探索BRCA突变型和hr野生型高级别浆液性卵巢癌之间的差异：多组学分析

IF 4.5 2区医学 Q1 OBSTETRICS & GYNECOLOGY

Gynecologic oncology Pub Date : 2025-02-18 DOI:10.1016/j.ygyno.2025.02.010

Ayesha B. Alvero , Sharon Wu , Alex Farrell , Seongho Kim , John J. Wallbillich , Ira Winer , Robert Morris , David Spetzler , Matthew L. Anderson , Alberto Puccini , Nathaniel L. Jones , Thomas J. Herzog , Premal H. Thaker , Gil Mor , Radhika P. Gogoi

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引用次数: 0

摘要

目的利用CARIS数据库，比较BRCA1突变体（BRCA1mut）和BRCA2突变体（BRCA2mut） HGSOC与同源重组野生型（HRwt）肿瘤的转录组学特征。方法全转录组测序（WTS）；Caris Life Sciences, Phoenix， AZ)对2745份HGSOC肿瘤样本进行了研究。BRCA突变被定义为导致蛋白质功能丧失的变异，HRwt被定义为BRCA1和BRCA2以及其他28个HR基因畸变的样本野生型。HRwt组进一步分为HRwt/LOH-low组（< 16%）和HRwt/LOH-high组（≥16%）。基因组分析包括突变分析和TMB和MSI的测量。转录组学分析包括鉴定差异表达基因（DEGs）、GSEA和免疫反褶积。结果共鉴定出519例（19%）BRCA1-mut， 302例（11%）BRCA2-mut， 739例（27%）HRwt/LOH高，1181例（43%）HRwt/LOH低。TP53是所有组中最常见的突变基因。与BRCA1-mut和BRCA2-mut HGSOC相比，PIK3CA突变在HRwt/LOH-low中最常见。与BRCA1-mut、HRwt/LOH高和HRwt/LOH低的肿瘤相比，BRCA2-mut中TMB-H最高。相比之下，在BRCA1-mut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。我们的研究结果强调了基于BRCA1和BRCA2突变的差异免疫谱，并提出了潜在的治疗靶点，包括结合免疫治疗和靶向特异性基因组改变的治疗策略。

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Exploring the differences between BRCA mutated and HRwild-type high grade serous ovarian cancer: A multiomic analysis

Objective

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.

Methods

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.

Results

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.

Conclusion

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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来源期刊

Gynecologic oncology 医学-妇产科学

CiteScore

8.60

自引率

6.40%

发文量

1062

审稿时长

37 days

期刊介绍： Gynecologic Oncology, an international journal, is devoted to the publication of clinical and investigative articles that concern tumors of the female reproductive tract. Investigations relating to the etiology, diagnosis, and treatment of female cancers, as well as research from any of the disciplines related to this field of interest, are published. Research Areas Include: • Cell and molecular biology • Chemotherapy • Cytology • Endocrinology • Epidemiology • Genetics • Gynecologic surgery • Immunology • Pathology • Radiotherapy