LBPO.MCB01 · 分子与细胞生物学 · Late-Breaking
评估临床全基因组测序与癌症基因panel检测相比的治疗和诊断效用
Evaluating the therapeutic and diagnostic utility of clinical whole-genome sequencing in comparison with cancer gene panel testing
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摘要 Abstract
中文摘要
靶向癌症基因panel检测已广泛用于癌症基因组医学;然而,临床相关的非编码变异和结构变异(SV)可能被遗漏。为将panel检测无法检出的变异与癌症诊断和治疗相联系,需要全基因组测序的临床实施。为评估基因组测序的临床效用,我们在2021年10月至2024年3月期间对癌研会有明医院(JFCR癌症研究所医院)获得的1,050份样本进行了扩展至全基因组的临床测序。该队列由640名男性和410名女性组成,中位年龄为65岁(15-91岁),包括肉瘤(n=155)、直肠癌(n=150)和口腔癌(n=106)。在107个与遗传性癌症综合征相关的基因中,94例识别出种系变异,其中34例检测到二次打击变异,提示为驱动变异。在体细胞变异中,TP53(n=610)改变最为频繁,其次是CDKN2A(n=267)、APC(n=196)和TERT(n=193)。为评估基因组测序对治疗决策的临床影响,我们分析了136例复发疾病病例。根据OncoKB以及日本临床肿瘤学会、日本临床肿瘤学会(JSCO)和日本癌症协会制定的指南,选择可采取行动的变异。我们在122例中检测到可采取行动的变异。63例提出了治疗方案,12例(7.6%)接受了基因组指导的治疗(肺癌(n=4)、胃癌(n=3)、卵巢癌(n=2)),与panel检测所实现的相当。我们将基因组测序的分析性能与日本广泛使用的panel检测进行了比较:FoundationOne(n=23)、NCC Oncopanel(n=23)和TruSight Oncology 500(n=24)。基因组测序检测到这些panel识别的大多数体细胞SNV和插入缺失,在使用配对的正常-肿瘤DNA样本时观察到更高的一致性。基因组测序在16种癌症类型的86例病例中检测到48个不同的驱动SV,包括肉瘤(n=45)、唾液腺癌(n=11)和肺癌(n=4)。其中,67例中检测到的36个SV位于panel靶区域之外,并包括具有诊断和治疗相关性的变异。总之,应用于临床癌症样本的基因组测序能够检测与诊断和治疗相关的变异,与panel检测相当,同时识别超出panel覆盖范围的致病性SV。
查看英文原文 English abstract
Targeted cancer gene panel testing has been widely used in cancer genomic medicine; however, clinically relevant non-coding variants and structural variants (SVs) may be missed. To link the variants undetectable by panel testing to cancer diagnosis and treatment, the clinical implementation of whole-genome sequencing is required.To evaluate the clinical utility of genome sequencing, we performed clinical sequencing extended to the genome-wide on 1,050 samples obtained at the Cancer Institute Hospital of JFCR between Oct 2021 and Mar 2024.The cohort consisted of 640 males and 410 females, with a median age of 65 years (15-91), including sarcoma (n = 155), rectal cancer (n = 150), and oral cancer (n = 106). Germline variants in 107 genes associated with hereditary cancer syndromes were identified in 94 cases, and second-hit variants were detected in 34 of these, suggesting driver variants. Among somatic variants, TP53 (n = 610) was most frequently altered, followed by CDKN2A (n = 267), APC (n = 196), and TERT (n = 193).To assess the clinical impact of genome sequencing on therapeutic decision-making, we analyzed 136 cases with recurrent disease. Actionable variants were selected on OncoKB and guidance established by Japanese Society of Medical Oncology, Japan Society of Clinical Oncology, and Japanese Cancer Association. We detected actionable variants in 122 cases. Treatment was proposed in 63 cases, and 12 cases (7.6%) received genome-guided therapy (lung (n = 4), gastric (n = 3), ovarian (n = 2)), comparable to that achieved with panel testing.We compared the analytical performance of genome sequencing with panel tests widely used in Japan: FoundationOne (n = 23), NCC Oncopanel (n = 23), and TruSight Oncology 500 (n = 24). Genome sequencing detected most somatic SNVs and indels identified by these panels, with higher concordance observed when matched normal-tumor DNA samples were used.Genome sequencing detected 48 distinct driver SVs across 86 cases of 16 cancer types, including sarcoma (n = 45), salivary gland cancer (n = 11), and lung cancer (n = 4). Of these, 36 SVs detected in 67 cases were located outside panel target regions and included diagnostically and therapeutically relevant variants.In conclusion, genome sequencing applied to clinical cancer samples enables the detection of variants relevant to diagnosis and treatment, comparable to that of panel testing, while identifying pathogenic SVs beyond panel coverage.
利益披露 Disclosure
N. Tanaka, None..
O. Gotoh, None..
I. Fukada, None..
A. Ueki, None..
T. Ueno, None..
S. Takahashi, None..
S. Mori, None..
T. Noda, None.