加拿大英属哥伦比亚大学Samuel Aparicio等研究人员合作揭示癌症中突变过程引起的单细胞基因组变异。相关论文于2022年10月26日在线发表于国际学术期刊《自然》。

通过对野生型、TP53缺陷和TP53缺陷；BRCA1缺陷或TP53缺陷；BRCA2缺陷的乳腺上皮细胞（13818个基因组），以及原发性三阴性乳腺癌（TNBC）和高级别浆液性卵巢癌（HGSC）细胞（22057个基因组）进行按比例的单细胞全基因组测序，研究人员确定了由细胞间结构变化定义的三种不同的“前景”突变模式。细胞和克隆特异性高级别扩增、平行单倍型特异性拷贝数改变和拷贝数片段长度变化（锯齿状结构变异）具有可衡量的表型和演化后果。在TNBC和HGSC中，相对于有同源重组缺陷的肿瘤，已知致癌基因的克隆特异性高级别扩增在有折返倒置的肿瘤中非常普遍，并与克隆间的表型变异增加有关。

平行的单倍型特异性改变也经常被观察到，导致系统演化的多样性和克隆特异性的单等位表达。锯齿状变体在有向后者的倒置的肿瘤中增加，并与细胞群的基因组多样性增加高度相关。总之，这些发现表明，细胞间的结构变异有助于TNBC和HGSC的表型和演化多样性的起源，并提供了对单个癌症细胞的基因组和突变状态的洞察。

据介绍，人类癌症中支撑基因组不稳定性的细胞间拷贝数改变如何驱动基因组和表型变异，并因此导致癌症的演化，仍未得到充分研究。

附：英文原文

Title: Single-cell genomic variation induced by mutational processes in cancer

Author: Funnell, Tyler, OFlanagan, Ciara H., Williams, Marc J., McPherson, Andrew, McKinney, Steven, Kabeer, Farhia, Lee, Hakwoo, Salehi, Sohrab, Vzquez-Garca, Ignacio, Shi, Hongyu, Leventhal, Emily, Masud, Tehmina, Eirew, Peter, Yap, Damian, Zhang, Allen W., Lim, Jamie L. P., Wang, Beixi, Brimhall, Jazmine, Biele, Justina, Ting, Jerome, Au, Vinci, Van Vliet, Michael, Liu, Yi Fei, Beatty, Sean, Lai, Daniel, Pham, Jenifer, Grewal, Diljot, Abrams, Douglas, Havasov, Eliyahu, Leung, Samantha, Bojilova, Viktoria, Moore, Richard A., Rusk, Nicole, Uhlitz, Florian, Ceglia, Nicholas, Weiner, Adam C., Zaikova, Elena, Douglas, J. Maxwell, Zamarin, Dmitriy, Weigelt, Britta, Kim, Sarah H., Da Cruz Paula, Arnaud, Reis-Filho, Jorge S., Martin, Spencer D., Li, Yangguang, Xu, Hong, de Algara, Teresa Ruiz, Lee, So Ra, Llanos, Viviana Cerda, Huntsman, David G., McAlpine, Jessica N., Shah, Sohrab P., Aparicio, Samuel

Issue&Volume: 2022-10-26

Abstract: How cell-to-cell copy number alterations that underpin genomic instability1 in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer2, remains understudied. Here, by applying scaled single-cell whole-genome sequencing3 to wild-type, TP53-deficient and TP53-deficient;BRCA1-deficient or TP53-deficient;BRCA2-deficient mammary epithelial cells (13,818 genomes), and to primary triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSC) cells (22,057 genomes), we identify three distinct ‘foreground’ mutational patterns that are defined by cell-to-cell structural variation. Cell- and clone-specific high-level amplifications, parallel haplotype-specific copy number alterations and copy number segment length variation (serrate structural variations) had measurable phenotypic and evolutionary consequences. In TNBC and HGSC, clone-specific high-level amplifications in known oncogenes were highly prevalent in tumours bearing fold-back inversions, relative to tumours with homologous recombination deficiency, and were associated with increased clone-to-clone phenotypic variation. Parallel haplotype-specific alterations were also commonly observed, leading to phylogenetic evolutionary diversity and clone-specific mono-allelic expression. Serrate variants were increased in tumours with fold-back inversions and were highly correlated with increased genomic diversity of cellular populations. Together, our findings show that cell-to-cell structural variation contributes to the origins of phenotypic and evolutionary diversity in TNBC and HGSC, and provide insight into the genomic and mutational states of individual cancer cells.

DOI: 10.1038/s41586-022-05249-0

Source: https://www.nature.com/articles/s41586-022-05249-0