Two Distinct Categories of Focal Deletions in Cancer Genomes

One of the key questions about genomic alterations in cancer is whether they are functional in the sense of contributing to the selective advantage of tumor cells. The frequency with which an alteration occurs might reflect its ability to increase cancer cell growth, or alternatively, enhanced instability of a locus may increase the frequency with which it is found to be aberrant in tumors, regardless of oncogenic impact. Here we’ve addressed this on a genome-wide scale for cancer-associated focal deletions, which are known to pinpoint both tumor suppressor genes (tumor suppressors) and unstable loci. Based on DNA copy number analysis of over one-thousand human cancers representing ten different tumor types, we observed five loci with focal deletion frequencies above 5%, including the A2BP1 gene at 16p13.3 and the MACROD2 gene at 20p12.1. However, neither RNA expression nor functional studies support a tumor suppressor role for either gene. Further analyses suggest instead that these are sites of increased genomic instability and that they resemble common fragile sites (CFS). Genome-wide analysis revealed properties of CFS-like recurrent deletions that distinguish them from deletions affecting tumor suppressor genes, including their isolation at specific loci away from other genomic deletion sites, a considerably smaller deletion size, and dispersal throughout the affected locus rather than assembly at a common site of overlap. Additionally, CFS-like deletions have less impact on gene expression and are enriched in cell lines compared to primary tumors. We show that loci affected by CFS-like deletions are often distinct from known common fragile sites. Indeed, we find that each tumor tissue type has its own spectrum of CFS-like deletions, and that colon cancers have many more CFS-like deletions than other tumor types. We present simple rules that can pinpoint focal deletions that are not CFS-like and more likely to affect functional tumor suppressors.癌症基因组改变（genomic alterations）领域的核心议题之一，在于此类改变是否具备功能活性——即是否能够赋予肿瘤细胞增殖选择优势。某一基因组改变的发生频率，既可能反映其促进癌细胞增殖的能力；也可能源于某基因座（locus）本身的不稳定性升高，使其在肿瘤中被检出为异常的概率增加，而与其致癌效应无关。 本研究针对癌症相关局灶性缺失（focal deletions）开展了全基因组尺度的分析，以此解答上述核心议题。这类缺失已被证实可精准定位肿瘤抑制基因（tumor suppressor genes）与不稳定基因座（locus，复数为loci）。本研究基于涵盖10种不同肿瘤类型的逾1000例人类癌症的DNA拷贝数分析数据，共发现5个局灶性缺失频率超过5%的基因座，其中包括位于16p13.3区域的A2BP1基因，以及位于20p12.1区域的MACROD2基因。 然而，RNA表达与功能实验均未证实这两个基因具备抑癌功能。进一步分析表明，这些基因座实为基因组不稳定性升高的区域，且与常见脆性位点（common fragile sites, CFS）特征相似。全基因组分析揭示了CFS样复发性缺失的特有属性，使其可与靶向肿瘤抑制基因的缺失相区分：这类缺失仅局限于特定基因座，与其他基因组缺失区域互不重叠；缺失片段尺寸显著更小；且在受影响的基因座内呈弥散分布，而非聚集于共同的重叠区域。 此外，CFS样缺失对基因表达的影响较弱，且相较于原发性肿瘤（primary tumors），这类缺失在细胞系中更为富集。本研究证实，受CFS样缺失影响的基因座，通常与已报道的常见脆性位点并不重合。进一步而言，不同肿瘤组织类型各自拥有独特的CFS样缺失谱，且结直肠癌的CFS样缺失数量远多于其他肿瘤类型。本研究提出了一套简便的判定规则，可用于精准识别非CFS样的局灶性缺失——这类缺失更有可能靶向功能性抑癌基因。