A Multiomics Signature Highlights Alterations Underlying Homologous Recombination Deficiency in Triple-Negative Breast Cancer
A Multiomics Signature Highlights Alterations Underlying Homologous Recombination Deficiency in Triple-Negative Breast Cancer
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多组学特征凸显了三阴性乳腺癌同源重组缺陷背后的改变
DOI：
10.1245/s10434-022-11958-7
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发表时间：
2022-01
影响因子：
3.7
通讯作者：
Chao You
中科院分区：
文献类型：
--
作者：
Guan-Hua Su;Lin Jiang;Yi Xiao;Ren-Cheng Zheng;He Wang;Yi-Zhou Jiang;Wei-Jun Peng;Zhi-Ming Shao;Ya-Jia Gu;Chao You
背景同源重组（Homogeneous recombination，HR）是DNA双链损伤修复的关键途径。HR缺陷（HRD）在三阴性乳腺癌（TNBC）中比其他乳腺癌亚型更常见。几项临床试验已经证明了HRD的价值分层乳腺癌患者成不同的群体，根据他们的反应聚（ADP核糖）聚合酶抑制剂和chemotherapy.MethodsWe回顾性收集TNBC样本建立一个多组学队列（n = 343），并探讨了生物学和表型机制的基础上更好的预后高HRD评分的患者。进行基因集富集分析，以阐明低HRD评分的患者的潜在途径，并建立了一个放射组学模型，通过一个非侵入性的方法预测HRD评分。结果多变量考克斯分析显示，独立的预后价值低HRD评分（风险比2.20，95%置信区间1.05-4.59; p = 0.04）。此外，氨基酸和脂质代谢途径在低HRD评分患者的肿瘤中高度富集，这也通过差异丰富代谢物分析证实。开发了一种无创放射组学方法来预测HRD状态，并在独立验证队列中表现良好（支持向量机模型：曲线下面积[AUC 0.739，灵敏度0.571，特异性0.824;逻辑回归模型：AUC 0.695，灵敏度0.571，特异性0.882）。结论我们揭示了HRD评分的预后价值，用非侵入性放射组学特征预测HRD状态，初步探索了低HRD评分TNBC患者的用药靶点。
BackgroundHomologous recombination (HR) is a key pathway in DNA double-strand damage repair. HR deficiency (HRD) occurs more commonly in triple-negative breast cancers (TNBCs) than in other breast cancer subtypes. Several clinical trials have demonstrated the value of HRD in stratifying breast cancer patients into distinct groups based on their responses to poly(ADP ribose) polymerase inhibitors and chemotherapy.MethodsWe retrospectively collected TNBC samples to establish a multiomics cohort (n = 343) and explored the biological and phenotypic mechanisms underlying the better prognosis of patients with high HRD scores. Gene set enrichment analysis was conducted to elucidate the underlying pathways in patients with low HRD scores, and a radiomics model was established to predict the HRD score via a noninvasive method.ResultsMultivariable Cox analysis revealed the independent prognostic value of a low HRD score (hazard ratio 2.20, 95% confidence interval 1.05–4.59; p = 0.04). Furthermore, amino acid and lipid metabolism pathways were highly enriched in tumors from patients with low HRD scores, which was also demonstrated by differential abundant metabolite analysis. A noninvasive radiomics method was developed to predict the HRD status and it performed well in the independent validation cohort (support vector machine model: area under the curve [AUC 0.739, sensitivity 0.571, and specificity 0.824; logistic regression model: AUC 0.695, sensitivity 0.571, and specificity 0.882).ConclusionsWe revealed the prognostic value of the HRD score, predicted the HRD status with noninvasive radiomics features, and preliminarily explored druggable targets for TNBC patients with low HRD scores.
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影响因子：
28.2
作者：
Birkbak NJ;Wang ZC;Kim JY;Eklund AC;Li Q;Tian R;Bowman-Colin C;Li Y;Greene-Colozzi A;Iglehart JD;Tung N;Ryan PD;Garber JE;Silver DP;Szallasi Z;Richardson AL
通讯作者：
Richardson AL
影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
三阴性乳腺癌的基因组和转录组景观：亚型和治疗策略
影响因子：
50.3
作者：
Jiang, Yi-Zhou;Ma, Ding;Shao, Zhi-Ming
通讯作者：
Shao, Zhi-Ming
分子亚型分析和基因组分析拓展了难治性转移性三阴性乳腺癌的精准医疗：FUTURE 试验
影响因子：
44.1
作者：
Jiang YZ;Liu Y;Xiao Y;Hu X;Jiang L;Zuo WJ;Ma D;Ding J;Zhu X;Zou J;Verschraegen C;Stover DG;Kaklamani V;Wang ZH;Shao ZM
通讯作者：
Shao ZM
多组学分析揭示了独特的微环境特征并提出了三阴性乳腺癌的免疫逃逸机制
影响因子：
11.5
作者：
Xiao, Yi;Ma, Ding;Shao, Zhi-Ming
通讯作者：
Shao, Zhi-Ming