Publications of Vincent Bours
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See detailLe syndrome de Klinefelter : actualités cliniques et thérapeutiques
VALDES SOCIN, Hernan Gonzalo ULiege; Rey, R; COPPENS, Luc ULiege et al

in Vaisseaux, Coeur, Poumons (in press), 24(1),

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See detailNeonatal Screening for Sickle Cell Disease in Belgium for More than 20 Years: An Experience for Comprehensive Care Improvement
Gulbis, Beatrice; Lê, Phu-Quoc; Ketelslegers et al

in International Journal of Neonatal Screening (2018)

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See detailTowards an accurate cancer diagnosis modelization: Comparison of Random Forest strategies
Debit, Ahmed ULiege; Poulet, Christophe ULiege; JOSSE, Claire ULiege et al

Poster (2018, October 05)

Machine learning approaches are heavily used to produce models that will one day support clinical decisions. To be reliably used as a medical decision, such diagnosis and prognosis tools have to harbor a ... [more ▼]

Machine learning approaches are heavily used to produce models that will one day support clinical decisions. To be reliably used as a medical decision, such diagnosis and prognosis tools have to harbor a high-level of precision. Random Forests have been already used in cancer diagnosis, prognosis, and screening. Numerous Random Forests methods have been derived from the original random forest algorithm from Breiman et al. in 2001. Nevertheless, the precision of their generated models remains unknown when facing biological data. The precision of such models can be therefore too variable to produce models with the same accuracy of classification, making them useless in daily clinics. Here, we perform an empirical comparison of Random Forest based strategies, looking for their precision in model accuracy and overall computational time. An assessment of 15 methods is carried out for the classification of paired normal - tumor patients, from 3 TCGA RNA-Seq datasets: BRCA (Breast Invasive Carcinoma), LUSC (Lung Squamous Cell Carcinoma), and THCA (Thyroid Carcinoma). Results demonstrate noteworthy differences in the precisions of the model accuracy and the overall time processing, between the strategies for one dataset, as well as between datasets for one strategy. Therefore, we highly recommend to test each random forest strategy prior to modelization. This will certainly improve the precision in model accuracy while revealing the method of choice for the candidate data. [less ▲]

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See detailPredictive and prognostic role of peripheral blood eosinophil count in triple-negative and hormone receptor-negative/HER2-positive breast cancer patients undergoing neoadjuvant treatment
ONESTI, Concetta Elisa ULiege; JOSSE, Claire ULiege; Poncin, Aurélie ULiege et al

in Oncotarget (2018)

In current clinical practices, up to 27% of all breast cancer patients receive neoadjuvant chemotherapy. High pathological complete response rate is frequently associated with tumor-infiltrating ... [more ▼]

In current clinical practices, up to 27% of all breast cancer patients receive neoadjuvant chemotherapy. High pathological complete response rate is frequently associated with tumor-infiltrating lymphocytes. Additionally, circulating immune cells are also often linked to chemotherapy response. We performed a retrospective analysis on a cohort of 112 breast cancer patients (79 triple-negative, 33 hormone receptor-negative/HER2-positive) treated with standard neoadjuvant chemotherapy. Eosinophil and lymphocyte counts were collected from whole blood at baseline and during follow-ups and their associations with pathological complete response, relapse, disease-free and breast cancer-specific survival were analyzed. We observed a higher pathological complete response rate in patients who presented at baseline a relative eosinophil count ≥ 1.5% (55.6%) than in those with a relative eosinophil count < 1.5% (36.2%)(p = 0.04). An improvement in breast cancerspecific survival in patients with high relative eosinophil count (p = 0.05; HR = 0.336; 95% CI = 0.107–1.058) or with high relative lymphocyte count (threshold = 17.5%, p = 0.01; HR = 0.217; 95% CI = 0.060–0.783) were also observed. Upon combining the two parameters into the eosinophil x lymphocyte product with a threshold at 35.8, associations with pathological complete response (p = 0.002), relapse (p = 0.028), disease-free survival (p = 0.012) and breast cancer-specific survival (p = 0.001) were also recorded. In conclusion, the relative eosinophil count and eosinophil x lymphocyte product could be promising, affordable and accessible new biomarkers that are predictive for neoadjuvant chemotherapy response and prognostic for longer survival in triplenegative and hormone receptors-negative/HER2-positive breast cancers. Confirmation of these results in a larger patient population is needed. [less ▲]

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See detailRole of DNA methylation in INK4a-ARF-INK4b locus expression in breast cancer
Latgé, Guillaume ULiege; JOSSE, Claire ULiege; Poulet, Christophe ULiege et al

Poster (2018, September 13)

Breast cancer is a public health problem : one woman in 9 will suffer of it during her lifetime. The estrogen receptor expressing sub-type (ER+) is the most frequent, with 75 % of the cases. Those tumors ... [more ▼]

Breast cancer is a public health problem : one woman in 9 will suffer of it during her lifetime. The estrogen receptor expressing sub-type (ER+) is the most frequent, with 75 % of the cases. Those tumors frequently become resistant to hormonotherapy and spread as metastasis. In this case, chemotherapy needs to be administrated. The CDK4/6 inhibitors in combination with hormonotherapy appears as the new standard treatment for metastatic disease and allows to postpone the chemotherapy. Those drugs play the same role as the endogenous p16-p15 proteins, and it is expected that the patients who have lost their protein expression are also those who will present the best response to treatment. However, none of the currently tested biomarkers turns out to be predictive of treatment response. The INK locus, where p16/p14-p15 proteins are encoded, is often altered in cancers and is involved in cell cycle regulation. The p16/p14-p15 expression is negatively regulated by a non-coding RNA called ANRIL. My aim is to explore the molecular mechanisms linked to the non-coding RNA of the INK locus and involved in the expression regulation of the proteins p16/p14-p15, and to highlight potential biomarkers of the CDK4/6 inhibitors treatment response in ER+ breast cancer. To this end, I already collected In Vitro expression data by RT-qPCR in some cell lines with different expression patterns. DNA methylation are investigated thanks to a Deoxyazacytidine treatment, a DNA methylation inhibitor then by ImmunoPrecipitation of methylated DNA. So, the first links between the expression of the locus and its methylation can be done. In future, other treamtents, protein and RNA interactions will be studied to explain the potential links and molecular mechanisms. [less ▲]

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See detailPredictive and prognostic role of peripheral blood eosinophil count in triple negative and hormone receptor negative/HER2 positive breast cancers patients undergoing neoadjuvant treatment.
ONESTI, Concetta Elisa ULiege; JOSSE, Claire ULiege; PONCIN, Aurélie ULiege et al

Scientific conference (2018, September 13)

Introduction: In clinical practices, up to 27% of breast cancer (BC) patients receive neoadjuvant chemotherapy (NAC). In this context, a pathological complete response (pCR) is the most commonly used end ... [more ▼]

Introduction: In clinical practices, up to 27% of breast cancer (BC) patients receive neoadjuvant chemotherapy (NAC). In this context, a pathological complete response (pCR) is the most commonly used end-point. High pCR rate is frequently associated with tumor infiltrating lymphocytes. Besides, circulating immune cells are also often linked to chemotherapy response. Materials and methods: We performed a retrospective analysis on 112 BC patients (79 triple negative, 33 HR-/HER2+), treated with standard NAC. The median follow-up was 37.5 months (range 9-156). Eosinophil and lymphocyte count were collected at baseline, after surgery, at 1 year of follow-up and at relapse. The primary end-point is the association between the relative eosinophil count (REC) and pCR. The secondary end-points are the associations of REC, relative lymphocyte count (RLC) and eosinophil/lymphocyte product (ELP) with relapse, disease free (DFS) and breast cancer specific (BCSS) survival and to study the variation of REC and RLC during follow-up. Results: We observed a higher pCR rate in patients with REC≥1.5% vs patients with REC <1.5% (55.6% vs 36.2%, p = 0.04), and a higher median REC in patients with pCR (1.9% vs 1.2%, p 0.042). No statistically significant associations were detected with relapse, nor between RLC with pCR or relapse. We observed a 3-year BCSS of 91% vs 80% for high and low REC respectively (p 0.05; HR 0.336, 95% CI 0.107-1.058) and of 88% vs 49% in RLC≥17.5% and <17.5% respectively (p 0.01; HR 0.217, 95% CI 0.060-0.783). No significant differences were detected for DFS. Combining the two parameters in the ELP, we observed an association with pCR (59.6% in ELP≥35.8 vs 30.9% in ELP<35.8, p 0.002), relapse (12.3% vs 29.1% in high and low ELP, p 0.028), DFS (3-year DFS 90% vs 69% in high and low ELP, p 0.012; HR 0.337, 95% CI 0.138-0.823) and BCSS (3-year BCSS 95% vs 75% in high and low ELP, p 0.001; HR 0.129, 95% CI 0.029-0.573). Moreover, we observed a raise of REC after surgery from 1.4% to 2.6% (p 0.0001) and a significant reduction at relapse from 2.8% to 1.7% (p 0.021). Conversely, a reduction of RLC from 26.9% at baseline to 20.45% after surgery (p 0.0001), without significant variation at relapse, was detected. Conclusion: REC, RLC and ELP could be new promising, affordable and accessible biomarkers predictive for NAC response and prognostic for longer survival in TNBC and HR-/HER2+ BC. Confirmation in a larger cohort is needed. [less ▲]

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See detailBrain imaging and genetics in patients with congenital hypogonadotropic hypogonadism: a multicenter Belgian study.
VALDES SOCIN, Hernan Gonzalo ULiege; LIBIOULLE, Cécile ULiege; HARVENGT, Julie ULiege et al

in Jorgensen, Jens OL (Ed.) NENEG Abstract Book Communications (2018, April 19)

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See detailPheochromocytomas and pituitary adenomas in three patients with MAX exon deletions
Daly, Adrian ULiege; CASTERMANS, Emilie ULiege; Oudijk, Lindsey et al

in Endocrine-Related Cancer (2018), 25(5), 3742

Copy number variations (CNV), an important genetic mechanism in inherited tumor genetics, can affect large genetic regions or can be limited to smaller regions within genes, such deletions of single exons ... [more ▼]

Copy number variations (CNV), an important genetic mechanism in inherited tumor genetics, can affect large genetic regions or can be limited to smaller regions within genes, such deletions of single exons. Such exon deletions can be challenging to identify and sequencing can be normal in these cases. Multiplex ligation dependent probe amplification (MLPA) can identify CNV of individual exons. Mutations in the MAX gene are associated with a risk of sporadic and hereditary pheochromocytoma. As mutations in other pheochromocytoma related genes can also cause pituitary tumors (3P-Association), we studied whether MAX exon deletions were involved in the etiology of patients with an unexplained association of multiple endocrine neoplasia including pituitary adenoma and pheochromocytoma. Using MLPA we identified three patients with pheochromocytoma and pituitary adenomas who had normal MAX sequencing but presented germline heterozygous MAX exon deletions. The three patients had either acromegaly (n=2) or prolactinoma (n=1) in association with bilateral or recurrent pheochromocytoma. Two had germline heterozygous deletions of single exons of MAX, the other had a germline heterozygous deletion of MAX exons 1-3. MAX immunohistochemical staining was lost in the pheochromocytomas of all three patients and genetic analysis confirmed loss of heterozygosity in tumor DNA. A MAX exon deletion was also transmitted from one patient to a currently asymptomatic offspring. Screening studies of pheochromocytoma patients should take into account the potential for co-existing pituitary tumors. MLPA or other techniques to identify discrete MAX exon deletions should be considered in individuals with pheochromocytoma that are negative following comprehensive sequencing. [less ▲]

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See detailEhlers-Danlos syndrome in the University Hospital of Liege
KUKOR, Léna ULiege; BERTOLI, Sabrina ULiege; Bours, Vincent ULiege et al

Poster (2018, February 16)

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See detailNatural Antisense Transcripts: Molecular Mechanisms and Implications in Breast Cancers.
Latge, Guillaume ULiege; Poulet, Christophe ULiege; Bours, Vincent ULiege et al

in International Journal of Molecular Sciences (2018), 19(1),

Natural antisense transcripts are RNA sequences that can be transcribed from both DNA strands at the same locus but in the opposite direction from the gene transcript. Because strand-specific high ... [more ▼]

Natural antisense transcripts are RNA sequences that can be transcribed from both DNA strands at the same locus but in the opposite direction from the gene transcript. Because strand-specific high-throughput sequencing of the antisense transcriptome has only been available for less than a decade, many natural antisense transcripts were first described as long non-coding RNAs. Although the precise biological roles of natural antisense transcripts are not known yet, an increasing number of studies report their implication in gene expression regulation. Their expression levels are altered in many physiological and pathological conditions, including breast cancers. Among the potential clinical utilities of the natural antisense transcripts, the non-coding|coding transcript pairs are of high interest for treatment. Indeed, these pairs can be targeted by antisense oligonucleotides to specifically tune the expression of the coding-gene. Here, we describe the current knowledge about natural antisense transcripts, their varying molecular mechanisms as gene expression regulators, and their potential as prognostic or predictive biomarkers in breast cancers. [less ▲]

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See detailLe Syndrome de Kallmann: un vieux syndrome revisité par la génétique
VALDES SOCIN, Hernan Gonzalo ULiege; LIBIOULLE, Cécile ULiege; DEBRAY, François-Guillaume ULiege et al

in Urologic (2018), 14

Le contrôle neuroendocrinien de la reproduction chez l’homme est régi par un réseau d’environ 1.500 neurones hypothalamiques sécrétant la gonadotropin-releasing hormone (GnRH). Ce réseau module l’activité ... [more ▼]

Le contrôle neuroendocrinien de la reproduction chez l’homme est régi par un réseau d’environ 1.500 neurones hypothalamiques sécrétant la gonadotropin-releasing hormone (GnRH). Ce réseau module l’activité de l’axe de reproduction au cours de la vie. L’hypogonadisme hypogonadotrope congénital isolé (HHCI) est un syndrome clinique complexe, caractérisé par une insuffisance pubertaire partielle ou complète. Il peut découler d’une insuffisance hypothalamique sécrétoire de la GnRH ou d’une insuffisance de la sécrétion et/ou des effets des gonadotrophines hypophysaires. Chez l’homme, plusieurs gènes participant au développement olfactif et à la migration des neurones à GnRH interagissent pendant la vie embryonnaire. Les stéroïdes sexuels sont, à leur tour, nécessaires pour promouvoir la neurogenèse et le développement neurocognitif. Un nombre croissant de mutations de gènes participant à ce développement ont été identifiées comme étant responsables de HHCI. Sur base de la présence ou de l’absence d’un déficit de l’olfaction, l’HH est répertorié en deux syndromes, à savoir: HH avec altérations olfactives (syndrome de Kallmann) et l’hypogonadisme hypogonadotrophique idiopathique (IHH) avec une olfaction intacte ou normosmique (hypogonadisme IHH). Le syndrome de Kallmann (KS) est une condition hétérogène qui affecte 1 homme sur 5.000, avec un rapport homme/femme de 3/1. Le KS est associé à des mutations des gènes KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, SEMA7A, NELF, WDR11, SOX10, NSMF, AXL, FEZF1, DCC/NTN1 et KLB. Ces mutations entraînent des défauts de la migration neuronale, avec, comme possibles conséquences, un déficit variable au niveau de l’axe reproducteur, des troubles de l’olfaction, une surdité neurosensorielle. Des malformations y sont parfois associées, y compris un colobome, des syncinésies controlatérales, une malformation crâniofaciale et/ou une agénésie rénale. Dans cet article de synthèse, nous revisitons le syndrome de Kallmann vis-à-vis de ses conséquences sur la reproduction et sur le développement cérébral. [less ▲]

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See detailBoosting care and knowledge about hereditary cancer: European Reference Network on Genetic Tumour Risk Syndromes.
Vos, Janet R.; Giepmans, Lisette; Rohl, Claas et al

in Familial Cancer (2018)

Approximately 27-36 million patients in Europe have one of the ~ 5.000-8.000 known rare diseases. These patients often do not receive the care they need or they have a substantial delay from diagnosis to ... [more ▼]

Approximately 27-36 million patients in Europe have one of the ~ 5.000-8.000 known rare diseases. These patients often do not receive the care they need or they have a substantial delay from diagnosis to treatment. In March 2017, twenty-four European Reference Networks (ERNs) were launched with the aim to improve the care for these patients through cross border healthcare, in a way that the medical knowledge and expertise travels across the borders, rather than the patients. It is expected that through the ERNs, European patients with a rare disease get access to expert care more often and more quickly, and that research and guideline development will be accelerated resulting in improved diagnostics and therapies. The ERN on Genetic Tumour Risk Syndromes (ERN GENTURIS) aims to improve the identification, genetic diagnostics, prevention of cancer, and treatment of European patients with a genetic predisposition for cancer. The ERN GENTURIS focuses on syndromes such as hereditary breast cancer, hereditary colorectal cancer and polyposis, neurofibromatosis and more rare syndromes e.g. PTEN Hamartoma Tumour Syndrome, Li Fraumeni Syndrome and hereditary diffuse gastric cancer. [less ▲]

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See detailGenetic assessment and folate receptor autoantibodies in infantile-onset cerebral folate deficiency (CFD) syndrome
RAMAEKERS, Vincent ULiege; SEGERS, Karin ULiege; Sequeira, J. M. et al

in Molecular Genetics and Metabolism (2018), 124(1), 87-93

Introduction: Cerebral folate deficiency (CFD) syndromes are defined as neuro-psychiatric conditions with low CSF folate and attributed to different causes such as autoantibodies against the folate ... [more ▼]

Introduction: Cerebral folate deficiency (CFD) syndromes are defined as neuro-psychiatric conditions with low CSF folate and attributed to different causes such as autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus, FOLR1 gene mutations or mitochondrial disorders. High-dose folinic acid treatment restores many neurologic deficits. Study aims and methods: Among 36 patients from 33 families the infantile-onset CFD syndrome was diagnosed based on typical clinical features and low CSF folate. All parents were healthy. Three families had 2 affected siblings, while parents from 4 families were first cousins. We analysed serum FR autoantibodies and the FOLR1 and FOLR2 genes. Among three consanguineous families homozygosity mapping attempted to identify a monogenetic cause. Whole exome sequencing (WES) was performed in the fourth consanguineous family, where two siblings also suffered from polyneuropathy as an atypical finding. Results: Boys (72%) outnumbered girls (28%). Most patients (89%) had serum FR autoantibodies fluctuating over 5–6 weeks. Two children had a genetic FOLR1 variant without pathological significance. Homozygosity mapping failed to detect a single autosomal recessive gene. WES revealed an autosomal recessive polynucleotide kinase 3´phosphatase (PNKP) gene abnormality in the siblings with polyneuropathy. Discussion: Infantile-onset CFD was characterized by serum FR autoantibodies as its predominant pathology whereas pathogenic FOLR1 gene mutations were absent. Homozygosity mapping excluded autosomal recessive inheritance of any single responsible gene. WES in one consanguineous family identified a PNKP gene abnormality that explained the polyneuropathy and also its contribution to the infantile CFD syndrome because the PNKP gene plays a dual role in both neurodevelopment and immune-regulatory function. Further research for candidate genes predisposing to FRα-autoimmunity is suggested to include X-chromosomal and non-coding DNA regions. © 2018 Elsevier Inc. [less ▲]

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