Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
Harvard Medical School, Boston, MA.
JCO Precis Oncol. 2023 Sep;7:e2300295. doi: 10.1200/PO.23.00295.
rearrangements and activating point mutations represent targetable genomic alterations in advanced solid tumors. However, the frequency and clinicopathologic characteristics of wild-type amplification in cancer and its potential role as a targetable oncogenic driver are not well-characterized.
In two institutional cohorts of patients with solid cancers from the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC) whose tumors underwent next-generation sequencing (NGS), the frequency and clinicopathologic features of wild-type amplification in the absence of rearrangements or activating mutations was assessed. The findings were validated using merged data from The Cancer Genome Atlas (TCGA), Genomics Evidence Neoplasia Information Exchange (GENIE), and China Pan-Cancer data sets.
The frequency of wild-type amplification across all solid cancers was 0.08% (26 of 32,505) in the DFCI cohort, 0.05% (26 of 53,152) in the MSKCC cohort, and 0.25% (71 of 28,623) in the cohort from TCGA, GENIE, and China Pan-Cancer. Cancer types with amplification included non-small-cell lung cancer (NSCLC), hepatobiliary cancer, prostate cancer, breast cancer, and others. The median copy number in -amplified cases was 7.5 (range, 6-36) in the DFCI cohort and 5.7 (range, 4-27.7) in the MSKCC cohort. Among 11 -amplified NSCLCs, eight had no other concurrent driver mutations. Finally, we report on a 69-year-old man with recurrent NSCLC harboring high-level wild-type amplification (22-28 copies) as the only identified putative genomic driver who experienced both a systemic and intracranial confirmed response to the RET inhibitor selpercatinib.
Amplification of wild-type represents a novel, targetable molecular subset of cancer.
重排和激活点突变代表晚期实体瘤中可靶向的基因组改变。然而，在癌症中野生型扩增的频率和临床病理特征及其作为可靶向致癌驱动因素的潜在作用尚未得到很好的描述。
在来自 Dana-Farber 癌症研究所 (DFCI) 和 Memorial Sloan Kettering 癌症中心 (MSKCC) 的接受下一代测序 (NGS) 的实体癌患者的两个机构队列中，评估了在没有重排或激活突变的情况下野生型扩增的频率和临床病理特征。使用来自癌症基因组图谱 (TCGA)、基因组证据肿瘤信息交换 (GENIE) 和中国泛癌数据集的合并数据验证了这些发现。
DFCI 队列中所有实体癌的野生型扩增频率为 0.08%（26/32505），MSKCC 队列中为 0.05%（26/53152），TCGA、GENIE 和中国泛癌数据集中的队列为 0.25%（28623）。扩增的癌症类型包括非小细胞肺癌 (NSCLC)、肝胆癌、前列腺癌、乳腺癌和其他癌症。在 DFCI 队列中，-扩增病例的中位拷贝数为 7.5（范围，6-36），在 MSKCC 队列中为 5.7（范围，4-27.7）。在 11 例 -扩增的 NSCLC 中，有 8 例没有其他并发驱动突变。最后，我们报告了一名 69 岁男性复发性 NSCLC 患者，携带高水平野生型扩增（22-28 个拷贝），这是唯一确定的潜在基因组驱动因素，他对 RET 抑制剂塞普替尼（selpercatinib）既有全身反应又有颅内反应。
野生型扩增代表了癌症的一个新的可靶向分子亚群。
