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.

为了了解癌症转移过程中的遗传进化，我们分析了 3,732 名癌症患者的基因组图谱，其中几个肿瘤部位进行了纵向活检。在远处转移期间，观察到肿瘤积累拷贝数改变 （CNA） 的程度远大于突变。特别是，全基因组复制的发展是转移过程中的常见事件，在 28% 的患者中新发出现。11% 的患者在转移期间出现 9p （包括 CDKN2A） 丢失。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的基因也出现了突变和等位基因丢失。增加 CNA 但不增加突变载量与免疫治疗患者的免疫逃避相关。综上所述，这些数据表明，在癌症转移过程中，CNA 而不是突变积累富集，这可能是由于增强的细胞适应性与免疫原性之间取得了更有利的平衡。