Zhao Karena, Vos Joris, Lam Stanley, Boe Lillian A, Muldoon Daniel, Han Catherine Y, Valero Cristina, Lee Mark, Fitzgerald Conall, Lee Andrew S, Prasad Manu, Jain Swati, Deng Xinzhu, Chan Timothy A, Berger Michael F, Bandlamudi Chaitanya, Zhou Xi Kathy, Morris Luc G T
Department of Surgery, Laboratory of Experimental Cancer Immunogenomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Genet. 2025 Jun 2. doi: 10.1038/s41588-025-02204-3.
To understand genetic evolution in cancer during metastasis, we analyzed genomic profiles of 3,732 cancer patients in whom several tumor sites were longitudinally biopsied. During distant metastasis, tumors were observed to accumulate copy number alterations (CNAs) to a much greater degree than mutations. In particular, the development of whole genome duplication was a common event during metastasis, emerging de novo in 28% of patients. Loss of 9p (including CDKN2A) developed during metastasis in 11% of patients. To a lesser degree, mutations and allelic loss in human leukocyte antigen class I and other genes associated with antigen presentation also emerged. Increasing CNA, but not increasing mutational load, was associated with immune evasion in patients treated with immunotherapy. Taken together, these data suggest that CNA, rather than mutational accumulation, is enriched during cancer metastasis, perhaps due to a more favorable balance of enhanced cellular fitness versus immunogenicity.
为了解癌症转移过程中的基因进化，我们分析了3732例癌症患者的基因组图谱，这些患者的多个肿瘤部位接受了纵向活检。在远处转移过程中，观察到肿瘤积累拷贝数改变（CNA）的程度远大于突变。特别是，全基因组复制的发生是转移过程中的常见事件，在28%的患者中从头出现。9p（包括CDKN2A）缺失在11%的患者转移过程中出现。在较小程度上，人类白细胞抗原I类和其他与抗原呈递相关基因的突变和等位基因缺失也会出现。接受免疫治疗的患者中，CNA增加而非突变负荷增加与免疫逃逸相关。综上所述，这些数据表明，在癌症转移过程中CNA而非突变积累更为丰富，这可能是由于增强的细胞适应性与免疫原性之间更有利的平衡所致。
