Background:Administration of PARP inhibitors against breast and ovarian cancers with BRCA1 and BRCA2 mutations has shown clinical benefits in patients. However, these agents are also toxic and have a narrow therapeutic index.Objectives:In this work, we aimed to identify membrane proteins that are specifically upregulated in these cancers.Methods:We interrogated public datasets to analyze genes upregulated or downregulated when these mutations were present, compared with wild-type cancers. Surface protein expression and functional annotation analyses were also performed.Results:In breast cancer, we identified 11 upregulated and 44 downregulated transcripts in BRCA1-mut, while 10 upregulated and 57 downregulated transcripts were identified in BRCA2-mut cancers. In ovarian cancer, 79 transcripts were upregulated and 123 were downregulated in BRCA1-mut cancers, while five were upregulated and seven were downregulated in BRCA2-mut tumors. Regarding the biological function related to these genes, in BRCA1-mutated ovarian cancers, the main functions of upregulated genes included MHC assembly or regulation of the interferon gamma pathway; in BRCA2-mut ovarian cancers, regulation of phosphorylation and signaling; in BRCA1-mut breast cancers, cell damage repair and angiogenesis; and finally, in BRCA2-mut breast cancers, cytokine production and T-cell migration. Genes expressed in the surface membrane or extracellular matrix and related to patient outcomes included B3GNT7 and CTSV in BRCA2-mut breast cancers, exhibiting detrimental prognoses. CD6, CXCL9, and CXCL13 were associated with favorable outcomes in BRCA1-mutant ovarian cancers. The last three genes were also correlated with the infiltration of effector T cells and dendritic cells in ovarian tumors.Conclusions:In summary, we identified deregulated candidate genes that could be used as therapeutic targets.
背景：针对携带BRCA1和BRCA2突变的乳腺癌和卵巢癌患者使用PARP抑制剂已显示出临床获益。然而，这类药物同时具有毒性且治疗窗较窄。 目的：本研究旨在鉴定在这类癌症中特异性上调的膜蛋白。 方法：我们通过分析公共数据库，比较突变型与野生型癌症中基因表达的上调或下调情况，并进行表面蛋白表达及功能注释分析。 结果：在乳腺癌中，BRCA1突变型鉴定出11个上调转录本和44个下调转录本，BRCA2突变型则发现10个上调转录本和57个下调转录本。在卵巢癌中，BRCA1突变型存在79个上调转录本和123个下调转录本，而BRCA2突变型有5个上调转录本和7个下调转录本。关于这些基因相关的生物学功能：在BRCA1突变卵巢癌中，上调基因主要涉及MHC组装或干扰素γ通路调控；在BRCA2突变卵巢癌中，主要调控磷酸化及信号传导；在BRCA1突变乳腺癌中，主要参与细胞损伤修复与血管生成；在BRCA2突变乳腺癌中，则涉及细胞因子产生与T细胞迁移。在细胞表面膜或细胞外基质表达且与患者预后相关的基因中，BRCA2突变乳腺癌的B3GNT7和CTSV基因显示不良预后，而BRCA1突变卵巢癌的CD6、CXCL9和CXCL13基因与良好预后相关。后三个基因还与卵巢肿瘤中效应T细胞和树突状细胞的浸润相关。 结论：本研究鉴定出的失调候选基因可作为潜在治疗靶点。
肿瘤(癌症)患者之家