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Abstract：
The homologous recombination (HR) repair pathway for DNA damage, particularly the BRCA1 and BRCA2 genes, has become a target for cancer therapy, with poly ADP-ribose polymerase (PARP) inhibitors showing significant outcomes in treating germline BRCA1/2 (gBRCA1/2) mutated breast cancer. Recent studies suggest that some patients with somatic BRCA1/2 (sBRCA1/2) mutation or mutations in HR-related genes other than BRCA1/2 may benefit from PARP inhibitors as well, particularly those with PALB2 mutations. The current analysis aims to evaluate the prevalence of genetic alterations specific to BRCA1, BRCA2, and PALB2 in a large cohort of Taiwanese breast cancer patients through tumor-targeted sequencing.
A total of 924 consecutive assays from 879 Taiwanese breast cancer patients underwent tumor-targeted sequencing (Thermo Fisher Oncomine Comprehensive Assay v3). We evaluated BRCA1, BRCA2, and PALB2 mutational profiles, with variants annotated and curated by the ClinVAR, the Oncomine™ Knowledgebase Reporter, and the OncoKB™. We also conducted reflex germline testing using either whole exome sequencing (WES) or whole genome sequencing (WGS), which is ongoing.
Among the 879 patients analyzed (924 assays), 130 had positive mutations in BRCA1 (3.1%), BRCA2 (8.6%), and PALB2 (5.2%), with a total of 14.8% having genetic alterations. Co-occurrence was noted between BRCA1/BRCA2, BRCA1/PALB2, and BRCA2/PALB2 mutations. In BRCA1-mutated samples, only p.K654fs was observed in three patients, while other variants were observed no more than twice. For BRCA2, p.N372H was the most common (26 patients), followed by p.S2186fs, p.V2466A, and p.X159_splice (5 times each). For PALB2, p.I887fs was the most common mutation (30 patients). This study identified 176 amino acid changes; 60.2% (106) were not documented in either ClinVAR or the Oncomine™ Knowledgebase Reporter. Using the OncoKB™ for annotation, 171 (97.2%) were found to have clinical implications. For the result of reflex germline testing, three variants (BRCA1 c.1969_1970del, BRCA1 c.3629_3630del, BRCA2 c.8755-1G > C) were annotated as Pathogenic/Likely pathogenic (P/LP) variants by ClinVar and as likely loss-of-function or likely oncogenic by OncoKB; while one variant (PALB2 c.448C > T) was not found in ClinVar but was annotated as likely loss-of-function or likely oncogenic by OncoKB.
Our study depicted the mutational patterns of BRCA1, BRCA2, and PALB2 in Taiwanese breast cancer patients through tumor-only sequencing. This highlights the growing importance of BRCA1/2 and PALB2 alterations in breast cancer susceptibility risk and the treatment of index patients. We also emphasized the need to meticulously annotate variants in cancer-driver genes as well as actionable mutations across multiple databases.
A total of 924 consecutive assays from 879 Taiwanese breast cancer patients underwent tumor-targeted sequencing (Thermo Fisher Oncomine Comprehensive Assay v3). We evaluated BRCA1, BRCA2, and PALB2 mutational profiles, with variants annotated and curated by the ClinVAR, the Oncomine™ Knowledgebase Reporter, and the OncoKB™. We also conducted reflex germline testing using either whole exome sequencing (WES) or whole genome sequencing (WGS), which is ongoing.
Among the 879 patients analyzed (924 assays), 130 had positive mutations in BRCA1 (3.1%), BRCA2 (8.6%), and PALB2 (5.2%), with a total of 14.8% having genetic alterations. Co-occurrence was noted between BRCA1/BRCA2, BRCA1/PALB2, and BRCA2/PALB2 mutations. In BRCA1-mutated samples, only p.K654fs was observed in three patients, while other variants were observed no more than twice. For BRCA2, p.N372H was the most common (26 patients), followed by p.S2186fs, p.V2466A, and p.X159_splice (5 times each). For PALB2, p.I887fs was the most common mutation (30 patients). This study identified 176 amino acid changes; 60.2% (106) were not documented in either ClinVAR or the Oncomine™ Knowledgebase Reporter. Using the OncoKB™ for annotation, 171 (97.2%) were found to have clinical implications. For the result of reflex germline testing, three variants (BRCA1 c.1969_1970del, BRCA1 c.3629_3630del, BRCA2 c.8755-1G > C) were annotated as Pathogenic/Likely pathogenic (P/LP) variants by ClinVar and as likely loss-of-function or likely oncogenic by OncoKB; while one variant (PALB2 c.448C > T) was not found in ClinVar but was annotated as likely loss-of-function or likely oncogenic by OncoKB.
Our study depicted the mutational patterns of BRCA1, BRCA2, and PALB2 in Taiwanese breast cancer patients through tumor-only sequencing. This highlights the growing importance of BRCA1/2 and PALB2 alterations in breast cancer susceptibility risk and the treatment of index patients. We also emphasized the need to meticulously annotate variants in cancer-driver genes as well as actionable mutations across multiple databases.
摘要：
背景：DNA损伤的同源重组（HR）修复途径，特别是BRCA1和BRCA2基因，已经成为癌症治疗的目标，聚ADP-核糖聚合酶（PARP）抑制剂在治疗种系BRCA1/2（gBRCA1/2）突变的乳腺癌方面显示出显著的结果。最近的研究表明，一些体细胞BRCA1/2（sBRCA1/2）突变或BRCA1/2以外的HR相关基因突变的患者也可能受益于PARP抑制剂。特别是那些具有PALB2突变的。当前的分析旨在通过肿瘤靶向测序评估台湾乳腺癌患者的大型队列中BRCA1，BRCA2和PALB2特异性遗传改变的患病率。
方法：对来自879名台湾乳腺癌患者的924例连续检测进行了肿瘤靶向测序（ThermoFisherOncomine综合检测v3）。我们评估了BRCA1，BRCA2和PALB2突变谱，由ClinVAR注释和策划的变体，Oncomine™知识库记者，和OncoKB™。我们还使用全外显子组测序（WES）或全基因组测序（WGS）进行了反射种系测试。正在进行中。
结果：在分析的879名患者中（924项检测），130例BRCA1突变阳性（3.1%），BRCA2（8.6%），和PALB2（5.2％），共有14.8%的人有遗传改变。注意到BRCA1/BRCA2、BRCA1/PALB2和BRCA2/PALB2突变之间同时出现。在BRCA1突变的样本中，仅在三名患者中观察到p.K654fs，而其他变体观察不超过两次。对于BRCA2，p.N372H是最常见的（26例患者），其次是p.S2186fs，p.V2466A,和p.X159_splice（每个5次）。对于PALB2，p.I887fs是最常见的突变（30例患者）。该研究鉴定了176个氨基酸变化;在ClinVAR或Oncomine™知识库报告中没有记录60.2%(106)。使用OncoKB™进行注释，发现171（97.2％）具有临床意义。对于反射生殖系测试的结果，三个变体(BRCA1c.1969_1970del，BRCA1c.3629_3630del,BRCA2c.8755-1G>C）被ClinVar注释为致病性/可能致病性（P/LP）变体，并且可能是OncoKB的功能丧失或致癌；而在ClinVar中未发现一个变体（PALB2c.448C>T），但被注释为可能是功能丧失或可能是致癌的。
结论：我们的研究通过仅肿瘤测序描绘了台湾乳腺癌患者中BRCA1、BRCA2和PALB2的突变模式。这凸显了BRCA1/2和PALB2改变在乳腺癌易感性风险和索引患者治疗中的重要性。我们还强调需要精心注释癌症驱动基因中的变异以及跨多个数据库的可操作突变。
方法：对来自879名台湾乳腺癌患者的924例连续检测进行了肿瘤靶向测序（ThermoFisherOncomine综合检测v3）。我们评估了BRCA1，BRCA2和PALB2突变谱，由ClinVAR注释和策划的变体，Oncomine™知识库记者，和OncoKB™。我们还使用全外显子组测序（WES）或全基因组测序（WGS）进行了反射种系测试。正在进行中。
结果：在分析的879名患者中（924项检测），130例BRCA1突变阳性（3.1%），BRCA2（8.6%），和PALB2（5.2％），共有14.8%的人有遗传改变。注意到BRCA1/BRCA2、BRCA1/PALB2和BRCA2/PALB2突变之间同时出现。在BRCA1突变的样本中，仅在三名患者中观察到p.K654fs，而其他变体观察不超过两次。对于BRCA2，p.N372H是最常见的（26例患者），其次是p.S2186fs，p.V2466A,和p.X159_splice（每个5次）。对于PALB2，p.I887fs是最常见的突变（30例患者）。该研究鉴定了176个氨基酸变化;在ClinVAR或Oncomine™知识库报告中没有记录60.2%(106)。使用OncoKB™进行注释，发现171（97.2％）具有临床意义。对于反射生殖系测试的结果，三个变体(BRCA1c.1969_1970del，BRCA1c.3629_3630del,BRCA2c.8755-1G>C）被ClinVar注释为致病性/可能致病性（P/LP）变体，并且可能是OncoKB的功能丧失或致癌；而在ClinVar中未发现一个变体（PALB2c.448C>T），但被注释为可能是功能丧失或可能是致癌的。
结论：我们的研究通过仅肿瘤测序描绘了台湾乳腺癌患者中BRCA1、BRCA2和PALB2的突变模式。这凸显了BRCA1/2和PALB2改变在乳腺癌易感性风险和索引患者治疗中的重要性。我们还强调需要精心注释癌症驱动基因中的变异以及跨多个数据库的可操作突变。
