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Intratumoural heterogeneity (ITH) leads to regional biases of the mutational landscape in a single tumour and may influence the single biopsy-based clinical diagnosis and treatment decision. To evaluate the extent of ITH in unifocal prostate cancers (PCAs), we analysed multiple regional biopsies from three PCAs, using whole-exome sequencing, DNA copy number and gene expression profiling analyses. A substantial level of ITH was identified, in that 0-61% and 18-71% of somatic variants were common or private, respectively, within a given cancer. The enhanced mutation detection rate in the combined sequencing dataset across intratumoural biopsies was demonstrated with respect to the total number of mutations identified in a given tumour. Allele frequencies of the mutations were positively correlated with the levels of intratumoural recurrence (private

Early gastric cancers (EGCs) precede advanced gastric cancers (AGCs), with a favourable prognosis compared to AGC. To understand the progression mechanism of EGC to AGC, it is required to disclose EGC and AGC genomes in mutational and evolutionary perspectives. We performed whole-exome sequencing and copy number profiling of nine microsatellite (MS)-unstable (MSI-H) (five EGCs and four AGCs) and eight MS-stable (MSS) gastric cancers (four EGCs and four AGCs). In the cancers, we observed well-known driver mutations (TP53, APC, PIK3CA, ARID1A, and KRAS) that were enriched in cancer-related pathways, including chromatin remodelling and tyrosine kinase activity. The MSI-H genomes harboured ten times more mutations, but were largely depleted of copy number alterations (CNAs) compared to the MSS cancers. Interestingly, EGC genomes showed a comparable level of mutations to AGC in terms of the number, sequence composition, and functional consequences (potential driver mutations and affected pathways) of mutations. Furthermore, the CNAs between EGC and AGC genomes were not significantly different in either MSI-H and MSS. Evolutionary analyses using somatic mutations and MSI as molecular clocks further identified that EGC genomes were as old as AGC genomes in both MSS and MSI-H cancers. Our results suggest that the genetic makeup for gastric cancer may already be achieved in EGC genomes and that the time required for transition to AGC may be relatively short. Also, the data suggest a possibility that the mutational profiles obtained from early biopsies may be useful in the clinical settings for the molecular diagnosis and therapeutics of gastric cancer patients.

Intratumoural heterogeneity (ITH) leads to regional biases of the mutational landscape in a single tumour and may influence the single biopsy-based clinical diagnosis and treatment decision. To evaluate the extent of ITH in unifocal prostate cancers (PCAs), we analysed multiple regional biopsies from three PCAs, using whole-exome sequencing, DNA copy number and gene expression profiling analyses. A substantial level of ITH was identified, in that 0-61% and 18-71% of somatic variants were common or private, respectively, within a given cancer. The enhanced mutation detection rate in the combined sequencing dataset across intratumoural biopsies was demonstrated with respect to the total number of mutations identified in a given tumour. Allele frequencies of the mutations were positively correlated with the levels of intratumoural recurrence (private shared common), but some common mutations showed low allele frequency, suggesting that not all were clonally fixed. Regional biases in the presentation of a well-known TMPRSS2-ERG fusion was noted in one PCA and the somatic mutation- and copy number-based phylogenetic relationships between intratumoural biopsies were largely concordant. Genes showing intratumoural expression variability were commonly enriched in the molecular function of eicosanoid metabolism and PCA-relevant clinical markers. Taken together, our analyses identified a substantial level of genetic ITH in unifocal PCAs at the mutation, copy number and expression levels, which should be taken into account for the identification of biomarkers in the clinical setting.