Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
Department of Internal Medicine and the UNM Comprehensive Cancer Center, Albuquerque, NM.
JCO Precis Oncol. 2023 Mar;7:e2200439. doi: 10.1200/PO.22.00439.
Genomic classification of melanoma has thus far focused on the mutational status of , , and . The clinical utility of this classification remains limited, and the landscape of alterations in other oncogenic signaling pathways is underexplored.
Using primary samples from the InterMEL study, a retrospective cohort of cases with specimens collected from an international consortium with participating institutions throughout the United States and Australia, with oversampling of cases who ultimately died of melanoma, we examined mutual exclusivity and co-occurrence of genomic alterations in 495 stage II/III primary melanomas across 11 cancer pathways. Somatic mutation and copy number alterations were analyzed from next-generation sequencing using a clinical sequencing panel.
Mutations in the RTK-RAS pathway were observed in 81% of cases. Other frequently occurring pathways were TP53 (31%), Cell Cycle (30%), and PI3K (18%). These frequencies are generally lower than was observed in The Cancer Genome Atlas, where the specimens analyzed were predominantly obtained from metastases. Overall, 81% of the cases had at least one targetable mutation. The RTK-RAS pathway was the only pathway that demonstrated strong and statistically significant mutual exclusivity. However, this strong mutual exclusivity signal was evident only for the three common genes in the pathway (, , and ). Analysis of co-occurrence of different pathways exhibited no positive significant trends. However, interestingly, a high frequency of cases with none of these pathways represented was observed, 8.4% of cases versus 4.0% expected ( < .001). A higher frequency of RTK-RAS singletons (with no other pathway alteration) was observed compared with The Cancer Genome Atlas. Clonality analyses suggest strongly that both the cell cycle and RTK-RAS pathways represent early events in melanogenesis.
Our results confirm the dominance of mutations in the RTK-RAS pathway. The presence of many mutations in several well-known, actionable pathways suggests potential avenues for targeted therapy in these early-stage cases.
迄今为止，黑色素瘤的基因组分类一直集中在 、 、 和 的突变状态上。这种分类的临床实用性仍然有限，其他致癌信号通路改变的情况仍未得到充分探索。
利用来自 InterMEL 研究的原发性样本，这是一个回顾性队列病例，标本来自一个国际联盟，参与机构遍布美国和澳大利亚，对最终死于黑色素瘤的病例进行了过度抽样。我们检查了 495 例 II/III 期原发性黑色素瘤中 11 条致癌途径中基因组改变的互斥性和共存性。使用临床测序面板从下一代测序中分析体细胞突变和拷贝数改变。
在 81%的病例中观察到 RTK-RAS 通路的突变。其他经常发生的途径是 TP53（31%）、细胞周期（30%）和 PI3K（18%）。这些频率通常低于在癌症基因组图谱中观察到的频率，在癌症基因组图谱中，分析的标本主要来自转移。总的来说，81%的病例至少有一种可靶向的突变。RTK-RAS 途径是唯一显示出强烈且具有统计学意义的互斥性的途径。然而，这种强烈的互斥性信号仅在该途径的三个常见基因（ 、 和 ）中明显。对不同途径的共存性分析没有显示出明显的阳性趋势。然而，有趣的是，观察到大量没有这些途径的病例，占 8.4%，而预期为 4.0%（ <.001）。与癌症基因组图谱相比，观察到 RTK-RAS 单例（无其他途径改变）的频率较高。克隆性分析强烈表明，细胞周期和 RTK-RAS 途径都代表了黑色素生成中的早期事件。
我们的结果证实了 RTK-RAS 途径突变的主导地位。在几个众所周知的、可靶向的途径中存在许多突变，这表明在这些早期病例中可能有靶向治疗的途径。
