Interferon-γ signaling is associated with BRCA1 loss-of-function mutations in high grade serous ovarian cancer.,npj Precision Oncology

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Interferon-γ signaling is associated with BRCA1 loss-of-function mutations in high grade serous ovarian cancer.
npj Precision Oncology ( IF 6.8 ) Pub Date : 2019-12-06 , DOI: 10.1038/s41698-019-0103-4
Horacio Cardenas ₁ , Guanglong Jiang _{2,

3} , Jessica Thomes Pepin ₄ , J Brandon Parker ₁ , Salvatore Condello ₁ , Kenneth P Nephew _{4,

5,

6,

7} , Harikrishna Nakshatri _{5,

8} , Debabrata Chakravarti _{1,

9} , Yunlong Liu _{2,

5} , Daniela Matei _{1,

9,

10}

Affiliation

Loss-of-function mutations of the breast cancer type 1 susceptibility protein (BRCA1) are associated with breast (BC) and ovarian cancer (OC). To identify gene signatures regulated by epigenetic mechanisms in OC cells carrying BRCA1 mutations, we assessed cellular responses to epigenome modifiers and performed genome-wide RNA- and chromatin immunoprecipitation-sequencing in isogenic OC cells UWB1.289 (carrying a BRCA1 mutation, BRCA1-null) and UWB1.289 transduced with wild-type BRCA1 (BRCA1+). Increased sensitivity to histone deacetylase inhibitors (HDACi) was observed in BRCA1-null vs. BRCA1+ cells. Gene expression profiles of BRCA1-null vs. BRCA1+ cells and treated with HDACi were integrated with chromatin mapping of histone H3 lysine 9 or 27 acetylation. Gene networks activated in BRCA1-null vs. BRCA1 + OC cells related to cellular movement, cellular development, cellular growth and proliferation, and activated upstream regulators included TGFβ1, TNF, and IFN-γ. The IFN-γ pathway was altered by HDACi in BRCA1+ vs. BRCA1-null cells, and in BRCA1-mutated/or low vs. BRCA1-normal OC tumors profiled in the TCGA. Key IFN-γ-induced genes upregulated at baseline in BRCA1-null vs. BRCA1+OC and BC cells included CXCL10, CXCL11, and IFI16. Increased localization of STAT1 in the promoters of these genes occurred in BRCA1-null OC cells, resulting in diminished responses to IFN-γ or to STAT1 knockdown. The IFN-γ signature was associated with improved survival among OC patients profiled in the TCGA. In all, our results support that changes affecting IFN-γ responses are associated with inactivating BRCA1 mutations in OC. This signature may contribute to altered responses to anti-tumor immunity in BRCA1-mutated cells or tumors.

中文翻译：

干扰素-γ 信号传导与高级别浆液性卵巢癌中的 BRCA1 功能丧失突变相关。

乳腺癌 1 型易感蛋白 (BRCA1) 的功能丧失突变与乳腺癌 (BC) 和卵巢癌 (OC) 相关。为了识别携带 BRCA1 突变的 OC 细胞中受表观遗传机制调节的基因特征，我们评估了细胞对表观基因组修饰剂的反应，并在同基因 OC 细胞 UWB1.289（携带 BRCA1 突变、BRCA1 缺失）中进行了全基因组 RNA 和染色质免疫沉淀测序。 ) 和用野生型 BRCA1 (BRCA1+) 转导的 UWB1.289。与 BRCA1+ 细胞相比，BRCA1-null 细胞对组蛋白脱乙酰酶抑制剂 (HDACi) 的敏感性增加。将 BRCA1-null 细胞与 BRCA1+ 细胞并用 HDACi 处理的基因表达谱与组蛋白 H3 赖氨酸 9 或 27 乙酰化的染色质图谱进行整合。 BRCA1-null 与 BRCA1 + OC 细胞中与细胞运动、细胞发育、细胞生长和增殖相关的基因网络被激活，并且激活的上游调节因子包括 TGFβ1、TNF 和 IFN-γ。在 TCGA 中分析的 BRCA1+ 细胞与 BRCA1 缺失细胞中，以及 BRCA1 突变/或低突变/或 BRCA1 正常 OC 肿瘤中，HDACi 改变了 IFN-γ 通路。与 BRCA1+OC 和 BC 细胞相比，BRCA1-null 细胞中基线时 IFN-γ 诱导的关键基因上调，包括 CXCL10、CXCL11 和 IFI16。在 BRCA1 缺失的 OC 细胞中，这些基因启动子中 STAT1 的定位增加，导致对 IFN-γ 或 STAT1 敲低的反应减弱。 IFN-γ 特征与 TCGA 中描述的 OC 患者生存率改善相关。总之，我们的结果支持影响 IFN-γ 反应的变化与 OC 中 BRCA1 突变失活有关。该特征可能导致 BRCA1 突变细胞或肿瘤的抗肿瘤免疫反应发生改变。

更新日期：2019-12-06

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