PO.MCB08.01 · 分子与细胞生物学

从癌症基因组图谱（TCGA）全基因组数据集中发掘具有治疗靶向性的突变

Uncovering therapeutically targetable mutations from The Cancer Genome Atlas (TCGA) whole-genome datasets

编号 492 展板 4 时间 4/19 02:00–05:00 区域 Section 20 主讲 Ryul Kim, MD;PhD

分会场 Genomic Dissection to Define Novel Therapeutic Strategies

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作者与单位 Authors & Affiliations

Ryul Kim¹, Chunyang Bao¹, Hansol Park¹, Gang-Hee Lee¹, Won-Chul Lee¹, Jonghoon Lee¹, Yoonsuh Lee¹, Beomki Lee², David Lehotzky³, Ron Solan³, Antonia Kowalewski³, Xavi Loinaz³, Vasuki Narasimha Swamy³, David I. Heiman³, Samantha Van Seters³, Saveliy Belkin³, Sam Wiseman³, Andrew D. Cherniack³, Luis Antonio Corchete Sanchez³, Brian P Danysh³, Zachary Everton³, Chip Stewart³, Haruna Tomono³, Gengchao Wang³, Esther Rheinbay³, Gad Getz³, Young Seok Ju¹

¹Inocras, San Diego, CA,²Korea Advanced Institute of Science and Technology, Daejeon, Korea, Republic of,³Broad Institute of MIT and Harvard, Cambridge, MA

摘要 Abstract

中文摘要

系统性地识别跨肿瘤类型的具有治疗可操作性的基因组改变，对于推进精准肿瘤学至关重要。我们使用CancerVision™全基因组分析平台，分析了涵盖30余种癌症类型的超过8,000个全基因组测序（WGS）样本，以刻画临床可操作突变。可操作性根据Cancer Knowledgebase证据等级定义，其中A级表示与FDA批准的说明书内疗法相关的生物标志物。总体而言，2903名患者（约32%）携带至少一个A级可操作改变，共涵盖约20,100个事件（每个样本中位数为2个）。在超过半数的THCA（甲状腺癌）、KIRC（肾透明细胞癌）、SKCM（皮肤黑色素瘤）、BRCA（乳腺癌）和COAD（结肠腺癌）中检测到A级说明书内靶点，突显了其临床相关性。最常见的十个A级靶点为PIK3CA、KRAS、BRAF、VHL、PTEN、ERBB2、BRCA1/2、NRAS和EGFR，在不同癌症类型中呈现不同频率。在KRAS改变中，p.G12C是主要的可操作热点，主要见于肺腺癌，少数见于结直肠癌和直肠癌。整个队列共识别出950个融合靶点。BRCA的频率最高（45例；2.5%），包括40个ESR1-CCDC170融合，其次为THCA（55例；9.7%），以CCDC6-RET为主（25例）。在145个样本（1.7%）中发现NRG1融合，显著高于历史上的泛癌频率（约0.2%）。其他复发性可靶向融合包括NTRK（0.7%；60个样本）、RET（0.7%）、ALK（0.7%）、BRAF（0.6%）和FGFR（2.5%；210个样本），后者主要涉及FGFR2（约180例）。在所有融合类别中，超过80%保留了激酶结构域，支持其致癌潜力。与临床试验匹配的靶点最常见的是TP53、PIK3CA和CDKN2A，反映了它们在精准医学研究中的广泛纳入。这项全面的泛癌分析定义了迄今为止最广泛的基于WGS的可操作突变和可成药融合的图景。全基因组方法能够高分辨率地检测到靶向测序panel常常遗漏的罕见结构变异，突显了全基因组分析在发掘具有治疗相关性但未被充分认识的靶点方面的潜力，支持将WGS纳入未来的泛肿瘤（tumor-agnostic）临床试验设计。

查看英文原文 English abstract

The systematic identification of therapeutically actionable genomic alterations across tumor types is essential to advance precision oncology. Using the CancerVision TM whole-genome analysis platform, we analyzed >8,000 whole-genome sequencing (WGS) samples spanning more than 30 cancer types to characterize clinically actionable mutations. Actionability was defined according to the Cancer Knowledgebase evidence levels, where Level A denotes biomarkers linked to FDA-approved on-label therapies. Overall, 2903 patients (~32%) harbored at least one Level A actionable alteration encompassing ~20,100 events (median 2 per sample). Level A on-label targets were detected in more than half of THCA (thyroid cancer), KIRC (kidney clear-cell), SKCM (skin cutaneous melanoma), BRCA (breast cancer), and COAD (colon adenocarcinoma), underscoring their clinical relevance. The ten most frequent Level A targets were PIK3CA, KRAS, BRAF, VHL, PTEN, ERBB2, BRCA1/2, NRAS, and EGFR , showing variable frequencies among cancer types. Among KRAS alterations, p.G12C was the predominant actionable hotspot, mainly in lung adenocarcinoma with a few cases in colorectal and rectal cancers. A total of 950 fusion targets were identified across the cohort. BRCA exhibited the highest frequency (45 cases; 2.5%), including 40 ESR1-CCDC170 fusions, followed by THCA (55 cases; 9.7%), dominated by CCDC6-RET (25 cases). NRG1 fusions were found in 145 samples (1.7%), markedly higher than the historical pan-cancer frequency (~0.2%). Other recurrent targetable fusions included NTRK (0.7%; 60 samples), RET (0.7%), ALK (0.7%), BRAF (0.6%), and FGFR (2.5%; 210 samples), the latter largely involving FGFR2 (~180 cases). Across all fusion classes, >80% retained the kinase domain, supporting oncogenic potential. Clinical-trial-matched targets were most commonly TP53, PIK3CA , and CDKN2A , reflecting their broad inclusion in precision-medicine studies. This comprehensive pan-cancer analysis defines the most extensive WGS-based landscape to date of actionable mutations and druggable fusions. The whole-genome approach enabled high-resolution detection of rare structural variants that are often missed by targeted sequencing panels, highlighting the potential of whole-genome profiling to uncover therapeutically relevant but under-recognized targets, supporting the integration of WGS into future tumor-agnostic clinical trial design.

利益披露 Disclosure

R. Kim, None.. C. Bao, None.. H. Park, None.. G. Lee, None.. W. Lee, None.. J. Lee, None.. Y. Lee, None.. B. Lee, None.. D. Lehotzky, None.. R. Solan, None.. A. Kowalewski, None.. X. Loinaz, None.. V. Narasimha Swamy, None.. D. I. Heiman, None.. S. Van Seters, None.. S. Belkin, None.. S. Wiseman, None. A. D. Cherniack, Bayer ). L. Corchete Sanchez, None.. B. Danysh, None.. Z. Everton, None.. C. Stewart, None.. H. Tomono, None.. G. Wang, None. E. Rheinbay, Inocras ), E.R. receives research funding from Inocras, Inc. G. Getz, IBM ). Pharmacyclics/Abbvie ). Bayer ). Genentech ). Calico ). Ultima Genomics ). Inocras ). Google ). Kite ). Novartis ). Scorpion Therapeutics Stock Option, He is a founder, consultant, and holds privately held equity in Scorpion Therapeutics. Predicta Biosciences Stock Option, he is also a founder of, and holds privately held equity in, Predicta Biosciences. Antares Therapeutics Stock Option. Y. Ju, None.

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