CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Exploring the differences between BRCA mutated and HRwild-type high grade serous ovarian cancer: A multiomic analysis.
Exploring the differences between BRCA mutated and HRwild-type high grade serous ovarian cancer: A multiomic analysis.
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我们的发现强调了基于 BRCA1 和 BRCA2 突变的差异性免疫特征，并提示了潜在的治疗靶点，包括结合免疫治疗和针对特定基因组改变的治療策略。
本研究的目的是利用CARIS数据库，评估BRCA1突变（BRCA1mut）和BRCA2突变（BRCA2mut）HGSOC与同源重组野生型（HRwt）肿瘤相比的转录组谱。
下一代和全转录组测序（WTS；Caris Life Sciences，Phoenix，AZ）共对2745份HGSOC肿瘤样本进行。BRCA突变定义为导致蛋白质功能丧失的变异，HRwt定义为BRCA1和BRCA2以及另外28个HR基因均无异常的野生型样本。HRwt组进一步分为HRwt/LOH-low（<16 %）和HRwt/LOH-high（≥16 %）。基因组分析包括突变分析以及TMB和MSI的测定。转录组分析包括差异表达基因（DEGs）的鉴定、GSEA和免疫去卷积。
我们识别出519例（19%）BRCA1突变、302例（11%）BRCA2突变、739例（27%）HRwt/LOH高和1181例（43%）HRwt/LOH低的HGSOC。TP53是所有组中最常见的突变基因。与BRCA1突变和BRCA2突变HGSOC相比，PIK3CA突变在HRwt/LOH低中最为常见。与BRCA1突变、HRwt/LOH高和HRwt/LOH低肿瘤相比，TMB-H在BRCA2突变中最高。相反，在BRCA1突变肿瘤中观察到更高的NKT细胞浸润、更高的T细胞炎症和IFNγ评分以及更高的PDL1表达。
The purpose of this study was to evaluate the transcriptomic profile of BRCA1 mutant (BRCA1mut) and BRCA2 mutant (BRCA2mut) HGSOC compared to homologous recombination wild-type (HRwt) tumors utilizing the CARIS database.
Next-generation and Whole Transcriptome Sequencing (WTS; Caris Life Sciences, Phoenix, AZ) was performed on a total of 2745 HGSOC tumor samples. BRCA mutations were defined as variants resulting in loss-of-function of the protein and HRwt was defined as samples wildtype for aberrations in both BRCA1 and BRCA2, as well as for 28 other HR genes. HRwt group was further classified into HRwt/LOH-low (<16 %) and HRwt/LOH-high (≥16 %). Genomic analysis consists of mutation analysis and measurements of TMB and MSI. Transcriptomic analysis included identification of Differentially expressed genes (DEGs), GSEA and immune deconvolution.
We identified 519 (19 %) BRCA1-mut, 302 (11 %) BRCA2-mut, and 739 (27 %) HRwt/LOH high and 1181 (43 %) HRwt/LOH low HGSOC. TP53 was the most commonly mutated gene in all groups. Mutations in PIK3CA were most common in HRwt/LOH-low compared to BRCA1-mut and BRCA2-mut HGSOC. TMB-H was highest in BRCA2-mut compared to BRCA1-mut, HRwt/LOH high and HRwt/LOH low tumors. In contrast, higher NKT cell infiltration, higher T cell inflamed and IFNγ scores, and higher PDL1 expression were observed in BRCA1-mut tumors.
Our findings emphasize the differential immune profiles based on BRCA1 and BRCA2 mutations and suggest potential therapeutic targets, including treatment strategies that incorporate immunotherapy and target specific genomic alterations.
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