Somatic Copy Number Alterations in Human Cancers: An Analysis of Publicly Available Data From The Cancer Genome Atlas

Abstract

Somatic copy number alterations (SCNAs) are a pervasive trait of human cancers that contributes to tumorigenesis by affecting the dosage of multiple genes at the same time. In the past decade, The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) initiatives have generated and made publicly available SCNA genomic profiles from thousands of tumor samples across multiple cancer types. Here, we present a comprehensive analysis of 853,218 SCNAs across 10,729 tumor samples belonging to 32 cancer types using TCGA data. We then discuss current models for how SCNAs likely arise during carcinogenesis and how genomic SCNA profiles can inform clinical practice. Lastly, we highlight open questions in the field of cancer-associated SCNAs.

Keywords: 3D genome; TCGA; cancer; copy number alterations; cosmic genes.

Figure 1

Prevalence of SCNAs across different tumor types. (A) Percentage of arm-level aneuploidies, indels and SCNAs by tumor type. (B) Number of SCNAs by tumor type, separately for amplifications (AMP) and deletions (DEL). Each dot represents one tumor sample. Black horizontal bars: mean values. (C) Same as in (B) but considering the percentage of the reference genome either amplified or deleted in each tumor. n, number of samples analyzed for each tumor type. In (B, C), asterisks indicate statistical significance levels (Wilcoxon’s test, two-sided) at 0.05 (*), 0.01 (**), 0.001 (***) and 0.0001 (****). ns, not statistically significant. See Supplementary Table 4 for the list of tumor type abbreviations used.

Figure 2

Length and proportion of SCNAs across chromosomes. (A) Length of SCNAs by tumor type, separately for amplifications (AMP) and deletions (DEL). Each dot represents the average alteration length in one tumor sample. Black horizontal bars: mean values. Asterisks indicate statistical significance levels (Wilcoxon’s test, two-sided) at 0.05 (*), 0.01 (**), 0.001 (***) and 0.0001 (****). ns, not statistically significant. (B) Proportion of SCNAs in each chromosome normalized by chromosome length for each of the 32 tumor types analyzed. The normalization was done as following: (# of SCNAs in a chromosome)/(tot # of SCNAs) * (chromosome length in Mb). See Supplementary Table 4 for the list of tumor type abbreviations used.

Figure 3

COSMIC genes most frequently affected by SCNAs. (A) Percentage of all tumor types in which the 25 most frequently amplified (red) and deleted (blue) COSMIC genes are altered. (B) Percentage of tumors in which each COSMIC gene shown in (A) is altered in each of the 32 tumor types analyzed. (C) Frequency of COSMIC gene pairs that are either co-amplified (red) or co-deleted (blue) in at least 5% of all the 10,729 tumors analyzed. Intra-chromosomal pairs, which are the majority, are masked (grey squares) to make the inter-chromosomal pairs visible. The full list of inter-chromosomal pairs (including AMP-DEL events) sorted by tumor type is available in Supplementary Table 2.