泛癌种的基因组突变

不同癌症基因突变的情况各不相同

不同类型癌症中，基因组发生突变的比例差异很大^[1-7]；比如，Martincorena等的研究^[1]表明：AML中每兆碱基的突变数最低，而Melanoma每兆碱基的突变数最高。

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这些突变的类型包括基因组的改变和表观遗传的改变^[7]。

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基因组的突变类型包括碱基替换、插入缺失等^[5]。

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基因组的突变类型也包括体细胞拷贝数变异^[8]。

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突变的分类

Some somatic mutational processes generate multiple mutations in a single catastrophic event, typically clustered in genomic space, leading to substantial reconfiguration of the genome. Three such processes have previously been described: (1) chromoplexy, in which repair of co-occurring double-stranded DNA breaks—typically on different chromosomes—results in shuffled chains of rearrangements47,48 (Extended Data Fig. 5a); (2) kataegis, a focal hypermutation process that leads to locally clustered nucleotide substitutions, biased towards a single DNA strand49–51 (Extended Data Fig. 5b); and (3) chromothripsis, in which tens to hundreds of DNA breaks occur simultaneously, clustered on one or a few chromosomes, with near-random stitching together of the resulting fragments52–55 (Extended Data Fig. 5c). We characterized the PCAWG genomes for these three processes (Fig. 4).

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显著突变的基因^[3]

Genes under positive selection, either in individual or multiple tumour types, tend to display higher mutation frequencies above background.These SMGs are involved in a wide range of cellular processes, broadly classified into 20 categories (Fig. 2), including transcription factors/regulators, histone modifiers, genome integrity, receptor tyrosine kinase signalling, cell cycle, mitogen-activated protein kinases (MAPK) signalling, phosphatidylinositol-3-OH kinase (PI(3)K) signalling, Wnt/b-catenin signalling,histones, ubiquitin-mediated proteolysis, and splicing(Fig. 2). The identification of MAPK, PI(3)K andWnt/b-catenin signalling pathways is consistent with classical cancer studies.Notably, newer categories (for example, splicing, transcription regulators, metabolism, proteolysis and histones) emerge as exciting guides for the development of new therapeutic targets.

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驱动突变全景^[8]

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Timing clustered mutations in evolution

An unanswered question for clustered mutational processes is whether they occur early or late in cancer evolution. To address this, we used molecular clocks to define broad epochs in the life history of each tumour. One transition point is between clonal and subclonal mutations: clonal mutations occurred before, and subclonal mutations after, the emergence of the most-recent common ancestor.

In regions with copy-number gains, molecular time can be further divided according to whether mutations preceded the copy-number gain (and were themselves duplicated) or occurred after the gain (and therefore present on only one chromosomal copy).

Chromothripsis tended to have greater relative odds of being clonal than subclonal, suggesting that it occurs early in cancer evolution, especially in liposarcomas, prostate adenocarcinoma and squamous cell lung cancer (Fig. 5a).

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Driver mutations and tumour clonal architecture

To understand the temporal order of somatic events, we analysed the variant allele fraction (VAF) distribution of mutations in SMGs across AML, BRCA and UCEC.

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参考资料

1. Martincorena I, Campbell PJ: Somatic mutation in cancer and normal cells. Science 2015, 349(6255):1483-1489.

2. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C et al: Patterns of somatic mutation in human cancer genomes. Nature 2007, 446(7132):153-158.

3. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA et al: Mutational landscape and significance across 12 major cancer types. Nature 2013, 502(7471):333-339.

4. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW: Cancer Genome Landscapes. Science 2013, 339(6127):1546-1558.

5. Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Tian Ng AW, Wu Y, Boot A, Covington KR, Gordenin DA, Bergstrom EN et al: The repertoire of mutational signatures in human cancer. Nature 2020, 578(7793):94-101.

6. Consortium TITP-CAoWG: Pan-cancer analysis of whole genomes. Nature 2020, 578(7793):82-93.

7. Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C: Emerging landscape of oncogenic signatures across human cancers. Nature genetics 2013, 45(10):1127-1133.

8. Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B, Lawrence MS, Zhsng CZ, Wala J, Mermel CH et al: Pan-cancer patterns of somatic copy number alteration. Nature genetics 2013, 45(10):1134-1140.