title: Regional biases in mutation screening due to intratumoural heterogeneity of prostate cancer.
abstract: 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.
authors.affiliation: Cancer Evolution Research Centre, Catholic University of Korea, Seoul, South Korea.
authors.forename: Tae-Min
authors.initials: TM
authors.lastname: Kim
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Jung
authors.forename: In-Pyo
authors.initials: IP
authors.lastname: Baek
authors.forename: Sung-Hak
authors.initials: SH
authors.lastname: Lee
authors.forename: Youn-Jin
authors.initials: YJ
authors.lastname: Choi
authors.forename: Ji-Youl
authors.initials: JY
authors.lastname: Lee
authors.forename: Yeun-Jun
authors.initials: YJ
authors.lastname: Chung
authors.forename: Sug-Hyung
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000368:Aged; D015982:Bias; D001706:Biopsy; D056915:DNA Copy Number Variations / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D055088:Early Detection of Cancer / Q000379:methods*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm
keywords: cancer genome; copy number; heterogeneity; mutation; prostate cancer