 10.1002/cam4.70910.

DOI:10.1002/cam4.70910

PMID:40302146

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12040724/

Abstract

BACKGROUND

Emerging evidence suggests that tumour morphological heterogeneity may influence mutational profiles relevant to therapy response. In this pilot study, we aimed to assess whether mutations identified within specific morphological patterns or at the invasion front correlate with shorter time to progression after anti-EGFR therapy, as compared to whole-tissue analysis.

METHODS

We investigated genetic mutations in 142 samples from primary tumours of 39 KRAS wild-type metastatic colorectal cancer (CRC) patients receiving anti-EGFR therapy. Deep next-generation sequencing was performed on whole-tumour sections and six morphology-defined tumour regions.

RESULTS

Mutations in genes linked to anti-EGFR therapy response (KRAS, BRAF, NRAS, PTEN and PI3KCA) were found uniquely in the non-responder group, with substantial variability across morphological sub-regions. BRAF mutations were aligned with serrated and mucinous morphologies, while KRAS mutations (p.Lys147Glu and p.Ala146Thr) were associated with mucinous and desmoplastic morphologies. In all cases, the cumulative mutational profile from sub-regions provided more details than that of the whole-tumour profile.

CONCLUSION

Our findings highlight that comprehensive analysis, considering morphological heterogeneity, is crucial for personalised CRC treatment strategies.

摘要

背景

新出现的证据表明，肿瘤形态异质性可能会影响与治疗反应相关的突变谱。在这项初步研究中，我们旨在评估与全组织分析相比，在特定形态模式或侵袭前沿鉴定出的突变是否与抗表皮生长因子受体（EGFR）治疗后较短的疾病进展时间相关。

方法

我们调查了39例接受抗EGFR治疗的KRAS野生型转移性结直肠癌（CRC）患者原发肿瘤的142份样本中的基因突变情况。对全肿瘤切片和六个形态学定义的肿瘤区域进行了深度二代测序。

结果

与抗EGFR治疗反应相关的基因（KRAS、BRAF、NRAS、PTEN和PI3KCA）中的突变仅在无反应组中发现，且在形态学子区域中存在很大差异。BRAF突变与锯齿状和黏液性形态相关，而KRAS突变（p.Lys147Glu和p.Ala146Thr）与黏液性和促纤维增生性形态相关。在所有病例中，子区域的累积突变谱比全肿瘤谱提供了更多细节。