👤 Päivi Kärkkäinen

Lynch syndrome is a genetic cancer-predisposing syndrome caused by pathogenic mutations in DNA mismatch repair (path_MMR) genes. Due to the elevated cancer risk, novel screening methods, alongside current surveillance techniques, could enhance cancer risk stratification. Here we show how bi-omics integration could be utilized to pinpoint potential cancer-predicting biomarkers in Lynch syndrome. We studied which blood-based circulating microRNAs and metabolites could predict Lynch syndrome cancer occurrence within a 5.8-year prospective surveillance period. We used single- and bi-omics bioinformatic analyses and identified omics-level patterns and associations across these biological layers. Lasso Cox regression was used to highlight the most promising cancer-predicting biomarkers. Our findings revealed distinct circulating metabolite landscapes among path_MMR variant carriers and a circulating microRNA co-expression module significantly associated with future cancer incidence. These microRNAs regulate cancer-related pathways, including the PI3K/Akt signaling pathway. Additionally, a metabolite module consisting of ApoB-containing lipoproteins (low-, intermediate-, and very low-density lipoproteins) showed distinct levels across path_MMR variants. Notably, three biomarkers-hsa-miR-101-3p, hsa-miR-183-5p, and triglycerides in high-density lipoprotein particles (HDL_TG)-significantly predicted cancer risk, achieving a Harrel's Concordance Index (C-index) of 0.76 (p = .0007). Elevated levels of these biomarkers indicated increased cancer risk. Internal validation of the model yielded a C-index of 0.72. The bi-omics approach and the identified biomarkers offer promising insights for future studies regarding cancer risk identification in Lynch syndrome. Show less

Fatty acid desaturase 1 (FADS1) gene encodes for delta-5 desaturase enzyme which is needed in conversion of linoleic acid (LA) to arachidonic acid (AA). Recent studies have shown that response to dietary PUFAs differs between the genotypes in circulating fatty acids. However, interactions between the FADS1 genotype and dietary LA on overall metabolism have not been studied. We aimed to examine the interactions of FADS1 rs174550 genotypes (TT and CC) and high-LA diet to identify plasma metabolites that respond differentially to dietary LA according to the FADS1 genotype. A total of 59 men (TT n = 26, CC n = 33) consumed a sunflower oil supplemented diet for 4 weeks. Daily dose of 30, 40, or 50 ml was calculated based on body mass index. It resulted in 17-28 g of LA on top of the usual daily intake. Fasting plasma samples at the beginning and at the end of the intervention were analyzed with LC-MS/MS non-targeted metabolomics method. At the baseline, the carriers of FADS1 rs174550-TT genotype had higher abundance of long-chain PUFA phospholipids compared to the FADS1 rs174550-CC one. In response to the high-LA diet, LA phospholipids and long-chain acylcarnitines increased and lysophospholipids decreased in fasting plasma similarly in both genotypes. LysoPE (20:4), LysoPC (20:4), and PC (16:0₂₀:4) decreased and cortisol increased in the carriers of rs174550-CC genotype; however, these genotype-diet interactions were not significant after correction for multiple testing. Our findings show that both FADS1 rs174550 genotype and high-LA diet modify plasma phospholipid composition. The study was registered to ClinicalTrials: NCT02543216, September 7, 2015 (retrospectively registered). Show less

In the nationwide FinHCM Study including 306 Finnish patients with hypertrophic cardiomyopathy (HCM), we have previously identified two founder mutations in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes, accounting for 18% of all cases. Objective. To screen additional mutations, previously identified in eastern Finnish cohorts with HCM, in the FinHCM Study population. Ten mutations in the beta-myosin heavy chain gene (MYH7), TPM1, and MYBPC3 were screened. MYH7-R1053Q was found in 17 of 306 patients (5.6%). No carriers of MYH7-R719W or N696S were found. A novel TPM1-D175G mutation was found in a single patient. MYBPC3 mutations were found in 14 patients: IVS5-2A-C in two, IVS14-13G-A in two, K811del in six, and A851insT in four patients. Altogether, a HCM-causing mutation was identified in 32 patients, accounting for 10.5% of all cases. In addition, two MYBPC3 variants R326Q and V896M with uncertain pathogenicity were found in eight and in 10 patients, respectively. Combining the present findings with our previous results, a causative mutation was identified in 28% of the FinHCM cohort. MYH7-R1053Q was the third most common mutation, and should be screened in all new cases of HCM in Finland. Show less

Hypertrophic cardiomyopathy (HCM) is a genetically and clinically heterogeneous myocardial disease caused by mutations in genes encoding sarcomeric proteins. To assess the genetic background and phenotypic expression of HCM in eastern Finland, we screened 35 unrelated patients with HCM from the Kuopio University Hospital area for variants in 9 genes encoding sarcomeric proteins with the PCR-SSCP method. We herewith describe our previous findings in five sarcomeric genes and also report hitherto unpublished data on four additional sarcomeric genes. Mutations in the cardiac myosin-binding protein C gene (MYBPC3) were most frequent, accounting for 26% of cases. A novel mutation (Gln1061X) in this gene was the most common mutation, found in 6 of 35 families and accounting for 17% of all cases. Other novel mutations in MYBPC3 (IVS5-2A --> C, IVS14-13G --> A, and Ex25deltaLys) were found in one family each. A previously described alpha-tropomyosin (TPM1) mutation (Asp175Asn) was found in 11% of cases. Haplotype analysis suggested that the two most common variants (MYBPC3-Gln1061X and TPM1-Asp175Asn) were founder mutations. Only one mutation (Arg719Trp) in the beta-myosin heavy chain gene (MYH7) was found in one family, and no disease-causing mutations were found in the genes encoding alpha-actin, cardiac troponin I, T, C, or myosin essential and regulatory light chains. Altogether, the aforementioned 6 mutations found in MYBPC3, TPM1, and MYH7 accounted for 61% of familial and 40% of all HCM cases. The mutations were associated mostly with benign or intermediary phenotypes with only few HCM-related deaths. We conclude that the genetic profile of HCM in eastern Finland is unique, characterized by few founder mutations with benign or intermediary phenotypes. Show less

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by cardiac hypertrophy caused by mutations in genes encoding sarcomere proteins. This study screened all patients with HCM from the Kuopio University Hospital region in eastern Finland for variants in the cardiac myosin-binding protein C gene ( MYBPC3). All 35 exons of MYBPC3 were screened by the single-strand conformation polymorphism method in 37 unrelated patients with HCM. In MYBPC3 we identified seven novel (Gln1061X, IVS5-2A-->C, IVS14-13G-->A, Ex25DeltaLys, Pro147Leu, Ser236Gly, and Arg1138His) and two previously reported (Arg326Gln, Val896Met) variants, all of which are predicted to affect the structure of the encoded protein. Four of the nine variants, a nonsense mutation Gln1061X, a splice acceptor mutation (IVS5-2A-->C), a novel substitution in intron 14 (IVS14-13G-->A), and a novel 3-bp deletion in exon 25 (Ex25DeltaLys) were concluded to be disease-causing mutations because they cosegregated with the HCM phenotype or were absent in more than 200 normal chromosomes, or both. The mutation Gln1061X was found most frequently, being present in 6 families (23 subjects) while the other three mutations were found in single families each. Haplotype analysis indicated a likely founder effect among the families carrying the Gln1061X mutation. We found four novel mutations in MYBPC3, accounting for approx. 38% of familial and 24% of all cases of HCM. In our previous and unpublished studies no more frequent cause of HCM has been found in genetic analyses of other eight sarcomeric proteins. Consequently MYBPC3 is the predominant gene for HCM in eastern Finland. In addition, several amino acid substitutions in MYBPC3 suspected to be not associated with HCM were identified, indicating that some of the missense variants found in MYBPC3 are possibly not disease-causing mutations. Show less