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Abstract：
OBJECTIVE: Ovarian cancer (OC) is characterized by a high recurrence rate, and homologous recombination deficiency (HRD) is an important biomarker in the clinical management of OC. We investigated the differences in clinical genomic profiles between the primary and platinum-sensitive recurrent OC (PSROC), focusing on HRD status.
METHODS: A total of 40 formalin-fixed paraffin-embedded (FFPE) tissues of primary tumors and their first platinum-sensitive recurrence from 20 OC patients were collected, and comprehensive genomic profiling (CGP) analysis of FoundationOne®CDx (F1CDx) was applied to explore the genetic (dis)similarities of the primary and recurrent tumors.
RESULTS: By comparing between paired samples, we found that genomic loss of heterozygosity (gLOH) score had a high intra-patient correlation (r2 = 0.79) and that short variants (including TP53, BRCA1/2 and NOTCH1 mutations), tumor mutational burden (TMB) and microsatellite stability status remained stable. The frequency of (likely) pathological BRCA1/2 mutations was 30% (12/40) in all samples positively correlated with gLOH scores, but the proportion of gLOH-high status (score > 16%) was 50% (10/20) and 55% (11/20) in the primary and recurrent samples, respectively. An additional 20% (4/20) of patients needed attention, a quarter of which carried the pathological BRCA1 mutation but had a gLOH-low status (gLOH < 16%), and three-quarters had different gLOH status in primary-recurrent pairs. Furthermore, we observed the PSROC samples had higher gLOH scores (16.1 ± 9.24 vs. 19.4 ± 11.1, p = 0.007), more CNVs (36.1% vs. 15.1% of discordant genomic alternations), and significant enrichment of altered genes in TGF-beta signaling and Hippo signaling pathways (p < 0.05 for all) than their paired primaries. Lastly, mutational signature and oncodrive gene analyses showed that the computed mutational signature similarity in the primary and recurrent tumors were best matched the COSMI 3 signature (Aetiology of HRD) and had consistent candidate cancer driver genes of MSH2, NOTCH1 and MSH6.
CONCLUSIONS: The high genetic concordance of the short variants remains stable along OC recurrence. However, the results reveal significantly higher gLOH scores in the recurrent setting than in paired primaries, supporting further clinically instantaneity HRD assay strategy.
METHODS: A total of 40 formalin-fixed paraffin-embedded (FFPE) tissues of primary tumors and their first platinum-sensitive recurrence from 20 OC patients were collected, and comprehensive genomic profiling (CGP) analysis of FoundationOne®CDx (F1CDx) was applied to explore the genetic (dis)similarities of the primary and recurrent tumors.
RESULTS: By comparing between paired samples, we found that genomic loss of heterozygosity (gLOH) score had a high intra-patient correlation (r2 = 0.79) and that short variants (including TP53, BRCA1/2 and NOTCH1 mutations), tumor mutational burden (TMB) and microsatellite stability status remained stable. The frequency of (likely) pathological BRCA1/2 mutations was 30% (12/40) in all samples positively correlated with gLOH scores, but the proportion of gLOH-high status (score > 16%) was 50% (10/20) and 55% (11/20) in the primary and recurrent samples, respectively. An additional 20% (4/20) of patients needed attention, a quarter of which carried the pathological BRCA1 mutation but had a gLOH-low status (gLOH < 16%), and three-quarters had different gLOH status in primary-recurrent pairs. Furthermore, we observed the PSROC samples had higher gLOH scores (16.1 ± 9.24 vs. 19.4 ± 11.1, p = 0.007), more CNVs (36.1% vs. 15.1% of discordant genomic alternations), and significant enrichment of altered genes in TGF-beta signaling and Hippo signaling pathways (p < 0.05 for all) than their paired primaries. Lastly, mutational signature and oncodrive gene analyses showed that the computed mutational signature similarity in the primary and recurrent tumors were best matched the COSMI 3 signature (Aetiology of HRD) and had consistent candidate cancer driver genes of MSH2, NOTCH1 and MSH6.
CONCLUSIONS: The high genetic concordance of the short variants remains stable along OC recurrence. However, the results reveal significantly higher gLOH scores in the recurrent setting than in paired primaries, supporting further clinically instantaneity HRD assay strategy.
摘要：
目的：卵巢癌（OC）的特点是高复发率，同源重组缺陷(HRD)是OC临床治疗的重要生物标志物。我们调查了原发性和铂敏感性复发性OC（PSROC）之间临床基因组谱的差异，重点关注人力资源开发状况。
方法：收集20例OC患者原发肿瘤的福尔马林固定石蜡包埋(FFPE)组织40例及其首次铂类敏感复发组织，并应用FoundationOne®CDx(F1CDx)的综合基因组谱分析(CGP)分析探索原发性和复发性肿瘤的遗传(dis)相似性。
结果：通过比较配对样本，我们发现基因组杂合性缺失（gLOH）评分具有很高的患者内相关性（r2=0.79）和短变异（包括TP53，BRCA1/2和NOTCH1突变），肿瘤突变负荷（TMB）和微卫星稳定性状态保持稳定。所有样本中（可能）病理性BRCA1/2突变的频率为30%（12/40），与gLOH评分呈正相关，但在原发和复发样本中gLOH高状态（评分>16％）的比例为50％（10/20）和55％（11/20），分别。另外20%（4/20）的患者需要注意，其中四分之一携带病理性BRCA1突变，但具有gLOH低状态（gLOH<16％），在原发-复发对中，四分之三的人有不同的gLOH状态。此外，我们观察到PSROC样本的gLOH评分较高（16.1±9.24与19.4±11.1，p=0.007），更多的CNV（36.1%与15.1%的不一致基因组交替)，并且在TGF-β信号传导和Hippo信号传导途径中改变的基因的显著富集(全部p<0.05)比它们的配对初级。最后,突变特征和癌驱动基因分析显示,原发性和复发性肿瘤的计算突变特征相似性与COSMI3特征(HRD的病因)最匹配,并且具有一致的MSH2,NOTCH1和MSH6候选癌驱动基因.
结论：短变异体的高度遗传一致性在OC复发过程中保持稳定。然而,结果显示，复发设置中的gLOH分数明显高于配对初选中的gLOH分数，支持进一步的临床即时HRD检测策略。
方法：收集20例OC患者原发肿瘤的福尔马林固定石蜡包埋(FFPE)组织40例及其首次铂类敏感复发组织，并应用FoundationOne®CDx(F1CDx)的综合基因组谱分析(CGP)分析探索原发性和复发性肿瘤的遗传(dis)相似性。
结果：通过比较配对样本，我们发现基因组杂合性缺失（gLOH）评分具有很高的患者内相关性（r2=0.79）和短变异（包括TP53，BRCA1/2和NOTCH1突变），肿瘤突变负荷（TMB）和微卫星稳定性状态保持稳定。所有样本中（可能）病理性BRCA1/2突变的频率为30%（12/40），与gLOH评分呈正相关，但在原发和复发样本中gLOH高状态（评分>16％）的比例为50％（10/20）和55％（11/20），分别。另外20%（4/20）的患者需要注意，其中四分之一携带病理性BRCA1突变，但具有gLOH低状态（gLOH<16％），在原发-复发对中，四分之三的人有不同的gLOH状态。此外，我们观察到PSROC样本的gLOH评分较高（16.1±9.24与19.4±11.1，p=0.007），更多的CNV（36.1%与15.1%的不一致基因组交替)，并且在TGF-β信号传导和Hippo信号传导途径中改变的基因的显著富集(全部p<0.05)比它们的配对初级。最后,突变特征和癌驱动基因分析显示,原发性和复发性肿瘤的计算突变特征相似性与COSMI3特征(HRD的病因)最匹配,并且具有一致的MSH2,NOTCH1和MSH6候选癌驱动基因.
结论：短变异体的高度遗传一致性在OC复发过程中保持稳定。然而,结果显示，复发设置中的gLOH分数明显高于配对初选中的gLOH分数，支持进一步的临床即时HRD检测策略。
