Eturauhassyöpäspesifisen geenisäätelyverkon laskennallinen ennustaminen

Prostate cancer is a highly common disease in the Western countries with its prevalence growing every year with the standard of living and life expectancy. Despite extensive studies prostate cancer presents still considerable challenges to patient care, scientists and societies. As still no curing treatment exists for the recurrent form of the disease prostate cancer is likely to remain an intensive subject for study also in the future. Even though numerous studies exists that try to characterize individual components and pathways of regulation, no real attempts have been made to characterize the regulation profile of prostate cancer in a genome-wide level. This thesis forms a basis for this ambitious feat by using computational methods in transcription factor mediated regulation prediction and network inference. DNase I hypersensitivity guided genome scanning with transcription factor specific position weight matrices is performed in several manners, producing a catalogue of putative regulation connections in LNCaP cells. The predicted connections are subjected to thorough evaluation and several applications of the first method are presented, forming a strong set of basic guidelines for computational prediction based regulome assembly for future studies. In addition, as a further application gene expression data is applied to selectively extract a subnetwork of regulation present exclusively in the studied LNCaP cells. As a conclusion the genome-wide computational regulome assembly is presented as a functional but challenged approach with enormous potential due to its possible applications as cell type or disease specific network profiling tool

Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients

BackgroundFamilial dilated cardiomyopathy (DCM) causes heart failure and may lead to heart transplantation. DCM is typically a monogenic disorder with autosomal dominant inheritance. Currently disease-causing variants have been reported in over 60 genes that encode proteins in sarcomeres, nuclear lamina, desmosomes, cytoskeleton, and mitochondria. Over half of the patients undergoing comprehensive genetic testing are left without a molecular diagnosis even when patient selection follows strict DCM criteria.Methods and resultsThis study was a retrospective review of patients referred for genetic testing at Blueprint Genetics due to suspected inherited DCM. Next generation sequencing panels included 23–316 genes associated with cardiomyopathies and other monogenic cardiac diseases. Variants were considered diagnostic if classified as pathogenic (P) or likely pathogenic (LP). Of the 2,088 patients 514 (24.6%) obtained a molecular diagnosis; 534 LP/P variants were observed across 45 genes, 2.7% (14/514) had two diagnostic variants in dominant genes. Nine copy number variants were identified: two multigene and seven intragenic. Diagnostic variants were observed most often in TTN (45.3%), DSP (6.7%), LMNA (6.7%), and MYH7 (5.2%). Clinical characteristics independently associated with molecular diagnosis were: a lower age at diagnosis, family history of DCM, paroxysmal atrial fibrillation, absence of left bundle branch block, and the presence of an implantable cardioverter-defibrillator.ConclusionsPanel testing provides good diagnostic yield in patients with clinically suspected DCM. Causative variants were identified in 45 genes. In minority, two diagnostic variants were observed in dominant genes. Our results support the use of genetic panels in clinical settings in DCM patients with suspected genetic etiology

Eturauhassyöpäspesifisen geenisäätelyverkon laskennallinen ennustaminen

Prostate cancer is a highly common disease in the Western countries with its prevalence growing every year with the standard of living and life expectancy. Despite extensive studies prostate cancer presents still considerable challenges to patient care, scientists and societies. As still no curing treatment exists for the recurrent form of the disease prostate cancer is likely to remain an intensive subject for study also in the future. Even though numerous studies exists that try to characterize individual components and pathways of regulation, no real attempts have been made to characterize the regulation profile of prostate cancer in a genome-wide level. This thesis forms a basis for this ambitious feat by using computational methods in transcription factor mediated regulation prediction and network inference. DNase I hypersensitivity guided genome scanning with transcription factor specific position weight matrices is performed in several manners, producing a catalogue of putative regulation connections in LNCaP cells. The predicted connections are subjected to thorough evaluation and several applications of the first method are presented, forming a strong set of basic guidelines for computational prediction based regulome assembly for future studies. In addition, as a further application gene expression data is applied to selectively extract a subnetwork of regulation present exclusively in the studied LNCaP cells. As a conclusion the genome-wide computational regulome assembly is presented as a functional but challenged approach with enormous potential due to its possible applications as cell type or disease specific network profiling tool

Circulating mutational portrait of cancer : manifestation of aggressive clonal events in both early and late stages

BioMed Central open acces

Protein phosphatase methylesterase-1 (PME-1) expression predicts a favorable clinical outcome in colorectal cancer

Colorectal cancer (CRC) accounts for high mortality. So far, there is lack of markers capable of predicting which patients are at risk of aggressive course of the disease. Protein phosphatase-2A (PP2A) inhibitor proteins have recently gained interest as markers of more aggressive disease in certain cancers. Here, we report the role of PP2A inhibitor PME-1 in CRC. PME-1 expression was assessed from a rectal cancer patient cohort by immunohistochemistry, and correlations were performed for various clinicopathological variables and patient survival. Rectal cancer patients with higher cytoplasmic PME-1 protein expression (above median) had less recurrences (P = 0.003, n = 195) and better disease-free survival (DFS) than the patients with low cytoplasmic PME-1 protein expression (below median). Analysis of PPME-1 mRNA expression from TCGA dataset of colon and rectal adenocarcinoma (COADREAD) patient cohort confirmed high PPME1 expression as an independent protective factor predicting favorable overall survival (OS) (P = 0.005, n = 396) compared to patients with low PPME1 expression. CRC cell lines were used to study the effect of PME-1 knockdown by siRNA on cell survival. Contrary to other cancer types, PME-1 inhibition in CRC cell lines did not reduce the viability of cells or the expression of active phosphorylated AKT and ERK proteins. In conclusion, PME-1 expression predicts for a favorable outcome of CRC patients. The unexpected role of PME-1 in CRC in contrast with the oncogenic role of PP2A inhibitor proteins in other malignancies warrants further studies of cancer-specific function for each of these proteins

Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses

Androgen receptor deregulation drives bromodomain-mediated chromatin alterations in prostate cancer

Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses