Wang Meng, Fukushima Satoshi, Sheen Yi-Shuan, Ramelyte Egle, Pacheco Noel Cruz, Shi Chenxu, Liu Shanshan, Banik Ishani, Aquino Jamie D, Acosta Martin Sangueza, Levesque Mitchell, Dummer Reinhard, Liau Jau-Yu, Chu Chia-Yu, Shain A Hunter, Yeh Iwei, Bastian Boris C
Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
bioRxiv. 2023 Oct 19:2023.10.18.562802. doi: 10.1101/2023.10.18.562802.
Acral melanoma is an aggressive type of melanoma with unknown origins, arising on the sole, palm, or nail apparatus. It is the most common type of melanoma in individuals with dark skin and is notoriously challenging to treat. Our study examined exome sequencing data from 139 tissue samples, spanning different progression stages, collected from 37 patients. We found that 78.4% of the melanomas displayed one or more clustered copy number transitions with focal amplifications, recurring predominantly on chromosomes 5, 11, 12, and 22. These genomic "hailstorms" were typically shared across all progression stages within individual patients. Genetic alterations known to activate also arose early. By contrast, mutations in the MAP-kinase pathway appeared later during progression, often leading to different tumor areas harboring non-overlapping driver mutations. We conclude that the evolutionary trajectories of acral melanomas substantially diverge from those of melanomas on sun-exposed skin, where MAP-kinase pathway activation initiates the neoplastic cascade followed by immortalization later. The punctuated formation of hailstorms, paired with early activation, suggests a unique mutational mechanism underlying the origins of acral melanoma. Our findings highlight an essential role for telomerase, likely in re-stabilizing tumor genomes after hailstorms have initiated the tumors. The marked genetic heterogeneity, in particular of MAP-kinase pathway drivers, may partly explain the limited success of targeted and other therapies in treating this melanoma subtype.
肢端黑色素瘤是一种起源不明的侵袭性黑色素瘤，发生于足底、手掌或甲器。它是深色皮肤个体中最常见的黑色素瘤类型，治疗极具挑战性。我们的研究检查了来自37例患者的139个组织样本的外显子组测序数据，这些样本跨越不同进展阶段。我们发现78.4%的黑色素瘤显示出一个或多个伴有局灶性扩增的聚集性拷贝数转变，主要发生在5号、11号、12号和22号染色体上。这些基因组“雹暴”通常在个体患者的所有进展阶段中都存在。已知激活的基因改变也出现得较早。相比之下，MAP激酶途径中的突变在进展过程中出现较晚，常常导致不同肿瘤区域存在不重叠的驱动突变。我们得出结论，肢端黑色素瘤的进化轨迹与暴露于阳光下皮肤的黑色素瘤有很大不同，在后者中，MAP激酶途径激活启动肿瘤形成级联反应，随后是永生化。雹暴的间断形成，加上早期的激活，提示肢端黑色素瘤起源存在独特的突变机制。我们的发现突出了端粒酶的重要作用，可能是在雹暴引发肿瘤后重新稳定肿瘤基因组。明显的基因异质性，特别是MAP激酶途径驱动基因的异质性，可能部分解释了靶向治疗和其他疗法在治疗这种黑色素瘤亚型方面效果有限的原因。
