Abstract
A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.
Highlights
Somatic copy-number alterations (SCNAs) occur very frequently in human cancer and exactly how these alterations contribute to cancer development is a subject of considerable interest.Mapping of somatic copy number alteration (SCNA) has identified recurrent sites of alterations in many cancer types, but only a small proportion of such sites have unambiguously been assigned to specific cancer genes [1].Several models based on clonal evolution and selection may be invoked to explain recurrent regions of chromosomal loss in the autosomes and sex chromosomes
Copy number changes, including duplications, amplifications, and deletions, are a common type of DNA change observed in cancer cells but it is not always clear which of the changes are important in driving cancer development
We have examined this class of genetic alteration in prostate cancer by DNA sequencing the whole genome in 103 cancers. 64 recurrent copy number changes were detected, of which 28 were new
Summary
Somatic copy-number alterations (SCNAs) occur very frequently in human cancer and exactly how these alterations contribute to cancer development is a subject of considerable interest.Mapping of SCNAs has identified recurrent sites of alterations in many cancer types, but only a small proportion of such sites have unambiguously been assigned to specific cancer genes [1].Several models based on clonal evolution and selection may be invoked to explain recurrent regions of chromosomal loss in the autosomes and sex chromosomes. In the classic model of cancer development proposed by Knudson [2], mutations are required in each of the two copies of a single gene: the loss of an allele is considered as one mutation and the remaining allele would be altered by loss (homozygous deletion), mutation or rearrangement. This is due to strong positive selective pressure for alteration of both alleles. This model is supported in prostate cancer by transgenic mouse studies for NKX3.1 and p27Kip1 [3,4]
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