The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma.
The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma.
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早期卵巢高级别浆液性癌的基因组图谱
DOI：
10.1158/1078-0432.ccr-21-1643
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发表时间：
2022-07-01
期刊：
影响因子：
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通讯作者：
McNeish IA
中科院分区：
文献类型：
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作者：
Cheng Z;Mirza H;Ennis DP;Smith P;Morrill Gavarró L;Sokota C;Giannone G;Goranova T;Bradley T;Piskorz A;Lockley M;BriTROC-1 Investigators;Kaur B;Singh N;Tookman LA;Krell J;McDermott J;Macintyre G;Markowetz F;Brenton JD;McNeish IA
卵巢高级别浆液性癌(HGSC)通常在晚期诊断。我们调查了与早期肿瘤相比，晚期HGSC是否具有与获得进化优势一致的独特基因组特征。我们对43例FIGO I-IIA期HGSC患者进行了靶向下一代测序和浅层全基因组测序(SWGS)，以研究体细胞突变和拷贝数(CN)改变(SCNA)。我们将结果与来自BriTROC-1研究的52名IIIC/IV期HGSC患者的治疗前样本进行了比较。早期和晚期患者的诊断年龄没有差异(中位数分别为61.3岁和62.3岁)。TP53突变在两组人群中几乎是普遍的(早期89%，晚期100%)，其他体细胞突变的比率没有显著差异，包括BRCA1和BRCA2。我们也没有观察到可以解释生物行为的队列特异性焦点SCNA。然而，晚期(中位数3.0)的倍性高于早期(中位数1.9)。CN特征暴露在队列之间存在显著差异，早期的相对特征3暴露更多，晚期的特征4更大。基于CN签名的非监督聚类确定了三个具有预测意义的聚类。早期和晚期HGSC具有高度相似的突变模式和局灶性SCNA。然而，CN特征分析表明，晚期疾病具有与全基因组复制一致的明显特征暴露。将需要进一步的分析来确定这些差异是否反映了早期阶段和后期阶段之间的真正生物学差异，或者仅仅是进化适应性的与时间相关的标记。见杨等人的相关评论，第2730页
Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. See related commentary by Yang et al., p. 2730