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Article: Functional Analysis of Promoter Variants in Genes Involved in Sex Steroid Action, DNA Repair and Cell Cycle Control.

Hamdi, Yosr / Leclerc, Martin / Dumont, Martine / Dubois, Stéphane / Tranchant, Martine / Reimnitz, Guy / Soucy, Penny / Cassart, Pauline / Ouimet, Manon / Sinnett, Daniel / Chaieb, M'Hamed Lajmi Lakhal / Simard, Jacques

Genes

2019 Volume 10, Issue 3

Abstract: Genetic variants affecting the regulation of gene expression are among the main causes of human diversity. The potential importance of regulatory polymorphisms is underscored by results from Genome Wide Association Studies, which have already implicated ... ...

Abstract	Genetic variants affecting the regulation of gene expression are among the main causes of human diversity. The potential importance of regulatory polymorphisms is underscored by results from Genome Wide Association Studies, which have already implicated such polymorphisms in the susceptibility to complex diseases such as breast cancer. In this study, we re-sequenced the promoter regions of 24 genes involved in pathways related to breast cancer including sex steroid action, DNA repair, and cell cycle control in 60 unrelated Caucasian individuals. We constructed haplotypes and assessed the functional impact of promoter variants using gene reporter assays and electrophoretic mobility shift assays. We identified putative functional variants within the promoter regions of estrogen receptor 1 (
MeSH term(s)	Breast Neoplasms/genetics ; Cell Cycle Proteins/genetics ; DNA-Binding Proteins/genetics ; Estrogen Receptor alpha/genetics ; Estrogen Receptor beta/genetics ; European Continental Ancestry Group/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; HeLa Cells ; Hepatocyte Nuclear Factor 3-alpha/genetics ; Histone Chaperones/genetics ; Humans ; MCF-7 Cells ; Nuclear Proteins/genetics ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Protein-Serine-Threonine Kinases/genetics ; Receptors, Steroid/genetics
Chemical Substances	Cell Cycle Proteins ; DNA-Binding Proteins ; ESR1 protein, human ; ESR2 protein, human ; Estrogen Receptor alpha ; Estrogen Receptor beta ; FOXA1 protein, human ; Hepatocyte Nuclear Factor 3-alpha ; Histone Chaperones ; Nuclear Proteins ; Receptors, Steroid ; UIMC1 protein, human ; CDC7 protein, human (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2019-02-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes10030186
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Article: Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.

Li, Na / Zethoven, Magnus / McInerny, Simone / Devereux, Lisa / Huang, Yu-Kuan / Thio, Niko / Cheasley, Dane / Gutiérrez-Enríquez, Sara / Moles-Fernández, Alejandro / Diez, Orland / Nguyen-Dumont, Tu / Southey, Melissa C / Hopper, John L / Simard, Jacques / Dumont, Martine / Soucy, Penny / Meindl, Alfons / Schmutzler, Rita / Schmidt, Marjanka K /

Adank, Muriel A / Andrulis, Irene L / Hahnen, Eric / Engel, Christoph / Lesueur, Fabienne / Girard, Elodie / Neuhausen, Susan L / Ziv, Elad / Allen, Jamie / Easton, Douglas F / Scott, Rodney J / Gorringe, Kylie L / James, Paul A / Campbell, Ian G

NPJ breast cancer

2021 Volume 7, Issue 1, Page(s) 52

Abstract: Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. ... ...

Abstract	Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82-1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09-1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
Language	English
Publishing date	2021-05-12
Publishing country	United States
Document type	Journal Article
ISSN	2374-4677
ISSN	2374-4677
DOI	10.1038/s41523-021-00255-3
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Article ; Online: Paternal age and sperm DNA decay: discrepancy between chromomycin and aniline blue staining.

Belloc, Stéphanie / Benkhalifa, Moncef / Junca, Anne Marie / Dumont, Martine / Bacrie, Paul Cohen / Ménézo, Yves

Reproductive biomedicine online

2009 Volume 19, Issue 2, Page(s) 264–269

Abstract: The effect of paternal age on sperm DNA fragmentation and decondensation was determined in a retrospective study involving 1769 patients. TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling (TUNEL) assay was used to assess ... ...

Abstract	The effect of paternal age on sperm DNA fragmentation and decondensation was determined in a retrospective study involving 1769 patients. TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling (TUNEL) assay was used to assess fragmentation, and DNA decondensation was measured with either chromomycin or aniline blue staining. The impact of atypical forms was also analysed. DNA fragmentation increases with age, but is independent of the percentage of atypical forms. Both staining techniques revealed a negative correlation between the quality of sperm packaging and the percentage of atypical forms. Decondensation increases with increasing age and fragmentation when measured with chromomycin; however, an inverse relationship is observed when testing is performed using aniline blue. These observations are discussed in relation to the specificity of the dyes, the deposition of protamines and the impact of age and reactive oxygen species on protamine cross-linking.
MeSH term(s)	Adult ; Aniline Compounds/chemistry ; Chromomycins/chemistry ; DNA/metabolism ; DNA Fragmentation ; Humans ; Male ; Middle Aged ; Paternal Age ; Spermatozoa/metabolism
Chemical Substances	Aniline Compounds ; Chromomycins ; aniline blue (8004-91-9) ; DNA (9007-49-2)
Language	English
Publishing date	2009-07-01
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2113823-0
ISSN	1472-6491 ; 1472-6483
ISSN (online)	1472-6491
ISSN	1472-6483
DOI	10.1016/s1472-6483(10)60083-1
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Article: Perspective: prostate cancer susceptibility genes.

Simard, Jacques / Dumont, Martine / Soucy, Penny / Labrie, Fernand

Endocrinology

2002 Volume 143, Issue 6, Page(s) 2029–2040

Abstract: In many developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal, and/or genetic ... ...

Abstract	In many developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal, and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that association of candidate genetic markers to this multifactorial malignancy is more difficult than the identification of susceptibility genes for some common cancers such as breast, ovary, and colon cancer. Several reasons may explain such a difficulty: 1) prostate cancer is diagnosed at a late age, thus often making it impossible to obtain DNA samples from living affected men for more than one generation; 2) the presence within high-risk pedigrees of phenocopies, associated with the lack of distinguishing features between hereditary and sporadic forms; and 3) the genetic heterogeneity of this complex disease along with the accompanying difficulty of developing appropriate statistical transmission models taking into account simultaneously multiple susceptibility genes, frequently showing moderate or low penetrance. Despite the localization of seven susceptibility loci, there has been limited confirmatory evidence of linkage for currently known candidate genes. Nonetheless, the discovery of the first prostate cancer susceptibility gene characterized by positional cloning, ELAC2 was achieved taking advantage of the Utah Family Resource. Moreover, common missense mutations in the ELAC2 gene were found to be significantly associated with an increased risk of diagnosis of prostate cancer in some studies. More recently, recombination map-ping and candidate gene analysis were used to map several genes, including the 2'-5'-oligoadenylate-dependent ribonuclease L (RNASEL) gene, to the critical region of HPC1. Two deleterious mutations in RNASEL segregate independently with the disease in two of the eight HPC1-linked families. Additional studies using larger cohorts are needed to fully evaluate the role of these two susceptibility genes in prostate cancer risk. Although a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, some of the familial risks may be due to shared environment and more specifically to common low-penetrance genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action, led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants, such as those found in 5alpha-reductase type 2 and AR genes.
MeSH term(s)	Alleles ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Chromosomes, Human, Pair 17/genetics ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Prostatic Neoplasms/epidemiology ; Prostatic Neoplasms/genetics ; Ribonucleases/genetics
Chemical Substances	BRCA1 Protein ; BRCA2 Protein ; Ribonucleases (EC 3.1.-)
Language	English
Publishing date	2002-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endo.143.6.8890
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Article ; Online: Author Correction: Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.

Wilcox, Naomi / Dumont, Martine / González-Neira, Anna / Carvalho, Sara / Joly Beauparlant, Charles / Crotti, Marco / Luccarini, Craig / Soucy, Penny / Dubois, Stéphane / Nuñez-Torres, Rocio / Pita, Guillermo / Gardner, Eugene J / Dennis, Joe / Alonso, M Rosario / Álvarez, Nuria / Baynes, Caroline / Collin-Deschesnes, Annie Claude / Desjardins, Sylvie / Becher, Heiko /

Behrens, Sabine / Bolla, Manjeet K / Castelao, Jose E / Chang-Claude, Jenny / Cornelissen, Sten / Dörk, Thilo / Engel, Christoph / Gago-Dominguez, Manuela / Guénel, Pascal / Hadjisavvas, Andreas / Hahnen, Eric / Hartman, Mikael / Herráez, Belén / Jung, Audrey / Keeman, Renske / Kiechle, Marion / Li, Jingmei / Loizidou, Maria A / Lush, Michael / Michailidou, Kyriaki / Panayiotidis, Mihalis I / Sim, Xueling / Teo, Soo Hwang / Tyrer, Jonathan P / van der Kolk, Lizet E / Wahlström, Cecilia / Wang, Qin / Perry, John R B / Benitez, Javier / Schmidt, Marjanka K / Schmutzler, Rita K / Pharoah, Paul D P / Droit, Arnaud / Dunning, Alison M / Kvist, Anders / Devilee, Peter / Easton, Douglas F / Simard, Jacques

Nature genetics

2023 Volume 55, Issue 11, Page(s) 2009

Language	English
Publishing date	2023-09-26
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-023-01549-x
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Article ; Online: Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.

Nature genetics

2023 Volume 55, Issue 9, Page(s) 1435–1439

Abstract: Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a ...

Abstract	Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10
MeSH term(s)	Female ; Humans ; Exome Sequencing ; Exome/genetics ; Mutation, Missense/genetics ; Neoplasms
Language	English
Publishing date	2023-08-17
Publishing country	United States
Document type	Meta-Analysis ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-023-01466-z
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Article ; Online: Mutation analysis and characterization of HSD17B2 sequence variants in breast cancer cases from French Canadian families with high risk of breast and ovarian cancer.

Plourde, Marie / Manhes, Caroline / Leblanc, Gilles / Durocher, Francine / Dumont, Martine / Sinilnikova, Olga / Simard, Jacques

Journal of molecular endocrinology

2008 Volume 40, Issue 4, Page(s) 161–172

Abstract: Estrogen exposure is a risk factor for breast cancer. Given that HSD17B2 gene encodes an enzyme that catalyses estradiol inactivation, it appears as a good candidate breast cancer susceptibility gene. This study was designed to screen for HSD17B2 ... ...

Abstract	Estrogen exposure is a risk factor for breast cancer. Given that HSD17B2 gene encodes an enzyme that catalyses estradiol inactivation, it appears as a good candidate breast cancer susceptibility gene. This study was designed to screen for HSD17B2 germline mutations potentially involved in breast cancer predisposition. Our re-sequencing analysis did not identify any deleterious germline mutations, and therefore mutations in HSD17B2 do not explain the clustering of breast cancer cases in non-BRCA1/2 high-risk French Canadian families. However, six sequence variants were identified, including two novel missense variants. Expression assays revealed that p.Ala111Asp and p.Gly160Arg did not alter the catalytic properties of 17beta-hydroxysteroid dehydrogenase type 2 enzyme, although p.Ala111Asp appears to affect protein stability resulting in significant decreases in the protein levels, providing valuable information on structure-function relationship.
MeSH term(s)	Adult ; Aged ; Amino Acid Sequence ; Breast Neoplasms/genetics ; Case-Control Studies ; Cells, Cultured ; DNA Mutational Analysis ; Estradiol Dehydrogenases/genetics ; Estradiol Dehydrogenases/metabolism ; Family ; Female ; Gene Expression Regulation, Enzymologic ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Humans ; Middle Aged ; Ovarian Neoplasms/genetics ; Polymorphism, Single Nucleotide ; Quebec ; Risk Factors ; Sequence Homology, Amino Acid ; Transfection
Chemical Substances	Estradiol Dehydrogenases (EC 1.1.1.62) ; HSD17B2 protein, human (EC 1.1.1.62)
Language	English
Publishing date	2008-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	645012-x
ISSN	1479-6813 ; 0952-5041
ISSN (online)	1479-6813
ISSN	0952-5041
DOI	10.1677/JME-07-0101
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Article ; Online: Altered sleep brain functional connectivity in acutely depressed patients.

Leistedt, Samuël J J / Coumans, Nathalie / Dumont, Martine / Lanquart, Jean-Pol / Stam, Cornelis J / Linkowski, Paul

Human brain mapping

2008 Volume 30, Issue 7, Page(s) 2207–2219

Abstract: Recent evidence suggests that problems in information processing within neural networks may underlie depressive disease. In this study, we investigated whether sleep functional brain networks are abnormally organized during a major depressive episode ( ... ...

Abstract	Recent evidence suggests that problems in information processing within neural networks may underlie depressive disease. In this study, we investigated whether sleep functional brain networks are abnormally organized during a major depressive episode (MDE). We characterized spatial patterns of functional connectivity by computing the "synchronization likelihood" (SL) of 19 sleep EEG channels in 11 acutely depressed patients [42 (20-51) years] and 14 healthy controls [32.9 (27-42) years]. To test whether disrupting an optimal pattern ["small-world network" (SWN)] of functional brain connectivity underlies MDE, graph theoretical measures were then applied to the resulting synchronization matrices, and a clustering coefficient (C, measure of local connectedness) and a shortest path length (L, measure of overall network integration) were determined. In the depressed group, the mean SL was lower in the delta, theta and sigma frequency bands. Acutely depressed patients showed a significantly lower path length in the theta and delta frequency bands, whereas the cluster coefficient showed no significant changes. The present study provides further support that sleep functional brain networks exhibit "small-world" properties. Sleep neuronal functional networks in depressed patients are characterized by a functional reorganization with a lower mean level of global synchronization and loss of SWN characteristics. These results argue for considering an MDE as a problem of neuronal network organization and a problem of information processing.
MeSH term(s)	Adult ; Brain/physiopathology ; Cluster Analysis ; Cortical Synchronization ; Delta Rhythm ; Depressive Disorder, Major/physiopathology ; Female ; Humans ; Male ; Middle Aged ; Neural Pathways/physiopathology ; Signal Processing, Computer-Assisted ; Sleep/physiology ; Theta Rhythm ; Young Adult
Language	English
Publishing date	2008-09-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1197207-5
ISSN	1097-0193 ; 1065-9471
ISSN (online)	1097-0193
ISSN	1065-9471
DOI	10.1002/hbm.20662
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Article: Factors associated with an individual's decision to withdraw from genetic testing for breast and ovarian cancer susceptibility: implications for counseling.

Godard, Béatrice / Pratte, Annabelle / Dumont, Martine / Simard-Lebrun, Adèle / Simard, Jacques

Genetic testing

2007 Volume 11, Issue 1, Page(s) 45–54

Abstract: Our study aimed to examine why individuals withdraw from genetic testing for breast and ovarian cancer susceptibility. We explored the characteristics of 334 individuals from high-risk breast and ovarian cancer families who declined genetic testing for ... ...

Abstract	Our study aimed to examine why individuals withdraw from genetic testing for breast and ovarian cancer susceptibility. We explored the characteristics of 334 individuals from high-risk breast and ovarian cancer families who declined genetic testing for BRCA1/2 mutations, when, and why they did so. Individuals who declined genetic testing were older, and a greater proportion had never developed breast or ovarian cancer. Fifty one per cent (51.1%) of individuals withdrew after the first genetic counseling session. Most of those who declined were afraid of the psychological effects of genetic testing (36.3%). The next most-cited explanations concerned logistic problems such as a limited ability to travel, lack of time, personal issues, advanced age, or health problems (21.7%). The third category included individuals who did not see any advantage in being tested (14.5%). Insurability was a concern (5.9%), mainly for men. Surprisingly, confidentiality was not a frequently reported issue (1.3%). Sixty eight per cent (68%) of individuals belonging to a family in which at least one individual has been tested withdrew after the presence of a deleterious BRCA1/2 mutation in a relative was disclosed, compared to 42% after the disclosure of a nonconclusive test result in at least one relative. Concern about the psychological effects of the result was still one of the major reasons. Several factors may influence an individual's decision to decline genetic testing; a greater understanding of these issues may help health professionals to better meet the needs and concerns of individuals from high-risk families, thus possibly improving their health outcomes.
MeSH term(s)	Adult ; Breast Neoplasms/genetics ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Counseling ; Genetic Testing/psychology ; Humans ; Male ; Middle Aged ; Ovarian Neoplasms/genetics
Language	English
Publishing date	2007
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1345729-9
ISSN	1557-7473 ; 1090-6576
ISSN (online)	1557-7473
ISSN	1090-6576
DOI	10.1089/gte.2006.9998
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Article: Scale-free dynamics of the synchronization between sleep EEG power bands and the high frequency component of heart rate variability in normal men and patients with sleep apnea-hypopnea syndrome.

Dumont, Martine / Jurysta, Fabrice / Lanquart, Jean-Pol / Noseda, André / van de Borne, Philippe / Linkowski, Paul

Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology

2007 Volume 118, Issue 12, Page(s) 2752–2764

Abstract: Objective: To investigate the dynamics of the synchronization between heart rate variability and sleep electroencephalogram power spectra and the effect of sleep apnea-hypopnea syndrome.: Methods: Heart rate and sleep electroencephalogram signals ... ...

Abstract	Objective: To investigate the dynamics of the synchronization between heart rate variability and sleep electroencephalogram power spectra and the effect of sleep apnea-hypopnea syndrome. Methods: Heart rate and sleep electroencephalogram signals were recorded in controls and patients with sleep apnea-hypopnea syndrome that were matched for age, gender, sleep parameters, and blood pressure. Spectral analysis was applied to electrocardiogram and electroencephalogram sleep recordings to obtain power values every 20s. Synchronization likelihood was computed between time series of the normalized high frequency spectral component of RR-intervals and all electroencephalographic frequency bands. Detrended fluctuation analysis was applied to the synchronizations in order to qualify their dynamic behaviors. Results: For all sleep bands, the fluctuations of the synchronization between sleep EEG and heart activity appear scale free and the scaling exponent is close to one as for 1/f noise. We could not detect any effect due to sleep apnea-hypopnea syndrome. Conclusions: The synchronizations between the high frequency component of heart rate variability and all sleep power bands exhibited robust fluctuations characterized by self-similar temporal behavior of 1/f noise type. No effects of sleep apnea-hypopnea syndrome were observed in these synchronizations. Significance: Sleep apnea-hypopnea syndrome does not affect the interdependence between the high frequency component of heart rate variability and all sleep power bands as measured by synchronization likelihood.
MeSH term(s)	Action Potentials/physiology ; Adult ; Analysis of Variance ; Arrhythmias, Cardiac/diagnosis ; Arrhythmias, Cardiac/etiology ; Arrhythmias, Cardiac/physiopathology ; Cortical Synchronization ; Electrocardiography ; Electroencephalography/methods ; Heart Rate/physiology ; Humans ; Male ; Reference Values ; Sleep/physiology ; Sleep Apnea Syndromes/complications ; Sleep Apnea Syndromes/diagnosis ; Sleep Apnea Syndromes/physiopathology ; Statistics as Topic
Language	English
Publishing date	2007-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1463630-x
ISSN	1872-8952 ; 1388-2457 ; 0921-884X
ISSN (online)	1872-8952
ISSN	1388-2457 ; 0921-884X
DOI	10.1016/j.clinph.2007.08.018
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