👤 Tiina Jokela

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

Disturbed action of sex steroid hormones, i.e. androgens and estrogens, is involved in the pathogenesis of various severe diseases in humans. Interestingly, recent studies have provided data further supporting the hypothesis that the circulating hormone concentrations do not explain all physiological and pathological processes observed in hormone-dependent tissues, while the intratissue sex steroid concentrations are determined by the expression of steroid metabolising enzymes in the neighbouring cells (paracrine action) and/or by target cells themselves (intracrine action). This local sex steroid production is also a valuable treatment option for developing novel therapies against hormonal diseases. Hydroxysteroid (17β) dehydrogenases (HSD17Bs) compose a family of 14 enzymes that catalyse the conversion between the low-active 17-keto steroids and the highly active 17β-hydroxy steroids. The enzymes frequently expressed in sex steroid target tissues are, thus, potential drug targets in order to lower the local sex steroid concentrations. The present review summarises the recent data obtained for the role of HSD17B1, HSD17B2, HSD17B7 and HSD17B12 enzymes in various metabolic pathways and their physiological and pathophysiological roles as revealed by the recently generated genetically modified mouse models. Our data, together with that provided by others, show that, in addition to having a role in sex steroid metabolism, several of these HSD17B enzymes possess key roles in other metabolic processes: for example, HD17B7 is essential for cholesterol biosynthesis and HSD17B12 is involved in elongation of fatty acids. Additional studies in vitro and in vivo are to be carried out in order to fully define the metabolic role of the HSD17B enzymes and to evaluate their value as drug targets. Show less

137 Russians living in Estonia was screened by isoelectric focusing and immunoblotting procedures to determine the distribution of genetic variations in apolipoprotein E (apoE) and apolipoprotein A-IV (apoA-IV) genes. The apoA-IV-2 allele and epsilon4 allele frequency of the Russians tended to be lower than in most other European populations. Show less

Apolipoprotein A-IV (apoA-IV) is a glycoprotein constituent of triglyceride-rich and high-density lipoproteins (HDL) and may thus play an important role in lipid metabolism. In Finland two common isoforms (A-IV-1 and A-IV-2) of apoA-IV have been found. The isoforms are the result of the G to T substitution in the third base of the codon 360 in the apoA-IV-2 allele of the apoA-IV gene. The purpose of the study was to determine the apoA-IV allele frequencies in the Saami and the Finns, and to relate the apoA-IV phenotypes to serum lipids. The sample was drawn in connection with a Reindeer Herders' Health Survey performed in northern Finland in 1989. The study group included 248 men with known ethnic origin, Saami and Finns, who lived in the area of the nine northernmost municipalities of Finland. ApoA-IV phenotypes from 71 Saami (both parents Saami) and 177 Finns (both parents Finns) were determined by isoelectric focusing and Western blotting. Serum lipids were determined enzymatically. ApoA-IV allele frequencies in the Saami and the Finns were for A-IV-1 0.894 vs 0.944 and for A-IV-2 0.106 vs 0.056, respectively (chi2-test, P < 0.05). The effect of the apoA-IV phenotype on serum HDL-cholesterol levels differed significantly between the Saami and the Finns (two-way ANCOVA, interaction between ethnicity and apoA-IV phenotype, P < 0.02). In the Saami, HDL-cholesterol levels were significantly higher in the apoA-IV-2/1 than in the apoA-IV-1/1 phenotypes (ANCOVA, P < 0.05). Mean total cholesterol, low-density lipoprotein (LDL)-cholesterol, apolipoprotein B, HDL-cholesterol and triglyceride levels did not differ statistically significantly between the Saami and the Finns. Yet, there was a trend in the Saami of having higher mean total cholesterol, LDL-cholesterol and apolipoprotein B levels than the Finns among the apoA-IV-2/1 phenotypes, while there was only a small difference in these parameters between the Saami and the Finns among the apoA-IV-1/1 phenotypes. In conclusion, the Saami have a higher frequency of the apoA-IV-2 allele than the Finns and most of the other studied populations. Show less