Genomic spectra of lymphovascular invasion in breast cancer.

IF 7 2区 医学 Q1 ONCOLOGY
Chuhan Shen, Caijin Lin, Feilin Qu, Chao Chen, Zhiming Shao, Yizhou Jiang, Xin Hu, Genhong Di
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引用次数: 0

Abstract

Objective: Lymphovascular invasion (LVI) is a crucial step in metastasis and is closely associated with poor prognosis in patients with breast cancer. However, its clinical and molecular characteristics remain insufficiently defined. We aimed to identify molecular targets for LVI-positive (LVI+) breast cancer and predict patient prognosis via the analysis of genomic variations using targeted sequencing.

Methods: We established a large-scale targeted sequencing cohort of 4,079 breast cancer samples, which included 3,159 early-stage and locally advanced patients with available LVI statuses. Comparisons of somatic mutation frequencies and germline pathogenic/likely pathogenic (P/LP) mutation frequencies, mutational signature analyses, and mutual exclusivity and co-occurrence analyses were performed to identify key genomic features involved in LVI+ patients. Additionally, Kaplan-Meier survival analysis was conducted to further explore the prognostic value of co-mutations in LVI+ cases.

Results: We observed that LVI+ patients with the hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) and triple-negative breast cancer (TNBC) subtypes exhibited worse disease-free survival. Notably, HR+/HER2- and HER2+ breast cancer patients with LVI displayed distinct genomic features compared with LVI- tumors. Specifically, LVI+ HR+/HER2- tumors exhibited greater frequencies of somatic mutations in TP53 and ESR1, germline BRCA2 P/LP variations, and an enrichment of clock-like single-base substitution (SBS)1 mutational signatures. In contrast, LVI+ HER2+ tumors demonstrated a higher incidence of somatic PIK3CA mutations and increased activity of the apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC)-associated SBS2 signature. Furthermore, we revealed that the co-mutation of TP53 and NF1 could serve as a potential prognostic marker for LVI+ HR+/HER2- patients.

Conclusions: Our findings provide a comprehensive overview of the genomic characteristics of LVI in breast cancer, thereby offering insights that may help in refining precision treatment strategies for LVI+ breast cancer patients.

乳腺癌淋巴血管浸润的基因组谱。
目的:淋巴血管侵袭(LVI)是乳腺癌转移的关键步骤,与乳腺癌患者预后不良密切相关。然而,其临床和分子特征仍不明确。我们的目的是确定LVI阳性(LVI+)乳腺癌的分子靶点,并通过使用靶向测序分析基因组变异来预测患者预后。方法:我们建立了4079例乳腺癌样本的大规模靶向测序队列,其中包括3159例具有可用LVI状态的早期和局部晚期患者。比较LVI+患者的体细胞突变频率和种系致病/可能致病(P/LP)突变频率,进行突变特征分析,相互排他性和共发生分析,以确定LVI+患者的关键基因组特征。此外,我们还进行Kaplan-Meier生存分析,进一步探讨LVI+病例中共突变的预后价值。结果:我们观察到LVI+患者的激素受体阳性/人表皮生长因子受体2阴性(HR+/HER2-)和三阴性乳腺癌(TNBC)亚型表现出更差的无病生存。值得注意的是,与LVI-肿瘤相比,HR+/HER2-和HER2+乳腺癌LVI患者表现出不同的基因组特征。具体来说,LVI+ HR+/HER2-肿瘤表现出更高频率的TP53和ESR1体细胞突变,种系BRCA2 P/LP变异,以及钟样单碱基替代(SBS)1突变特征的富集。相比之下,LVI+ HER2+肿瘤表现出更高的体细胞PIK3CA突变发生率和载脂蛋白B mRNA编辑酶催化多肽(APOBEC)相关SBS2特征的活性增加。此外,我们发现TP53和NF1的共突变可以作为LVI+ HR+/HER2-患者的潜在预后标志物。结论:我们的研究结果全面概述了乳腺癌LVI的基因组特征,从而为LVI+乳腺癌患者的精确治疗策略提供了见解。
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
自引率
9.80%
发文量
1726
审稿时长
4.5 months
期刊介绍: Chinese Journal of Cancer Research (CJCR; Print ISSN: 1000-9604; Online ISSN:1993-0631) is published by AME Publishing Company in association with Chinese Anti-Cancer Association.It was launched in March 1995 as a quarterly publication and is now published bi-monthly since February 2013. CJCR is published bi-monthly in English, and is an international journal devoted to the life sciences and medical sciences. It publishes peer-reviewed original articles of basic investigations and clinical observations, reviews and brief communications providing a forum for the recent experimental and clinical advances in cancer research. This journal is indexed in Science Citation Index Expanded (SCIE), PubMed/PubMed Central (PMC), Scopus, SciSearch, Chemistry Abstracts (CA), the Excerpta Medica/EMBASE, Chinainfo, CNKI, CSCI, etc.
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