Genomics alterations of metastatic and primary tissues across 15 cancer types

Abstract

Metastasis is an important event for cancer evolution and prognosis. In this article, we analyzed the differences in genomic alterations between primary and metastatic tissues at hotspot regions in 15 cancer types and 10,456 samples. Differential somatic mutations at the amino acid, protein domain and gene levels, mutational exclusiveness, and copy number variations were identified in these cancers, while no significant nucleotide and gene fusion differences were detected. The homogeneity and heterogeneity of these differences in cancers were also detected. By characterizing the genomic alterations of these genes, important signaling pathways during metastasis were also identified. In summary, the metastatic cancer tissues retained most genomic features of the primary tumor at the biological level and acquired new signatures during cancer cell migration.

Figure 1

Sample distributions in categories. The distribution of cancer types (A), age, gender, race (B), and primary/metastatic tissues (C).

Figure 2

Mutational difference of primary/metastatic tissues. The differentially mutated genes in cancer types (A). The left panel indicates the mutational rate in metastatic and primary cancerous tissues; the top panel refers to the mutational frequencies of each sample in regions detected; the green barplot in the right panel represents the log2 transformed p values of mutational difference between metastatic and primary tissues; the blue barplot in the right panel indicates the mutational odds ratio of metastatic/primary mutation rates; the middle panel refers to the mutation type of each sample in each gene. The mutational difference between primary and metastatic tissue on each amino acid was shown in needle plot (B). The height represents the mutational counts in different regions and domains, the needles upward indicates the primary and needles on the other side refers to metastatic tissues. The mutational difference between primary/metastatic tissue was also shown (C). Mutational exclusive pairs in primary/metastatic tissues in each cancer type (D). The width of each bar indicates the pair number and the height indicates the proportion.

Figure 3

Copy number difference of primary/metastatic tissue. Average copy number difference between metastatic and primary tissues (A). The y-axis indicates average copy number of metastatic tissue - average copy number of primary tissue, and x-axis refers to chromosomal locations (chr1-chrY). The detailed copy number distribution of most significantly different genes in each cancer type was shown (B). Most significantly altered genes in metastatic/primary tissues across cancers. The red indicates copy number increased in metastatic tissues and blue refers to decreased.

Figure 4

Altered genes and pathways in cancers. The integrated mutation, copy number variation and gene fusion rate in primary and metastatic tissues (A). Among KEGG pathways, we noticed that MAPK signaling pathway was significantly different genes involved in CRC (B) and ERBB signaling pathway in glioma (C). The red pie plots indicate the mutation rates and greens indicate copy number alteration rates. All genes with pie plots were statistically different between primary and metastatic tissues.