PO.MD01.02 · 分子诊断与数据
AACR Project GENIE 中 101,240 例肿瘤样本的同源重组修复（HRR）基因改变的泛癌富集：对肿瘤不可知性 PARP 抑制剂扩展应用的意义
Pan cancer enrichment of homologous recombination repair (HRR) gene alterations in 101,240 tumor samples from AACR Project GENIE: Implications for tumor-agnostic PARP inhibitor expansion
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：PARP 抑制剂仅限于一部分 BRCA 相关癌症，但同源重组修复（HRR）缺陷标志着一种更广泛的基因组脆弱性，可能将治疗机会扩展到多种多样的恶性肿瘤。我们利用 AACR Project GENIE v18.0-public 来界定 HRR 基因改变的泛癌患病率。
方法：分析了来自 GENIE v18.0-public 的体细胞突变和临床样本数据。HRR 基因包括 BRCA1、BRCA2、ATM、CHEK2、PALB2、RAD51B/C/D、RAD51L1、BARD1、BRIP1 和核心 FANC 基因。使用独立样本按肿瘤类型计算 HRR 改变率；仅报告去标识化的汇总结果。
结果：在 101,240 例肿瘤中，HRR 基因改变在多种非 BRCA 相关癌症中频繁出现。最高的比率见于唾液腺母细胞瘤（100%）、大细胞髓母细胞瘤（50%）、恶性血管球瘤（50%）、肺癌（46.0%）、婴儿型纤维肉瘤（42.9%）、肝癌（40%）、肾癌（40%）、非黑色素瘤皮肤癌（36.9%）、结直肠癌（36.6%）、黑色素细胞瘤（34.2%）、胆道癌（33.3%）、膀胱癌（31.5%）和卵巢/输卵管癌（30.2%）。值得注意的是，肺癌、膀胱癌、肝胆癌、肾癌、胃肠癌和某些肉瘤亚型显示出等于或高于当前 PARP 适应证的 HRR 突变患病率，但尚未获得 FDA 批准。
结论：HRR 改变在实体瘤中广泛存在，往往超过符合 PARP 治疗条件的癌症中的比率。这些发现支持将肿瘤不可知性 HRR 基因组检测扩展到 BRCA 相关恶性肿瘤之外，并支持在 HRR 富集的肿瘤类型（如肺癌、膀胱癌、肝胆癌、肾癌、胃肠癌和儿科/罕见癌症）中前瞻性地开展 PARP 抑制剂试验。影响：来自 AACR Project GENIE 的大规模基因组谱分析表明，HRR 基因改变在多种多样的实体瘤中很常见，多种癌症类型的患病率超过了当前符合 PARP 抑制剂治疗条件的类型。这些发现支持在常规分子诊断中广泛实施 HRR 基因组检测，并为将 PARP 抑制剂的使用扩展到 BRCA 相关恶性肿瘤之外提供了理论依据。这些数据为在 HRR 富集的癌症（如肺癌、膀胱癌、肝胆癌、肾癌、胃肠癌以及部分儿科和罕见肿瘤）中前瞻性地开展肿瘤不可知性 PARP 抑制剂临床试验提供了正当理由；这可能会变革治疗决策并加速基于合成致死的靶向疗法的开发。
引用：AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831
致谢：AACR 和 Project GENIE
查看英文原文 English abstract
Background: PARP inhibitors are restricted to a subset of BRCA-associated cancers, but homologous recombination repair (HRR) deficiency signifies a broader genomic vulnerability that may extend therapeutic opportunities across diverse malignancies. We utilized AACR Project GENIE v18.0-public to define the pan-cancer prevalence of HRR gene alterations.
Methods: Somatic mutation and clinical sample data from GENIE v18.0-public were analyzed. HRR genes included BRCA1, BRCA2, ATM, CHEK2, PALB2, RAD51B/C/D, RAD51L1, BARD1, BRIP1, and core FANC genes. HRR alteration rates were calculated by tumor type using unique samples; only de-identified aggregate results are reported.
Results: Among 101,240 tumors, HRR gene alterations were frequent in multiple non-BRCA-associated cancers. Highest rates were seen in sialoblastoma (100%), large cell medulloblastoma (50%), malignant glomus tumor (50%), lung cancer (46.0%), infantile fibrosarcoma (42.9%), liver (40%), kidney (40%), non-melanoma skin (36.9%), colorectal (36.6%), melanocytoma (34.2%), biliary tract (33.3%), bladder (31.5%), and ovarian/fallopian tube (30.2%). Notably, lung, bladder, hepatobiliary, renal, gastrointestinal, and some sarcoma subtypes showed HRR mutation prevalence equal or higher than current PARP indications, yet lack FDA approval.
Conclusions:HRR alterations are widespread across solid tumors, often surpassing rates in cancers eligible for PARP treatment. These findings support expanding tumor-agnostic HRR genomic testing beyond BRCA-linked malignancies and warrant prospective trials of PARP inhibitors in HRR-enriched tumor types such as lung, bladder, hepatobiliary, renal, gastrointestinal, and pediatric/rare cancers. Impact: Large-scale genomic profiling from AACR Project GENIE demonstrates that HRR gene alterations are common across diverse solid tumors, with prevalence in multiple cancer types surpassing those currently eligible for PARP inhibitor therapy. These findings support broad implementation of HRR genomic testing in routine molecular diagnostics and provide a rationale for expanding PARP inhibitor use beyond BRCA-associated malignancies. The data justify prospective tumor-agnostic clinical trials of PARP inhibitors in HRR-enriched cancers such as lung, bladder, hepatobiliary, renal, gastrointestinal, and select pediatric and rare tumors; this could transform therapeutic decision-making and accelerate development of synthetic lethality-based targeted therapies
Citation: AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831
Acknowledgement: AACR and Project GENIE
利益披露 Disclosure
A. Abdelhakeem, None..
N. Ganatra, None..
D. Elantably, None..
T. Adeoye, None..
N. H. Abdel-Razeq, None..
O. M. Mosalem, None.