Project description:18 Families (66 individuals) from an established cohort for schizophrenia in Finland provided RNA for analysis of genome-wide gene expression levels in blood lymphocytes. These have been collected for the analysis of genetic risk variants for mental illness that are present within these families, under the hypothesis that genetic variants will lead to changes in the biological functioning that represent the mechanisms altered in the etiology of major mental illness, with gene expression providining a means to observe such alterations.
Project description:18 Families (66 individuals) from an established cohort for schizophrenia in Finland provided RNA for analysis of genome-wide gene expression levels in blood lymphocytes. These have been collected for the analysis of genetic risk variants for mental illness that are present within these families, under the hypothesis that genetic variants will lead to changes in the biological functioning that represent the mechanisms altered in the etiology of major mental illness, with gene expression providining a means to observe such alterations. Total RNA was extracted from fresh blood samples donated by 66 individuals from 18 families ascertained for schizophrenia. Gene expression was measured using 6 chips, with two individuals (samples 2 and 8) replicated across chips. The non-normalized matrix contains the complete data, including replicates.
Project description:In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar pathophysiological mechanisms. Grouping into molecularly homogeneous subsets may therefore be of potential value for further genetic analysis in order to identify new high penetrance breast cancer genes. In the current study, the aim was to investigate if global RNA profiling can be used to identify functional subgroups within breast tumors from families tested negative for BRCA1/2 germline mutations and how these subgroupings relate to different breast cancer patients within the same family. By analyzing a collection of 70 breast tumor biopsies from 58 families, we show that distinct functional subgroupings, similar to the intrinsic molecular breast cancer subtypes, exist. The distribution of subtypes was markedly different from the distribution found among BRCA1/2 mutation carriers. From 11 breast cancer families, breast tumor biopsies from more than one affected family member were included in the study. Notably, in 8 of these families we found that patients from the same family shared the same tumor subtype, showing a tendency of familial aggregation of tumor subtypes (p-value = 1.7e-3). Our finding indicates involvement of hereditary factors in these families in which family members may carry genetic susceptibility not just to breast cancer but to a particular subtype of breast cancer. Using our previously developed BRCA1/2-signatures, we identified 7 non-BRCA1/2 tumors with a BRCA1-like molecular phenotype and provide evidence for epigenetic inactivation of BRCA1 in three of the tumors. In addition, 7 BRCA2-like tumors were found. This is the first study to provide a biological link between breast cancers from family members of high risk non-BRCA1/2 families in a systematic manner, suggesting that future genetic analysis may benefit from subgrouping families into molecularly homogeneous subtypes in order to identify new high penetrance susceptibility genes.
Project description:In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar pathophysiological mechanisms. Grouping into molecularly homogeneous subsets may therefore be of potential value for further genetic analysis in order to identify new high penetrance breast cancer genes. In the current study, the aim was to investigate if global RNA profiling can be used to identify functional subgroups within breast tumors from families tested negative for BRCA1/2 germline mutations and how these subgroupings relate to different breast cancer patients within the same family. By analyzing a collection of 70 breast tumor biopsies from 58 families, we show that distinct functional subgroupings, similar to the intrinsic molecular breast cancer subtypes, exist. The distribution of subtypes was markedly different from the distribution found among BRCA1/2 mutation carriers. From 11 breast cancer families, breast tumor biopsies from more than one affected family member were included in the study. Notably, in 8 of these families we found that patients from the same family shared the same tumor subtype, showing a tendency of familial aggregation of tumor subtypes (p-value = 1.7e-3). Our finding indicates involvement of hereditary factors in these families in which family members may carry genetic susceptibility not just to breast cancer but to a particular subtype of breast cancer. Using our previously developed BRCA1/2-signatures, we identified 7 non-BRCA1/2 tumors with a BRCA1-like molecular phenotype and provide evidence for epigenetic inactivation of BRCA1 in three of the tumors. In addition, 7 BRCA2-like tumors were found. This is the first study to provide a biological link between breast cancers from family members of high risk non-BRCA1/2 families in a systematic manner, suggesting that future genetic analysis may benefit from subgrouping families into molecularly homogeneous subtypes in order to identify new high penetrance susceptibility genes. Gene expression profiling of 253 breast tumor samples. Breast tumor tissue from 125 patients with germline mutations in BRCA1 (n = 33) or BRCA2 (n = 22) or with no detectable germline mutation in BRCA1 or BRCA2 (n = 70) were included in the study. Serving as a representative control group, primary breast tumor samples (n = 128) were randomly selected among available samples originating from the same department and time period as for the hereditary samples. The study was conducted using Agilent-029949 Custom SurePrint G3 Human GE 8x60K Microarray platform.
Project description:Single-nucleus RNA-seq was performed to characterize the transcriptomes of cell types in human subcutaneous adipose tissue. Biopsies from 16 Finnish participants from the Finnish Twin Study and CRYO study were included.
Project description:A remarkable proportion of factors causing genetic predisposition to breast cancer (BC) are unknown in non-BRCA1/2 families. Exome sequencing was performed for 13 high-risk Finnish hereditary breast and/or ovarian cancer (HBOC) families to detect variants contributing to BC susceptibility
Project description:By the integrated analyses of histological, metabolomic and transcriptional data, we characterized two distinct subtypes of non-malignant breast tissue
Project description:Background Bordetella pertussis is a Gram-negative bacterium that infects the human respiratory tract and causes pertussis or whooping cough. The disease has resurged in many countries including Finland where the whole-cell pertussis vaccine has been used for more than 50 years. Antigenic divergence has been observed between vaccine strains and clinical isolates in Finland. To better understand genome evolution in B. pertussis circulating in the immunized population, we developed an oligonucleotide-based microarray for comparative genomic analysis of Finnish strains isolated during the period of 50 years. Methodology/Principal Findings The microarray consisted of 3,582 oligonucleotides (70-mer) and covered 94% of the genome of Tohama I, the strain of which the genome has been sequenced [21]. Twenty isolates from 1953 to 2004 were studied together with two Finnish vaccine strains and two international reference strains. The isolates were selected according to their characteristics, e.g. the year and place of isolation and pulsed-field gel electrophoresis profiles. Genomic DNA of the tested strains, along with reference DNA of Tohama I strain, was labelled and hybridized. The absence of genes as established with microarrays, was confirmed by PCR. Compared to the Tohama I strain, Finnish isolates lost 7 (8.6 kb) to 49 (55.3 kb) genes, clustered in one to four distinct loci. The number of lost genes increased with time, and one third of lost genes had functions related to ion transport, metabolism, or energy production and conversion. All four loci of lost genes were flanked by the insertion sequence element IS481. Conclusion/Significance Our results showed that the progressive gene loss occurred in Finnish B. pertussis strains isolated during a period of 50 years and confirmed that B. pertussis is dynamic and is continuously evolving, suggesting that the bacterium may use gene loss as one strategy to adapt to highly immunized populations. Keywords: comparetive genomic hybridisation
Project description:The main genetic factors for familial melanoma remain unknown in more than 75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain less than 3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3 and 6 families with 2, 3 and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4 and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD>1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409) and 11q13.3-q21 (max. TLOD 2.654). Future next generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.