Destabilization of mutated human PUS3 protein causes intellectual disability.

Pseudouridine (Ψ) is an RNA base modification ubiquitously found in many types of RNAs. In humans, the isomerization of uridine is catalyzed by different stand-alone pseudouridine synthases (PUS). Genomic mutations in the human pseudouridine synthase 3 gene (PUS3) have been identified in patients with neurodevelopmental disorders. However, the underlying molecular mechanisms that cause the disease phenotypes remain elusive. Here, we utilize exome sequencing to identify genomic variants that lead to a homozygous amino acid substitution (p.[(Tyr71Cys)];[(Tyr71Cys)]) in human PUS3 of two affected individuals and a compound heterozygous substitution (p.[(Tyr71Cys)];[(Ile299Thr)]) in a third patient. We obtain wild-type and mutated full-length human recombinant PUS3 proteins and characterize the enzymatic activity in vitro. Unexpectedly, we find that the p.Tyr71Cys substitution neither affect tRNA binding nor pseudouridylation activity in vitro, but strongly impair the thermostability profile of PUS3, while the p.Ile299Thr mutation causes protein aggregation. Concomitantly, we observe that the PUS3 protein levels as well as the level of PUS3-dependent Ψ levels are strongly reduced in fibroblasts derived from all three patients. In summary, our results directly illustrate the link between the identified PUS3 variants and reduced Ψ levels in the patient cells, providing a molecular explanation for the observed clinical phenotypes.

Current Achievements and Applications of Transcriptomics in Personalized Cancer Medicine.

Over the last decades, transcriptome profiling emerged as one of the most powerful approaches in oncology, providing prognostic and predictive utility for cancer management. The development of novel technologies, such as revolutionary next-generation sequencing, enables the identification of cancer biomarkers, gene signatures, and their aberrant expression affecting oncogenesis, as well as the discovery of molecular targets for anticancer therapies. Transcriptomics contribute to a change in the holistic understanding of cancer, from histopathological and organic to molecular classifications, opening a more personalized perspective for tumor diagnostics and therapy. The further advancement on transcriptome profiling may allow standardization and cost reduction of its analysis, which will be the next step for transcriptomics to become a canon of contemporary cancer medicine.

Clinical Observation of a Child with Prenatally Diagnosed De Novo Partial Trisomy of Chromosome 20.

BACKGROUND: Small supernumerary marker chromosomes (sSMCs) represent a group of structural chromosome rearrangements that cannot be characterized by conventional cytogenetic analysis, but can be identified by microarray studies. sSMCs are observed in approximately 0.075% of prenatal cytogenetic tests with clinical pathology in no more than 30% of sSMCS carriers. CASE: We present a boy who was diagnosed prenatally with a partial trisomy of chromosome 20. An increased nuchal translucency NT >99%tile, fetal neck cysts and abnormalities of the lumbosacral spine were observed in prenatal screening. After birth, facial dysmorphism, small male genitalia and defects of the vertebrae were observed. In the fourth year of life, dysmorphic features, brachydactyly, small male genitalia, short stature, psychomotor delay, hyperactivity as well as conductive hearing loss became apparent. CONCLUSION: Partial trisomy of chromosome 20, covering the region 20q21→20q23, results in serious clinical complications, including dysmorphic features and delay in psychomotor development.

Personalized medicine in oncology. New perspectives in management of gliomas.

Studies on genetic and epigenetic mechanisms of carcinogenesis have led to the discovery of crucial genetic events for many of particular malignancies. This was followed by invention of new therapeutic approaches based on molecular mechanisms underlying cancer development and progression that bears the name of personalised medicine. In the case of gliomas, ascertainment of genetic/epigenetic markers was the basis for re-classification of tumours that until now depended on histopathological analysis. This article reviews recent advances in personalised medicine and the new World Health Organisation classification of gliomas.

Association of the vitamin D receptor FokI gene polymorphism with sex- and non-sex-associated cancers: A meta-analysis.

Currently higher morbidity and mortality rates are observed in cancer diseases, especially sex-dependent cancers. A positive role of endogenous vitamin D concentration in cancer diseases has been reported in many publications. Furthermore, there has been observed a relationship between serum vitamin D and testosterone concentrations in an elderly Caucasian population carrying the vitamin D receptor FokI gene polymorphism. The aim of this study was to investigate whether the vitamin D receptor FokI polymorphism is associated with cancerogenesis in sex-dependent cancers. The MEDLINE and ResearchGate databases were used to search for articles up to January 2017, and 96 articles concerning the FokI polymorphism were chosen. Odds ratios with 95% confidence intervals were used to assess the strength of associations between polymorphisms of vitamin D receptor and cancer risk in the described populations. The fixed-effects model and the DerSimonian-Laird random-effects model (with weights based on the inverse variance) were used to calculate summary odds ratios, and both within- and between-study variation were considered. Generally, the F variant reduces the risk of cancer by 4% (odds ratio = 0.96, p value = 0.0057). This effect is particularly evident in female sex-associated cancers (odds ratio = 0.96, 95% confidence interval: 0.93-0.99, p value = 0.0259), but it is not observed in non-sex-associated cancers. Polymorphism FokI is associated with breast and ovarian cancers.

Fragile X syndrome in females - a familial case report and review of the literature.

BACKGROUND: Fragile X syndrome (FXS), one of the manifestations of FMR1-related disorders, is one of the most frequent genetic causes of intellectual disability. In over 99% of all cases it results from the expansion of CGG repeats in the 5'-untranslated region of the FMR1 gene and presents in males and in about 50% of the females with an FMR1 full mutation, usually with a milder phenotype. OBJECTIVE: Although the morphologic and behavioral phenotype in males is a well-recognized entity, the presentation in females is variable and not as specific. The objective of this paper is to present a family with quite a severe expression of the disorder in two sisters with a full mutation. METHODS: We report on a two-generation family where both males and females were found to be affected by FXS. We also present the diagnostic pathway and methods that led to the diagnosis of fragile X syndrome in the two sisters, as well as the method that explained the normal phenotype in their mother. RESULTS: The CGG repeats analysis in the FMR1 gene showed one normal allele and one allele with a full mutation in both sisters (probands) and their mother. A full mutation was also found in three male cousins of the probands. The analysis of the X-chromosome methylation status has shown a random X inactivation in proband 1 and 2 and a non-random one in the proband's mother, with the normal allele predominantly active. CONCLUSION: The reasons for different clinical presentations are discussed; moreover a review of the literature on females with FXS is presented. We hope that this paper will facilitate the future diagnosis of fragile X syndromes in females.

Hexasomy 13q31.3q34 due to two marker chromosomes with inverted duplication in a fetus with increased nuchal translucency.

BACKGROUND: Small supernumerary marker chromosomes are structurally rearranged chromosomes that can be formed from different chromosomal fragments and cannot be identified using chromosomal banding analysis. Their examination has to be complemented by additional analyses like fluorescent in situ hybridization or array comparative genomic hybridization. METHODS: We report on partial hexasomy of chromosome 13q in a fetus of a pregnant woman referred to genetic counseling because of increased fetal nuchal translucency and increased risk of trisomy 21 and trisomy 18 in first-trimester combined prenatal screening. Using chromosome banding analysis, in situ hybridization and array comparative hybridization we revealed the presence of two marker chromosomes with inverted duplication resulting in hexasomy of a 22.6 Mbp fragment in chromosomal region 13q31.3-13q34 with the lack of chromosome 13 centromere. RESULTS: The fetus presented dysmorphic facial features, head and body disproportion, wide neck, ambiguous genitalia, incorrect position of the anus, and symmetrical shortening of the long bones were present in our described case. Some of these features were in accordance with other published cases. Other most often described features in tetrasomy were: microphtalmia or other major eye defects, ear abnormalities and deafness, hemangiomata, hypotelorism, severe learning disability and seizures. Despite a low risk of recurrence for small supernumerary marker chromosomes the possibility of germ line mosaicism exists, thus genetic counseling was offered to the examined family. CONCLUSION: A full characterization of small supernumerary marker chromosomes in fetal karyotype is necessary for pregnancy prognosis and genetic counseling.

[Rapid diagnosis of the most common fetal aneuploidies with the QF-PCR method--a study of 100 cases]. / Szybka diagnostyka najczestszych aneuploidii u plodu meaoda QF-PCR--analiza 100 przypadków.

UNLABELLED: The aim of the study was to assess whether commercial kit QF-PCR can be used as the only method for rapic prenatal dia gnosis of chromosomes 13, 18, 21, X and Y aneuploidies, omitting cell culture and complete cyt6genetik analysis of fetal chromosomes. MATERIAL AND METHODS: DNA from amniocytes (94 cases) and trophoblast cells (6 cases) was analyzed witt QF-PCR according to the manufacturer's protocol. The obtained products were separated using ABI 310 Genetic Analyzer and the resulting data were analyzed using GeneMarker software. RESULTS: The results of QF-PCR were obtained in 95 out of 100 cases (95%). Abnormalities were found in 28 casea (29.5%). All these results were confirmed in subsequent cytogenetic analysis. Normal results were obtained in 62 patients (70.5%). However in that group, we found three chromosomal aberrations other than those analyzed b3 QF-PCR. Additionally two abnormal and three normal karyotypes were found in patients with inconclusive QF-POF results. CONCLUSIONS: QF-PCR is a fast and reliable tool for chromosomal aneuploidy analysis and can be used as the only method without a full analysis of the karyotype, but only in cases of suspected fetal 13, 18, 21 trisomy or numerica aberrations of X chromosome. In other cases, fetal karyotype analysis from cells obtained after cell culture should be offered to the patient.

Vitamin D receptor gene polymorphisms in relation to the risk of colorectal cancer in the Polish population.

The protective effect of vitamin D against several cancers including colorectal cancer is modulated by the vitamin D receptor (VDR) and its ligand, the active form of vitamin D. VDR response has been found to play a role in various genes encoding proteins involved in crucial cellular pathways. Single nucleotide polymorphisms (SNPs) of the VDR gene that modulate its activity are located in the promoter region, exons 2-9, and their vicinity and also in the 3'UTR region. Some of them have been previously studied in relation to cancer susceptibility and prognosis. The aim of our study was to investigate four polymorphisms, BsmI, ApaI, TaqI, and FokI, of the VDR gene in Polish patients with sporadic colorectal cancer and to evaluate their association with susceptibility to cancer. We found a significant association between the BsmI genotype and cancer (individuals with the bb genotype are more susceptible to cancer compared to those with other genotypes, p = 0.025, Fisher's exact test for 2 × 2 table). Also, the TT genotype at TaqI and the AA genotype at ApaI are correlated with a higher risk of cancer (p = 0.00071 and p = 1.0 × 10(-5), respectively). We found relatively strong linkage disequilibrium between the TaqI and ApaI loci (T with A and t with a, respectively). Both of these loci are associated with cancer. We do not observe any such association for the FokI polymorphism. In conclusion, a small modification in VDR expression may play a role in such a multipathway process as tumorigenesis.

[Non-invasive fetal trisomy (NIFTY) test in prenatal diagnosis]. / Nieinwazyjny test NIFTY w diagnostyce najczestszych trisomii chromosomowych u plodu.

NIFTY (Non-invasive Fetal Trisomy Test) is a non-invasive prenatal test which is used for diagnosing fetal trisomy. The test is based on the analysis of cell free fetal DNA (cffDNA) present in the plasma and serum of a pregnant woman. NIFTY allows to detect fetal trisomy of chromosomes 13, 18, 21, X and Y and also X monosomy. Abnormal NIFTY results still need to be verified using other diagnostic techniques. However the sensitivity of NIFTY for trisomy 21, 18 and 13 is estimated at 99%, 97% and 79% respectively with false positive rate for all examined trisomies and X monosomy of < 1%. NIFTY is currently available in Poland as a commercial service, used as a good screening test for common trisomies (apart from ultrasound and biochemical tests) in the case of patient anxiety and in situation when the patient does not consent to invasive prenatal diagnostic tests. The sensitivity and specificity of NIFTY will most likely be improved as laboratory methods develop, and after a sufficiently large group of pregnant patients has been tested. Therefore, this test may soon become the primary diagnostic tool for common trisomies, allowing to avoid invasive prenatal testing in this indication. With high probability cffDNA obtained from the serum of pregnant women will also be used with time in the diagnosis of fetal structural chromosomal aberrations and other genetic changes. The aim of our study is to present a new diagnostic method.

Relationship in development of malocclusions to polymorphisms of selected vitamin D receptors.

BACKGROUND: The development of malocclusion is related to various factor, many of which are still not fully explained. The steroid hormone, 1,25-dihydroxyvitamin D3, has pleiotropic effects. It plays a key role in skeletal metabolism and the control of cell repair by attaching to the nuclear vitamin D steroid receptor (VDR). This vitamin affects bone turnover through the processes of bone tissue formation and resorption via its action on cells of the osteoblastic and osteoclastic lineage, exerts a modulating effect on the immune system, and is involved in the regulation of cell proliferation and differentiation. The role of vitamin D3 (VD3) and its receptor polymorphisms is a rarely studied topic in dentistry. Due to the proven influence on bone turnover processes and immune responses, the main research topic is its relation to periodontal diseases, but so far, its role in the formation and development of malocclusions has not been assessed. OBJECTIVES: This study aimed to assess the association of selected VDR polymorphisms: Cdx2 (rs11658820), TaqI (rs7975232), BsmI (rs1544410), ApaI (rs7975232), and FokI (rs2228570) with the development of malocclusions. MATERIAL AND METHODS: A prospective observational study was performed. The examination consisted of a medical interview, intraand extraoral orthodontic diagnosis, alginate impression, cone beam computed tomography (CBCT), and venous blood sample to obtain genomic DNA and assess VDR polymorphisms. RESULTS: The rs11658820 polymorphism causes an almost 4-fold increase in the probability of the presence of a malocclusion. GT and TT genotypes of rs7975232 are also associated with a similar risk - almost 6 and almost 5 times higher, respectively. In turn, the effect of the rs2228570-AG and GG genotype polymorphisms on the occurrence of transversal anomalies was demonstrated (odds ratio (OR) = 8.46 and OR = 6.92, respectively). CONCLUSIONS: The association of individual polymorphisms with specific malocclusions should be carefully assessed, especially since some trends have been indicated.

Genetic testing for inherited cardiovascular diseases. A position statement of the Polish Cardiac Society endorsed by Polish Society of Human Genetics and Cardiovascular Patient Communities.

According to the latest guidelines of European and American medical societies, genetic testing (GT) is essential in cardiovascular diseases for establishing diagnosis, predicting prognosis, enabling initiation of disease-modifying therapy, and preventing sudden cardiac death. The GT result may be relevant for cascade GT in the patient's relatives, for planning his/her profession and physical activity, and for procreative counseling. This position statement has been prepared due to the scarcity of GT in cardiovascular diseases in Poland and the need to expand its availability. We give a concise description of the genetic background of cardiomyopathies, channelopathies, aortopathies, familial hypercholesterolemia, pheochromocytomas, and paragangliomas. The article discusses various aspects of GT in specific populations, such as children or athletes, and also presents prenatal genetic diagnostics. We propose recommendations for GT and counselling, which take into account Polish needs and capabilities. We give an outline of legal regulations, good clinical practice in GT with respect for patient rights, the role of cardiologists and clinical geneticists in GT planning and post-test counseling, and the requirements for laboratories performing genetic tests. The Polish Cardiac Society and Polish Society of Human Genetics experts speak with one voice with cardiovascular patient communities to underline the need for a law on GT and increasing the availability of GT for cardiovascular patients.

ERRATUM: Genetic testing for inherited cardiovascular diseases. A position statement of the Polish Cardiac Society endorsed by Polish Society of Human Genetics and Cardiovascular Patient Communities.

According to the latest guidelines of European and American medical societies, genetic testing (GT) is essential in cardiovascular diseases for establishing diagnosis, predicting prognosis, enabling initiation of disease-modifying therapy, and preventing sudden cardiac death. The GT result may be relevant for cascade GT in the patient's relatives, for planning his/her profession and physical activity, and for procreative counseling. This position statement has been prepared due to the scarcity of GT in cardiovascular diseases in Poland and the need to expand its availability. We give a concise description of the genetic background of cardiomyopathies, channelopathies, aortopathies, familial hypercholesterolemia, pheochromocytomas, and paragangliomas. The article discusses various aspects of GT in specific populations, such as children or athletes, and also presents prenatal genetic diagnostics. We propose recommendations for GT and counselling, which take into account Polish needs and capabilities. We give an outline of legal regulations, good clinical practice in GT with respect for patient rights, the role of cardiologists and clinical geneticists in GT planning and post-test counseling, and the requirements for laboratories performing genetic tests. The Polish Cardiac Society and Polish Society of Human Genetics experts speak with one voice with cardiovascular patient communities to underline the need for a law on GT and increasing the availability of GT for cardiovascular patients.

Protein tyrosine phosphatase receptor-like genes are frequently hypermethylated in sporadic colorectal cancer.

The activity of phosphatases could be influenced by genetic, as well as epigenetic alterations. In our study, we have investigated the methylation status of four PTPRs: PTPRM, PTPRT, PTPRR and PTPRZ1, which were pre-selected using microarray techniques as being alternatively methylated in sporadic colorectal cancer (CRC). The analyses were carried out on 131 surgical specimens obtained from sporadic CRC patients. The methylation status of the four genes was examined using methyl specific PCR (MSP). The analysis of promoter methylation using an Illumina 27K microarray revealed four protein tyrosine phosphatases PTPRM, PTPRT, PTPRR and PTPRZ1 as being hypermethylated with ß-value ≥0.2 and P≤0.05. Subsequent analysis using MSP confirmed these observations-the frequency of promoter methylation was significantly higher in tumor cells compared with matched normal tissue for each of the analyzed genes. There was no association observed between the methylation status of PTPRs and either CIMP, K-ras (codon 12) and BRAF (exon 15, V600E) mutations or tumor localization (proximal/distal). The results of our study show a statistically significant difference between promoter methylation in cancerous and healthy tissue. This result supports the hypothesis that the PTPR family has an important role in the etiology of CRC.

[New molecular methods in prenatal invasive diagnostics]. / Nowoczesne metody molekularne w prenatalnej diagnostyce inwazyjnej.

New diagnostic techniques employed in laboratories all over the world enable to create new tests for prenatal genetic diagnosis. They include cytogenetics, molecular-cytogenetics and molecular methods. Chromosomal numerical aberrations (aneuploidies) remain to be the most frequent genetic changes diagnosed prenatally Therefore, our paper presents the latest methods used mainly in prenatal diagnosis of the most common chromosome numerical changes, as well as other methods applicable in detecting chromosome structural changes or gene mutations. One of the main advantages of these new approaches is the short period of time needed to obtain a result. Some of these techniques are used world-wide: QF-PCR (Fluorescence Quantitive Polymerase Chain Reaction)--based on the analysis of the short polymorphic sequences characteristic for each individual; MLPA (Multiplex Ligation-dependent Probe Amplification)--based on the probes ligation to complementary genomic fragments in patient DNA; microarray CGH (Comparative Genomic Hybridization)--based on genomic hybridization to microarray, which enables analysis of the entire genome. Other new methods are also gradually introduced to invasive prenatal diagnosis: NGS (Next-generation DNA sequencing)--for the analysis of the whole genome at the DNA level; BoBs (BACS-on-Beads)--molecular-cytogenetic technique based on hybridization of probes immobilized on polystyrene microspheres with fetal DNA. Nowadays, rapid diagnosis of the most common chromosomal aneuploidies is not a standard procedure in Poland, as opposed to cytogenetics (karyotyping). However, for specific clinical indications, fast and reliable methods of genetic analysis present are likely to become standard procedures in prenatal diagnosis.

Copy Number Variations and Schizophrenia.

Schizophrenia is a neurodevelopmental disorder with genetic and environmental factors involved in its aetiology. Genetic liability contributing to the development of schizophrenia is a subject of extensive research activity, as reliable data regarding its aetiology would enable the improvement of its therapy and the development of new methods of treatment. A multitude of studies in this field focus on genetic variants, such as copy number variations (CNVs) or single-nucleotide variants (SNVs). Certain genetic disorders caused by CNVs including 22q11.2 microdeletion syndrome, Burnside-Butler syndrome (15q11.2 BP1-BP2 microdeletion) or 1q21.1 microduplication/microdeletion syndrome are associated with a higher risk of developing schizophrenia. In this article, we provide a unifying framework linking these CNVs and their associated genetic disorders with schizophrenia and its various neural and behavioural abnormalities.

Fast and reliable Sanger POLE sequencing protocol in FFPE tissues of endometrial cancer.

BACKGROUND: The new classification of endometrial carcinoma (EC) requires molecular interpretation of somatic polymerase epsilon (POLE) exonuclease domain mutations. The identification of pathogenic mutations within the POLE gene defines the important subtype of ultramutated tumours ("POLE-ultramutated") with specified prognostic and predictive utility. POLE somatic mutations are present in 7-12% of ECs, usually high-grade tumours with aggressive appearance. Molecular analysis of the POLE gene can be performed using a qPCR test, the Sanger sequencing method, a next generation sequencing (NGS) panel test and also in situ hybridisation (IHC) assay. We describe our current approach of identification of POLE mutations using Sanger sequencing technology, which is still the most robust, accurate and fast technique to sequence DNA. MATERIALS AND METHODS: We present a reliable protocol for Sanger sequencing of the entire sequence coding exonuclease domain of POLE - exons 9, 10, 11, 12, 13 and 14 (codons 268-491) with 5-10 nucleotides in exon/intron boundaries (reference sequences: NM_006231.4, NP_006222.2). RESULT: The protocol has been optimized for formalin-fixed, paraffin-embedded (FFPE) EC tissues. CONCLUSION: The method developed in our laboratory allows better diagnosis of patients with EC according to current standards.

Assessment of chromosomal imbalances in CIMP-high and CIMP-low/CIMP-0 colorectal cancers.

Data presented in a number of recent studies have revealed a negative correlation between CpG island methylator phenotype (CIMP) and chromosomal instability (CIN) measured by a loss of heterozygosity (LOH) of selected loci, suggesting that CIN and CIMP represent two independent mechanisms in sporadic colorectal cancer (CRC) carcinogenesis. However, CIN is a heterogeneous phenomenon, which may be studied not only by employing LOH analysis but also by observing chromosomal imbalances (gains and deletions). The current study aimed to investigate the relationship between CIMP and chromosomal gains and deletions (assessed by comparative genomic hybridization) in a group of 20 CIMP-high and 79 CIMP-low/CIMP-0 CRCs. Our results revealed that the mean numbers of gains and of total chromosomal imbalances were significantly greater (p = 0.004 and p = 0.007, respectively) in the CIMP-low/CIMP-0 group compared to the CIMP-high group, while no significant difference was observed between the mean numbers of losses (p = 0.056). The analysis of copy number changes of 41 cancer-related genes by multiplex ligation-dependent probe amplification showed that CRK gene was exclusively deleted in CIMP-low/CIMP-0 tumors (p = 0.02). Given that chromosomal losses play an important role in tumor suppressor inactivation and chromosomal gains, in the activation of proto-oncogenes, we hypothesize that tumor suppressor inactivation plays similar roles in both CIMP-high and CIMP-low/CIMP-0 CRCs, while the predominance of chromosomal gains in CIMP-low/CIMP-0 tumors may suggest that the activation of proto-oncogenes is the underlying mechanism of CIMP-low/CIMP-0 CRC progression.

The C/A polymorphism in intron 11 of the XPC gene plays a crucial role in the modulation of an individual's susceptibility to sporadic colorectal cancer.

Epidemiological data show that colorectal cancer (CRC) is the second most frequent malignancy worldwide. The involvement of "minor impact genes" such as XME and DNA-repair genes in the etiology of sporadic cancer has been postulated by other authors. We focused on analyzing polymorphisms in DNA-repair genes in CRC. We considered the following genes involved in DNA-repair pathways: base excision repair (OGG1 Ser326Cys, XRCC1 Trp194Arg and Arg399Gln); nucleotide excision repair [XPA (-4)G/A, XPC C/A (i11) and A33512C (Lys939Gln), XPD Asp312Asn and A18911C (Lys751Gln), XPF Arg415Gln, XPG Asp1104His, ERCC1 C118T]; homologous recombination repair [NBS1 Glu185Gln, Rad51 135G/C, XRCC3 C18067 (Thr241Met)]. The study group consisted of 133 patients diagnosed with sporadic CRC, while the control group was composed of 100 age-matched non-cancer volunteers. Genotyping was performed by PCR and PCR-RFLP. Fisher's exact test with a Bonferroni correction for multiple testing was used. We found that: (i) XPC C/A (i11) heterozygous variant is associated with increased risk of CRC [OR is 2.07 (95% CI 1.1391, 3.7782) P=0.038], (ii) XPD A18911C (Lys751Gln) is associated with decreased risk of CRC [OR=0.4497, (95% CI 0.2215, 0.9131) P=0.031] for an individual with at least one A allele at this locus. (1) The XPC C/A (i11) genotype is associated with an increased risk of sporadic colorectal cancer. (2) The NER pathway has been highlighted in our study, as a most important in modulation of individual susceptibility to sCRC.

Machine-learning-based Analysis Identifies miRNA Expression Profile for Diagnosis and Prediction of Colorectal Cancer: A Preliminary Study.

BACKGROUND: The stage of colorectal cancer (CRC) at the day of diagnosis has the greatest influence on survival rate. Thus, for CRC, which is mainly identified as advanced disease, non-invasive, molecular blood or stool tests could boost the diagnosis and lower mortality. Evaluation of miRNA expression levels in serum of patients diagnosed with CRC is a potential tool in early screening. Screening can be supported by machine learning (ML) as a tool for developing a cancer risk predictive model based on genetic data. MATERIALS AND METHODS: miRNA was isolated from the serum of 8 patients diagnosed with CRC and 10 patients from a control group matched for age and sex. The expression of 179 miRNAs was determined using a serum/plasma panel (Exiqon). Determinations were conducted using real-time PCR technique on an Applied Biosystems QuantStudio3 device in 96-well plates. A predictive model was developed through the Azure Machine Learning platform. RESULTS: A wide panel of 29 up-regulated miRNAs in CRC were identified and divided into two subgroups: 1) miRNAs with significantly higher serum level in cancer patients vs. controls (24 miRNAs) and 2) miRNAs detected only in cancer patients and not in controls (5 miRNAs). Re-analysis of published miRNA profiles of CRC tumours or CRC exosomes revealed that only 2 out of 29 miRNAs were up-regulated in all datasets including ours (miR-34a and miR-25-3p). CONCLUSION: Our research suggests the potential role of overexpressed miRNAs as diagnostic or prognostic biomarkers among CRC patients. Such clustering of miRNAs may be a potential direction for discovering new diagnostic panels of cancer (including CRC), especially using ML. The low correspondence between deregulation of miRNAs in serum and tumour tissue revealed in our study confirms previously published reports.