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Author

Sari Laitinen

Bio: Sari Laitinen is an academic researcher from University of Tampere. The author has contributed to research in topics: Prostate cancer & Cancer. The author has an hindex of 5, co-authored 5 publications receiving 766 citations.

Papers
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Journal ArticleDOI
TL;DR: It is shown through a high-resolution genome-wide single nucleotide polymorphism and copy number survey that most, if not all, metastatic prostate cancers have monoclonal origins and maintain a unique signature copy number pattern of the parent cancer cell while also accumulating a variable number of separate subclonally sustained changes.
Abstract: Many studies have shown that primary prostate cancers are multifocal and are composed of multiple genetically distinct cancer cell clones. Whether or not multiclonal primary prostate cancers typically give rise to multiclonal or monoclonal prostate cancer metastases is largely unknown, although studies at single chromosomal loci are consistent with the latter case. Here we show through a high-resolution genome-wide single nucleotide polymorphism and copy number survey that most, if not all, metastatic prostate cancers have monoclonal origins and maintain a unique signature copy number pattern of the parent cancer cell while also accumulating a variable number of separate subclonally sustained changes. We find no relationship between anatomic site of metastasis and genomic copy number change pattern. Taken together with past animal and cytogenetic studies of metastasis and recent single-locus genetic data in prostate and other metastatic cancers, these data indicate that despite common genomic heterogeneity in primary cancers, most metastatic cancers arise from a single precursor cancer cell. This study establishes that genomic archeology of multiple anatomically separate metastatic cancers in individuals can be used to define the salient genomic features of a parent cancer clone of proven lethal metastatic phenotype.

631 citations

Journal ArticleDOI
TL;DR: Ki‐67, EZH2 and MCM7 are potential prognostic biomarkers in prostatectomy treated patients and showed independent prognostic value with relative risks in multivariate analysis.
Abstract: The aim of the study was to evaluate the prognostic value of Ki-67, EZH2, MCM7 and EIF3S3 in prostatectomy treated patients. A retrospective population-based material of 249 radical prostatectomy specimens on tissue microarrays was utilized. The median follow-up of the patients was ∼5.5 years and the main end-point was biochemical progression. The expression of Ki-67, EZH2 and MCM7 was determined by immunohistochemistry and the gene copy number of EIF3S3 was analyzed by fluorescence in situ hybridization (FISH). In the whole material, increased immunostainings of EZH2, MCM7 and Ki-67 were significantly associated with a high Gleason score and a short progression-free survival. In multivariate analysis, MCM7 and Ki-67 showed independent prognostic value with relative risks (RR) of 2.65 (95%-confidence interval of 1.22–5.70), and 1.85 (1.14–3.01), respectively. In subgroup analysis of patients, whose treatment was evaluated to be truly radical (n = 226), EZH2 (3.14, 1.38–7.16), MCM7 (2.70, 1.16–6.30) and PSA (1.5, 1.03–2.20) showed independent prognostic value. In subgroup analysis of cases with a Gleason score <7, low Ki-67 staining was associated with favorable prognosis with RR of 0.09 (0.01–0.69). In conclusion, Ki-67, EZH2 and MCM7 are potential prognostic biomarkers in prostatectomy treated patients. © 2007 Wiley-Liss, Inc.

90 citations

Journal ArticleDOI
TL;DR: The identified genetic aberrations lay the groundwork for further detailed genetic analyses of these xenografts, suggesting that the transition of the growth from androgen dependency to independence does not involve major chromosomal aberration in these two models.
Abstract: A major problem in studying prostate cancer has been the lack of model systems because of the difficulties in growing prostate cancer cells in vitro. Recently, however, several human prostate cancer xenografts, grown in immune-deficient mice, have been established. Here, we characterized 13 such xenografts (LuCaP 23.8, 23.12, 35, 41, 49, 58, 69, 70, 73, LAPC-4AD, LAPC-4AI, LAPC-9AD, and LAPC-9AI) as well as one prostate cancer cell line (22Rv1) derived from a xenograft for chromosomal alterations by comparative genomic hybridization and a modification of multicolor fluorescence in situ hybridization. On average, the xenografts contained 13 (range 5-28) aberrations, 5 (1-13) gains, and 8 (1-15) losses, per case. The chromosome arms that most often contained losses were 2q, 5q, 6q, 8p, 13q, and 18q, and gains were 7q, 8q, and Xq. The same regions were previously shown to be often altered in advanced prostate carcinomas in patients. The androgen-dependent and corresponding androgen-independent sublines of LAPC-4 and LAPC-9 shared all genetic alterations, suggesting that the transition of the growth from androgen dependency to independence does not involve major chromosomal aberrations in these two models. In conclusion, the identified genetic aberrations lay the groundwork for further detailed genetic analyses of these xenografts.

61 citations

Journal ArticleDOI
TL;DR: The findings suggest that the long-term effect of androgen withdrawal on tumour growth is due to the inhibition of proliferation, suggesting that the biologic aggressiveness of a particular tumour is defined already at an early stage of disease.

16 citations


Cited by
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Journal ArticleDOI
14 Oct 2011-Cell
TL;DR: The invasion-metastasis cascade is a multistep cell-biological process that involves dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments as mentioned in this paper.

3,150 citations

Journal ArticleDOI
07 Apr 2011-Nature
TL;DR: It is shown that with flow-sorted nuclei, whole genome amplification and next generation sequencing the authors can accurately quantify genomic copy number within an individual nucleus and indicate that tumours grow by punctuated clonal expansions with few persistent intermediates.
Abstract: Genomic analysis provides insights into the role of copy number variation in disease, but most methods are not designed to resolve mixed populations of cells. In tumours, where genetic heterogeneity is common, very important information may be lost that would be useful for reconstructing evolutionary history. Here we show that with flow-sorted nuclei, whole genome amplification and next generation sequencing we can accurately quantify genomic copy number within an individual nucleus. We apply single-nucleus sequencing to investigate tumour population structure and evolution in two human breast cancer cases. Analysis of 100 single cells from a polygenomic tumour revealed three distinct clonal subpopulations that probably represent sequential clonal expansions. Additional analysis of 100 single cells from a monogenomic primary tumour and its liver metastasis indicated that a single clonal expansion formed the primary tumour and seeded the metastasis. In both primary tumours, we also identified an unexpectedly abundant subpopulation of genetically diverse 'pseudodiploid' cells that do not travel to the metastatic site. In contrast to gradual models of tumour progression, our data indicate that tumours grow by punctuated clonal expansions with few persistent intermediates.

2,426 citations

Journal ArticleDOI
TL;DR: Using microarray-based profiling of isogenic prostate cancer xenograft models, it is found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy.
Abstract: Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.

2,320 citations

Journal ArticleDOI
12 Jul 2012-Nature
TL;DR: The mutational landscape of a heavily treated metastatic cancer is described, novel mechanisms of AR signalling deregulated in prostate cancer are identified, and candidates for future study are prioritize.
Abstract: Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study.

2,141 citations

Journal ArticleDOI
09 Feb 2017-Cell
TL;DR: The cellular and molecular mechanisms involved in metastasis are summarized, with a focus on carcinomas where the most is known, and the general principles of metastasis that have begun to emerge are highlighted.

1,930 citations