鉴定乳腺癌中临床相关基因的潜在可操作改变。

Identification of putative actionable alterations in clinically relevant genes in breast cancer.

机构信息

Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.

出版信息

Br J Cancer. 2021 Oct;125(9):1270-1284. doi: 10.1038/s41416-021-01522-7. Epub 2021 Aug 28.

DOI:10.1038/s41416-021-01522-7

PMID:34455425

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8548334/

Abstract

BACKGROUND

Individualising treatment in breast cancer requires effective predictive biomarkers. While relatively few genomic aberrations are clinically relevant, there is a need for characterising patients across different subtypes to identify actionable alterations.

METHODS

We identified genomic alterations in 49 potentially actionable genes for which drugs are available either clinically or via clinical trials. We explored the landscape of mutations and copy number alterations (CNAs) in actionable genes in seven breast cancer subtypes utilising The Cancer Genome Atlas. To dissect the genomic complexity, we analysed the patterns of co-occurrence and mutual exclusivity in actionable genes.

RESULTS

We found that >30% of tumours harboured putative actionable events that are targetable by currently available drugs. We identified genes that had multiple targetable alterations, representing candidate targets for combination therapy. Genes predicted to be drivers in primary breast tumours fell into five categories: mTOR pathway, immune checkpoints, oestrogen signalling, tumour suppression and DNA damage repair. Our analysis also revealed that CNAs in 34/49 (69%) and mutations in 13/49 (26%) genes were significantly associated with gene expression, validating copy number events as a dominant oncogenic mechanism in breast cancer.

CONCLUSION

These results may enable the acceleration of personalised therapy and improve clinical outcomes in breast cancer.

摘要

背景

乳腺癌的个体化治疗需要有效的预测性生物标志物。虽然相对较少的基因组异常与临床相关，但需要对不同亚型的患者进行特征描述，以确定可采取的改变。

方法

我们确定了 49 个潜在可操作基因中的基因组改变，这些基因的药物要么在临床上可用，要么通过临床试验可用。我们利用癌症基因组图谱（The Cancer Genome Atlas）研究了七个乳腺癌亚型中可操作基因的突变和拷贝数改变（CNAs）的情况。为了剖析基因组的复杂性，我们分析了可操作基因中共同发生和相互排斥的模式。

结果

我们发现超过 30%的肿瘤携带可被现有药物靶向的潜在可操作事件。我们确定了多个可靶向改变的基因，这些基因是联合治疗的候选靶点。预测为原发性乳腺癌的驱动基因分为五类：mTOR 通路、免疫检查点、雌激素信号、肿瘤抑制和 DNA 损伤修复。我们的分析还表明，49 个基因中的 34 个（69%）和 49 个基因中的 13 个（26%）的 CNA 与基因表达显著相关，验证了 CNA 是乳腺癌中的主要致癌机制。