Publications by authors named "Yves Jean Bignon"

180 Publications

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing.

Eur J Cancer 2021 Feb 10;146:30-47. Epub 2021 Feb 10.

Medical Oncology Department, Hospital Nuestra Señora de Sonsoles, Ávila, Ávila, Spain. Electronic address:

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices.
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http://dx.doi.org/10.1016/j.ejca.2020.12.023DOI Listing
February 2021

The Functions of the Demethylase JMJD3 in Cancer.

Int J Mol Sci 2021 Jan 19;22(2). Epub 2021 Jan 19.

Department of Oncogenetics, Centre Jean Perrin, CBRV, 63001 Clermont-Ferrand, France.

Cancer is a major cause of death worldwide. Epigenetic changes in response to external (diet, sports activities, etc.) and internal events are increasingly implicated in tumor initiation and progression. In this review, we focused on post-translational changes in histones and, more particularly, the tri methylation of lysine from histone 3 (H3K27me3) mark, a repressive epigenetic mark often under- or overexpressed in a wide range of cancers. Two actors regulate H3K27 methylation: Jumonji Domain-Containing Protein 3 demethylase (JMJD3) and Enhancer of zeste homolog 2 (EZH2) methyltransferase. A number of studies have highlighted the deregulation of these actors, which is why this scientific review will focus on the role of JMJD3 and, consequently, H3K27me3 in cancer development. Data on JMJD3's involvement in cancer are classified by cancer type: nervous system, prostate, blood, colorectal, breast, lung, liver, ovarian, and gastric cancers.
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http://dx.doi.org/10.3390/ijms22020968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835890PMC
January 2021

Gene- and pathway-level analyses of iCOGS variants highlight novel signaling pathways underlying familial breast cancer susceptibility.

Int J Cancer 2021 Apr 9;148(8):1895-1909. Epub 2021 Jan 9.

Inserm, U900, Institut Curie, Paris, France.

Single-nucleotide polymorphisms (SNPs) in over 180 loci have been associated with breast cancer (BC) through genome-wide association studies involving mostly unselected population-based case-control series. Some of them modify BC risk of women carrying a BRCA1 or BRCA2 (BRCA1/2) mutation and may also explain BC risk variability in BC-prone families with no BRCA1/2 mutation. Here, we assessed the contribution of SNPs of the iCOGS array in GENESIS consisting of BC cases with no BRCA1/2 mutation and a sister with BC, and population controls. Genotyping data were available for 1281 index cases, 731 sisters with BC, 457 unaffected sisters and 1272 controls. In addition to the standard SNP-level analysis using index cases and controls, we performed pedigree-based association tests to capture transmission information in the sibships. We also performed gene- and pathway-level analyses to maximize the power to detect associations with lower-frequency SNPs or those with modest effect sizes. While SNP-level analyses identified 18 loci, gene-level analyses identified 112 genes. Furthermore, 31 Kyoto Encyclopedia of Genes and Genomes and 7 Atlas of Cancer Signaling Network pathways were highlighted (false discovery rate of 5%). Using results from the "index case-control" analysis, we built pathway-derived polygenic risk scores (PRS) and assessed their performance in the population-based CECILE study and in a data set composed of GENESIS-affected sisters and CECILE controls. Although these PRS had poor predictive value in the general population, they performed better than a PRS built using our SNP-level findings, and we found that the joint effect of family history and PRS needs to be considered in risk prediction models.
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http://dx.doi.org/10.1002/ijc.33457DOI Listing
April 2021

Implementation of the TIP60/P400/H4K12ac Structure in Breast Cancer Cell Lines.

OMICS 2020 Dec 18. Epub 2020 Dec 18.

Department of Oncogenetics, Centre Jean Perrin, UFR de medécine, Clermont-Ferrand, France.

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http://dx.doi.org/10.1089/omi.2020.0196DOI Listing
December 2020

Role of UTX Histone Demethylase in Regulation of , , and Genes in Prostate Cancer Cell Lines.

OMICS 2021 Feb 18;25(2):129-131. Epub 2020 Dec 18.

Department of Oncogenetics, Centre Jean Perrin, CBRV, Clermont-Ferrand, France.

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http://dx.doi.org/10.1089/omi.2020.0183DOI Listing
February 2021

A high expression ratio of RhoA/RhoB is associated with the migratory and invasive properties of basal-like Breast Tumors.

Int J Med Sci 2020 1;17(17):2799-2808. Epub 2020 Oct 1.

INSERM U1240 IMoST, University of Clermont Auvergne, Clermont-Ferrand, F-63000, France.

Basal-like breast cancer is among the most aggressive cancers and there is still no effective targeted treatment. In order to identify new therapeutic targets, we performed mRNA-Seq on eight breast cancer cell lines. Among the genes overexpressed in basal-like tumors, we focused on the RhoA and RhoB genes, which encode small GTPases known to play a role in the actin cytoskeleton, allowing cells to migrate. qRT-PCR and Western blotting were used for expression studies. Migratory and invasive properties were analysed by wound healing and Boyden chambers assays. Stress fibers formation was evaluated by fluorescent actin labeling. Rho siRNA, small inhibitor Rhosin treatment and BRCA1 transfection were performed to study the role of Rho and BRCA1 proteins. We showed that strong expression of RhoA and low expression of RhoB was associated with the basal-like subtype of breast cancer. Decreasing RhoA expression reduced the migratory and invasive capacities of basal-like cell lines, while decreasing RhoB expression increased these capacities. Rhosin, an inhibitor of RhoA, could also reduce the migration of basal-like cell lines. Rho proteins are involved in the formation of stress fibers, a conformation of the actin cytoskeleton found in migrating cells: inhibition of RhoA expression decreased the formation of these fibers. , a gene frequently inactivated in basal-like tumors, appears to play a role in the differential expression of RhoA and RhoB in these tumors, as the restoration of BRCA1 expression in a BRCA1-mutated basal-like cell line decreased expression of RhoA and increased expression of RhoB, resulting in reduced migratory capacity. These results suggest Rho proteins as potential therapeutic targets for basal-like and BRCA1-mutated breast cancer, as migration and acquisition of mesenchymal properties are key functional pathways in these tumors with high metastatic potential.
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http://dx.doi.org/10.7150/ijms.43101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645338PMC
October 2020

Analysis of 11 candidate genes in 849 adult patients with suspected hereditary cancer predisposition.

Genes Chromosomes Cancer 2021 Feb 10;60(2):73-78. Epub 2020 Nov 10.

INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, Clermont-Ferrand, France.

Hereditary predisposition to cancer concerns between 5% and 10% of cancers. The main genes involved in the most frequent syndromes (hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome) were identified in the 1990s. Exploration of their functional pathways then identified novel genes for hereditary predisposition to cancer, and candidate genes whose involvement remains unclear. To determine the contribution of truncating variants in 11 candidate genes (BARD1, FAM175A, FANCM, MLH3, MRE11A, PMS1, RAD50, RAD51, RAD51B, RINT1, and XRCC2) to cancer predisposition in a population of interest, panel sequencing was performed in 849 patients with a suspected hereditary predisposition to cancer for whom a diagnostic panel of 38 genes identified no causal mutation. Sixteen truncating variants were found in FANCM (n = 7), RINT1 (n = 4), RAD50 (n = 2), BARD1, PMS1, and RAD51B. FANCM (adjusted P-value: .03) and RINT1 (adjusted P-value: .04) were significantly associated with hereditary breast and ovarian cancer. However, further studies are required to determinate the risk of cancer, including the segregation of the variants in the families of our cases. No mutation was identified in RAD51, MRE11A, FAM175A, XRCC2, or MLH3. The involvement of these genes in the hereditary predisposition to cancer cannot be ruled out, although if it exists it is rare or does not seem to involve truncating variants.
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http://dx.doi.org/10.1002/gcc.22911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756731PMC
February 2021

TIP60/P400/H4K12ac Plays a Role as a Heterochromatin Back-up Skeleton in Breast Cancer.

Cancer Genomics Proteomics 2020 Nov-Dec;17(6):687-694

Department of Oncogenetics, Centre Jean Perrin, CBRV, Clermont-Ferrand, France

Background/aim: In breast cancer, initiation of carcinogenesis leads to epigenetic dysregulation, which can lead for example to the loss of the heterochromatin skeleton SUV39H1/H3K9me3/HP1 or the supposed secondary skeleton TIP60/P400/H4K12ac/BRD (2/4), which allows the maintenance of chromatin integrity and plasticity. This study investigated the relationship between TIP60, P400 and H4K12ac and their implications in breast tumors.

Materials And Methods: Seventy-seven patients diagnosed with breast cancer were included in this study. Chromatin immunoprecipitation (ChIP) assay was used to identify chromatin modifications. Western blot and reverse transcription and quantitative real-time PCR were used to determine protein and gene expression, respectively.

Results: We verified the variation in H4K12ac enrichment and the co-localization of H4K12ac and TIP60 on the euchromatin and heterochromatin genes, respectively, by ChIP-qPCR and ChIP-reChIP, which showed an enrichment of H4K12ac on specific genes in tumors compared to the adjacent healthy tissue and a co-localization of H4K12ac with TIP60 in different breast tumor types. Furthermore, RNA and protein expression of TIP60 and P400 was investigated and overexpression of TIP60 and P400 mRNA was associated with tumor aggressiveness.

Conclusion: There is a potential interaction between H4K12ac and TIP60 in heterochromatin or euchromatin in breast tumors.
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http://dx.doi.org/10.21873/cgp.20223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675650PMC
August 2020

MUTYH-associated polyposis: Review and update of the French recommendations established in 2012 under the auspices of the National Cancer institute (INCa).

Eur J Med Genet 2020 Dec 12;63(12):104078. Epub 2020 Oct 12.

Department of Genetics. Institut Curie. PSL Research University, Paris, France. Electronic address:

MUTYH-associated polyposis (MAP) was first described in 2002. It is an autosomal recessive condition associated with germline pathogenic variants of both MUTYH alleles. In 2011, a group of French experts reviewed the available data on this syndrome and established recommendations concerning the indications and strategies for molecular analysis of the MUTYH gene in index cases and their relatives, as well as the clinical management of affected individuals under the auspices of the French Institut National du Cancer (INCa). Some of these recommendations have become obsolete as a result of recent progress, especially those concerning the molecular strategy for MUTYH testing, as this gene has recently been included in a consensus panel of 14 colorectal cancer predisposition genes, justifying revision of the previous report. We report here the revised version of this work, which successively considers the phenotype and tumor risks associated with this genotype, differential diagnoses, criteria and strategy for molecular genetic testing and recommendations for the management of affected individuals. We also discuss the phenotype and tumor risks associated with monoallelic pathogenic variants of MUTYH.
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http://dx.doi.org/10.1016/j.ejmg.2020.104078DOI Listing
December 2020

Feedback of extended panel sequencing in 1530 patients referred for suspicion of hereditary predisposition to adult cancers.

Clin Genet 2021 Jan 21;99(1):166-175. Epub 2020 Oct 21.

Département d'Oncogénétique, Centre Jean Perrin, Clermont-Ferrand, France.

High-throughput sequencing analysis represented both a medical diagnosis and technological revolution. Gene panel analysis is now routinely performed in the exploration of hereditary predisposition to cancer, which is becoming increasingly heterogeneous, both clinically and molecularly. We present 1530 patients with suspicion of hereditary predisposition to cancer, for which two types of analyses were performed: a) oriented according to the clinical presentation (n = 417), or b) extended to genes involved in hereditary predisposition to adult cancer (n = 1113). Extended panel analysis had a higher detection rate compared to oriented analysis in hereditary predisposition to breast / ovarian cancer (P < .001) and in digestive cancers (P < .094) (respectively 15% vs 5% and 19.3%, vs 12.5%). This higher detection is explained by the inclusion of moderate penetrance genes, as well as the identification of incident mutations and double mutations. Our study underscores the utility of proposing extended gene panel analysis to patients with suspicion of hereditary predisposition to adult cancer.
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http://dx.doi.org/10.1111/cge.13864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821123PMC
January 2021

Digging Deeper into Breast Cancer Epigenetics: Insights from Chemical Inhibition of Histone Acetyltransferase TIP60 .

OMICS 2020 10 22;24(10):581-591. Epub 2020 Sep 22.

Department of Oncogenetics, Centre Jean Perrin, CBRV, Clermont-Ferrand, France.

Breast cancer is often sporadic due to several factors. Among them, the deregulation of epigenetic proteins may be involved. TIP60 or KAT5 is an acetyltransferase that regulates gene transcription through the chromatin structure. This pleiotropic protein acts in several cellular pathways by acetylating proteins. RNA and protein expressions of TIP60 were shown to decrease in some breast cancer subtypes, particularly in triple-negative breast cancer (TNBC), where a low expression of TIP60 was exhibited compared with luminal subtypes. In this study, the inhibition of the residual activity of TIP60 in breast cancer cell lines was investigated by using two chemical inhibitors, TH1834 and NU9056, first on the acetylation of the specific target, lysine 4 of histone 3 (H3K4) by immunoblotting, and second, by chromatin immunoprecipitation (ChIP)-qPCR (-quantitative Polymerase Chain Reaction). Subsequently, significant decreases or a trend toward decrease of H3K4ac in the different chromatin compartments were observed. In addition, the expression of 48 human nuclear receptors was studied with TaqMan Low-Density Array in these breast cancer cell lines treated with TIP60 inhibitors. The statistical analysis allowed us to comprehensively characterize the androgen receptor and receptors in TNBC cell lines after TH1834 or NU9056 treatment. The understanding of the residual activity of TIP60 in the evolution of breast cancer might be a major asset in the fight against this disease, and could allow TIP60 to be used as a biomarker or therapeutic target for breast cancer progression in the future.
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http://dx.doi.org/10.1089/omi.2020.0104DOI Listing
October 2020

Role of JMJD3 Demethylase and Its Inhibitor GSK-J4 in Regulation of , , , and Genes in Prostate Cancer Cell Lines.

OMICS 2020 08 11;24(8):505-507. Epub 2020 Jun 11.

Department of Oncogenetics, Centre Jean Perrin, CBRV, Clermont-Ferrand, France.

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http://dx.doi.org/10.1089/omi.2020.0054DOI Listing
August 2020

Effectiveness of a Global Multidisciplinary Supportive and Educational Intervention in Thermal Resort on Anthropometric and Biological Parameters, and the Disease-Free Survival after Breast Cancer Treatment Completion (PACThe).

J Oncol 2020 5;2020:4181850. Epub 2020 May 5.

Jean Perrin Comprehensive Cancer Centre, Department of Oncogenetics, 58 Rue Montalembert, 63011 Clermont-Ferrand, France.

A growing knowledge highlights the strong benefit of regular physical activity in the management of breast cancer patients, but few studies have considered biological parameters in their outcomes. In the prospective randomised trial after breast cancer treatment completion "PACThe," we determined the effects of physical activity and nutritional intervention on the biological and anthropometric status of patients after one year of follow-up, and clarified the link between biomarkers at allocation and disease-free survival. 113 patients from the population of the "PACThe" study ( = 251) were analysed for biological parameters. Patients were randomized after chemotherapy in two arms: the intervention "SPA" receiving a 2-week session of physical training, dietary education, and physiotherapy ( = 57), and the control "CTR" ( = 56). Diet questionnaire, anthropometric measures, and blood parameters were determined at allocation and one year later. Survival and recurrence were checked over 7 years. Data were considered as a function of BMI, i.e., ≤25 for normal, 25-30 for overweight, and >30 for obese patients. At allocation, the large standard deviation for nutrient-intake values reflected an unbalanced diet for some patients in the three groups. At one-year follow-up, we noticed an increase in glucose ( < 10), insulin ( < 10), and adiponectin ( < 0.022) plasma levels for both intervention arms, which were more accentuated for the >30 groups. Using the Cox model, we demonstrated that the highest testosterone plasma values were linked to an increase of the recurrence risk (HR [CI-95%] = 5.06 [1.66-15.41]; =0.004). One-year after a global multidisciplinary supportive and educational intervention, we found few anthropometric and biological changes, mainly related to the patient's initial BMI. We highlighted the importance of plasma testosterone in the evaluation of patient's recurrence risk. Future studies would help better understand the mechanisms by which such multidisciplinary interventions could interact with breast cancer recurrence and define the most effective modalities.
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http://dx.doi.org/10.1155/2020/4181850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222596PMC
May 2020

Epi-drugs as triple-negative breast cancer treatment.

Epigenomics 2020 04 12;12(8):725-742. Epub 2020 May 12.

Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 place Henri-Dunant, Clermont-Ferrand 63001, France.

Triple-negative breast cancer (TNBC) types with poor prognosis are due to the absence of estrogen receptors, progesterone receptors and HEGFR-2. The lack of suitable therapy for TNBC has led the research community to turn toward epigenetic regulation and its protagonists that can modulate certain oncogenes and tumor suppressors. This has opened an important new field of therapy using epi-drugs, in preclinical and clinical trials. The epi-drugs are natural or synthetic molecules capable of inhibiting or modulating the activity of epigenetic proteins such as DNA methyltransferases, modulating the expression of interferon microRNAs, as well as histone methyltransferases, demethylases, acetyltransferases and deacetylases. This review investigated the epi-drugs used in the treatment of TNBC.
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http://dx.doi.org/10.2217/epi-2019-0312DOI Listing
April 2020

[MUTYH-associated polyposis: Review and update of the French recommendations established in 2012 under the auspices of the National Cancer Institute (INCa)].

Bull Cancer 2020 May 1;107(5):586-600. Epub 2020 May 1.

PSL Research University, Institut Curie, département de génétique, 26, rue d'Ulm, 75248 Paris cedex 05, France. Electronic address:

MUTYH-associated polyposis (MUTYH-associated polyposis, MAP) is an autosomal recessive inheritance disorder related to bi-allelic constitutional pathogenic variants of the MUTYH gene which was first described in 2002. In 2011, a group of French experts composed of clinicians and biologists, performed a summary of the available data on this condition and drew up recommendations concerning the indications and the modalities of molecular analysis of the MUTYH gene in index cases and their relatives, as well as the management of affected individuals. In view of recent developments, some recommendations have become obsolete, in particular with regard to the molecular analysis strategy since MUTYH gene has been recently included in a consensus panel of 14 genes predisposing to colorectal cancer. This led us to revise all the points of the previous expertise. We report here the revised version of this work which successively considers the phenotype and the tumor risks associated with this genotype, the differential diagnoses, the indication criteria and the strategy of the molecular analysis and the recommendations for the management of affected individuals. We also discuss the phenotype and the tumor risks associated with mono-allelic pathogenic variants of MUTYH gene.
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http://dx.doi.org/10.1016/j.bulcan.2020.02.004DOI Listing
May 2020

Co-targeting EGFR and mTOR with gefitinib and everolimus in triple-negative breast cancer cells.

Sci Rep 2020 04 14;10(1):6367. Epub 2020 Apr 14.

Université Clermont Auvergne, Faculté de médecine, INSERM, U1240, Imagerie Moléculaire et Stratégies Théranostiques, 28 place Henri Dunant, BP38-, 63001, Clermont, Ferrand, France.

Triple-negative breast cancers (TNBC) are unlikely to respond to hormonal therapies and anti-HER2-targeted therapies. TNBCs overexpress EGFR and exhibit constitutive activation of the PI3K/AKT/mTOR signalling pathway. We hypothesized that simultaneously blocking EGFR and mTOR could be a potential therapeutic strategy for the treatment of TNBC. We examined the antitumour activity of the mTOR inhibitor everolimus combined with the EGFR tyrosine kinase inhibitor gefitinib in TNBC cell with or without activating mutations in the PI3K/AKT/mTOR signalling pathway. We demonstrated that everolimus and gefitinib induced synergistic growth inhibition in the PI3K and PTEN-mutant CAL-51 cell line but not in the PTEN-null HCC-1937 cell line. The antiproliferative effect was associated with synergistic inhibition of mTOR and P70S6K phosphorylation, as well as a significant reduction in 4E-BP1 activation in the CAL-51 cell line. We also showed that combination therapy significantly inhibited cell cycle progression and increased apoptosis in this cell line. Gene and protein expression analysis revealed significant downregulation of cell cycle regulators after exposure to combined treatment. Collectively, these results suggested that dual inhibition of mTOR and EGFR may be an effective treatment for TNBC with activating mutations of PI3K.
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http://dx.doi.org/10.1038/s41598-020-63310-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156377PMC
April 2020

The Inhibition of the Histone Methyltransferase EZH2 by DZNEP or SiRNA Demonstrates Its Involvement in , , , and Gene Regulation in Prostate Cancer.

OMICS 2020 02 31;24(2):116-118. Epub 2019 Dec 31.

Department of Oncogenetics, Centre Jean Perrin, CBRV, Clermont-Ferrand, France.

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http://dx.doi.org/10.1089/omi.2019.0162DOI Listing
February 2020

Is BRCA2 involved in early onset colorectal cancer risk?

Clin Genet 2020 04 26;97(4):668-669. Epub 2019 Dec 26.

Université Clermont Auvergne, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Clermont Ferrand, France.

A, Closed symbols indicate patients affected with cancer. Open symbols indicate healthy individuals. The type of cancer and age at presentation are given in brackets. Blue circle represents c.4471_4474del variant and red circle represents the c.9648 + 1G > A. B, RNA was extracted from blood of patient III-3 and his sisters III-1 and III-4. RT-PCR analysis was performed with primers mapping to exons 25 and 27, and PCR products were separated by Bioanalyzer electrophoresis. The sizes of the DNA marker (M) are indicated to the left. LM, lower marker; UM, upper marker. C, Each RT-PCR product from patient III-3 was gel-purified and analyzed by Sanger sequencing. The 297-bp band corresponds to the reference BRCA2 transcript and the 150-bp band corresponds to a BRCA2 transcript lacking exon 26.
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http://dx.doi.org/10.1111/cge.13679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078894PMC
April 2020

TIP60 Inhibitor TH1834 Reduces Breast Cancer Progression in Xenografts in Mice.

OMICS 2019 09;23(9):457-459

Department of Oncogenetics, Centre Jean Perrin, CBRV, Clermont-Ferrand, France.

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http://dx.doi.org/10.1089/omi.2019.0126DOI Listing
September 2019

Psychosocial and clinical factors of probands impacting intrafamilial disclosure and uptake of genetic testing among families with BRCA1/2 or MMR gene mutations.

Psychooncology 2019 08 19;28(8):1679-1686. Epub 2019 Jun 19.

Unité d'Oncogénétique, Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire Montpellier, MIVEGEC, Montpellier, France.

Objective: Intrafamilial disclosure of hereditary cancer predisposition in BRCA1/2 and mismatch repair gene (MMR) syndromes allows appropriate prevention strategies in at-risk relatives. We previously showed in a nationwide study that the uptake of genetic targeted testing (GTT) in these families was only 30%. We aimed to identify the clinical and psychosocial factors affecting the probands' intrafamilial disclosure and relatives' uptake of GTT in BRCA1/2 or MMR syndromes.

Methods: We assessed clinical variables, family history, and psychosocial variables of probands (depressive symptoms, anxiety, alexithymia, optimism, coping, family relationship, perception of cancer risks, and of hereditary transmission), together with disclosure and uptake of GTT within 103 French BRCA1/2 or MMR families.

Results: Among relatives eligible for GTT, 68% were informed of the predisposition, and 37% underwent GTT, according to probands' reports. Intrafamilial disclosure was inversely associated with the degree of kinship (P < .01). In multivariable analysis, disclosure increased with time since probands' genetic diagnosis (P < .01) and probands' feeling of family cohesion (0.01). GTT uptake increased with probands' depressive symptoms (0.02) and decreased with probands' perception of cancer risks (0.03). BRCA1/2 and MMR groups did not differ concerning family information and GTT uptake.

Conclusions: This study identified factors affecting disclosure to relatives and GTT uptake in BRCA1/2 and MMR syndromes and gives new insights to improve probands' follow-up and intrafamilial sharing of genetic information.
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http://dx.doi.org/10.1002/pon.5142DOI Listing
August 2019

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma.

Leukemia 2019 09 9;33(9):2324-2330. Epub 2019 Apr 9.

ProfilExpert, Lyon, France.

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http://dx.doi.org/10.1038/s41375-019-0452-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756025PMC
September 2019

BRACAVENIR: an observational study of expectations and coping in young women with high hereditary risk of breast and ovarian cancer.

Hered Cancer Clin Pract 2019 27;17. Epub 2019 Feb 27.

Oncogenetics department, Comprehensive Cancer Center Jean Perrin, 58, rue Montalembert, 63011 Clermont-Ferrand, France.

Background: In families with high risk of hereditary breast/ovarian cancer (HBOC), women before age 30 do not yet undergo clinical screening, but they are exposed to contradictory information from diverse sources. They may be presented with surgical prevention options at a key moment of their identity construction, the start of a marital relationship and/or at the onset of procreation projects. We tested an original psychoeducational intervention to help these women better cope with these difficult issues.

Methods: Seven young female counselees (26.4 ± 2.9 years [23-30]) from the Oncogenetics Department at Jean Perrin Comprehensive Cancer Center were enrolled. A weekend group workshop composed of short conferences, group sharing and role playing activities was supervised by a psychotherapist. A longitudinal analysis of questionnaires over one year of follow-up was performed. The Herth Hope Inventory was evaluated, as well as self-esteem, anxiety, perceived control, coping, and quality of life. Participants' comments were collected by a genetic counselor throughout the workshop.

Results: All participants were BRCA mutation carriers and six had lived with a close relative affected by breast/ovarian cancer. Hope, self-esteem and quality of life increased during the year after the workshop ( = 0.0003). Coping by focus on the problem increased in the first 6 months ( = 0.011) and returned to baseline values at one year, while coping by focus on emotions decreased steadily ( = 0.021). Debriefing from the workshop highlighted the new medical opportunities proposed and the challenges these young women face, such as whether to have prophylactic surgery, and if so before or after having children, and how surgery might affect their relationship with their partner.

Conclusion: A tailored two-day psychoeducational workshop may be sufficient to improve the way young women with BRCA mutations deal with the implications of HBOC risk.

Trial Registration: BRACAVENIR was registered in ClinicalTrials.gov with no NCT02705924.
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http://dx.doi.org/10.1186/s13053-019-0107-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391839PMC
February 2019

Association between hereditary predisposition to common cancers and congenital multimalformations.

Congenit Anom (Kyoto) 2020 Jan 12;60(1):22-31. Epub 2019 Mar 12.

Oncogenetics Department, Centre Jean Perri (Comprehensive Cancer Center), Clermont-Ferrand, France.

In a previous article we reported that mutations favoring cancer at adulthood seemed to improve fertility and limit miscarriages. Because spontaneous abortion may result from anomalies in embryo, we questioned if an increased frequency of congenital malformation could be evidenced among cancer-prone families. Oncogenetics database (≈193 000 members) of the comprehensive cancer center Jean Perrin was crossed with regional registry of congenital malformations (≈10 000). Among children born between 1986 and 2011, 176 children with malformation matched in both databases. In breast/ovaries cancer-prone families, the risk for malformations was multiplied by 2.4 [1.2-4.5] in case of a BRCA1 mutation. Frequencies of malformation in BRCA2 and MMR mutated families were similar to families without a cancer syndrome. In comparison to malformations concerning a unique anatomical system, multimalformations were significantly more frequent in case of BRCA or MMR mutations: compared to families without cancer syndrome, the risk of multimalformations was multiplied by 4.1 [0.8-21.7] for cancer-prone families but with no known deleterious mutation, by 6.9 [1.2-38.6] in families with a known mutation but an unknown parental mutational status and by 10.4 [2.3-46.0] when one parent carried the familial mutation. No association with the type of anatomical system was found, nor with multiple births. These results suggest that BRCA and MMR genes play an important role in human embryogenesis and that if their function is lowered because of heterozygote mutations, congenital malformations are either more likely (BRCA1 mutations) and/or more susceptible to concern several anatomical systems.
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http://dx.doi.org/10.1111/cga.12329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973007PMC
January 2020

Breaking down the Contradictory Roles of Histone Deacetylase SIRT1 in Human Breast Cancer.

Cancers (Basel) 2018 Oct 30;10(11). Epub 2018 Oct 30.

Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 place Henri-Dunant, 63001 Clermont-Ferrand, France.

Breast cancer (BC) is the most common type of cancer in women worldwide; it is a multifactorial genetic disease. Acetylation and deacetylation are major post-translational protein modifications that regulate gene expression and the activity of a myriad of oncoproteins. Aberrant deacetylase activity can promote or suppress tumorigenesis and cancer metastasis in different types of human cancers, including breast cancer. Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC) that deacetylates both histone and non-histone targets. The often-described 'regulator of regulators' is deeply implicated in apoptosis, gene regulation, genome maintenance, DNA repair, aging, and cancer development. However, despite the accumulated studies over the past decade, the role of SIRT1 in human breast cancer remains a subject of debate and controversy. The ambiguity surrounding the implications of SIRT1 in breast tumorigenesis stems from the discrepancy between studies, which have shown both tumor-suppressive and promoting functions of SIRT1. Furthermore, studies have shown that SIRT1 deficiency promotes or suppresses tumors in breast cancer, making it an attractive therapeutic target in cancer treatment. This review provides a comprehensive examination of the various implications of SIRT1 in breast cancer development and metastasis. We will also discuss the mechanisms underlying the conflicting roles of SIRT1, as well as its selective modulators, in breast carcinogenesis.
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http://dx.doi.org/10.3390/cancers10110409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266715PMC
October 2018

BRCA1/BRCA2 Mutations Shaped by Ancient Consanguinity Practice in Southern Mediterranean Populations

Asian Pac J Cancer Prev 2018 Oct 26;19(10):2963-2972. Epub 2018 Oct 26.

Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, Université de Tunis El Manar, Campus universitaire1060 El Manar I Tunis, Tunisia. Email:

The aim of this study is to investigate the involvement of consanguinity on BRCA1/2 mutation incidence in Southern Mediterranean populations and to confirm their low penetrance by comparison of their recurrence in sporadic and familial breast cancer in a context of ancient consanguinity practice. Our study comprises of two parts: First, a comparison of the consanguinity rates of the South Mediterranean countries in a relationship with the frequency of BRCA1 deleterious mutations in breast cancer families and the recurrence of these mutations. Second, we investigated 23patients with a family history of breast cancer, 51 patients without a family history of breast cancer using next-generation sequencing of BRCA2 and then confirmed by Sanger sequencing for the novel mutation. As results, we clearly show a strong relationship between the frequency of BRCA1 deleterious mutations in breast cancer families and rate of consanguinity, since they are significantly inversely correlated. Four deleterious mutations were found in BRCA2 gene including a novel frame-shift mutationc.9382_9383dup in a patient with familial breast cancer and three other frame-shift mutations c.6591_6592del, c.1310_1313del and c.7654dup in patients with sporadic breast cancer.These results are discussed in a context of selective pressure of ancient consanguinity practice. In conclusion, the study of BRCA1/2 gene in Southern Mediterranean countries revealed low penetrance recurrent mutations in sporadic and familial breast cancer. These mutations have been selected in a context of ancient consanguinity practice along with protective genetic and environmental factors.
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http://dx.doi.org/10.22034/APJCP.2018.19.10.2963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291031PMC
October 2018

TIP60: an actor in acetylation of H3K4 and tumor development in breast cancer.

Epigenomics 2018 11 16;10(11):1415-1430. Epub 2018 Oct 16.

Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 Place Henri-Dunant, 63001, Clermont-Ferrand, France.

Aim: The acetyltransferase TIP60 is reported to be downregulated in several cancers, in particular breast cancer, but the molecular mechanisms resulting from its alteration are still unclear.

Materials & Methods: In breast tumors, H3K4ac enrichment and its link with TIP60 were evaluated by chromatin immunoprecipitation-qPCR and re-chromatin immunoprecipitation techniques. To assess the biological roles of TIP60 in breast cancer, two cell lines of breast cancer, MDA-MB-231 (ER-) and MCF-7 (ER+) were transfected with shRNA specifically targeting TIP60 and injected to athymic Balb-c mice.

Results: We identified a potential target of TIP60, H3K4. We show that an underexpression of TIP60 could contribute to a reduction of H3K4 acetylation in breast cancer. An increase in tumor development was noted in sh-TIP60 MDA-MB-231 xenografts and a slowdown of tumor growth in sh-TIP60 MCF-7 xenografts.

Conclusion: This is evidence that the underexpression of TIP60 observed in breast cancer can promote the tumorigenesis of ER-negative tumors.
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http://dx.doi.org/10.2217/epi-2018-0004DOI Listing
November 2018

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.

Int J Cancer 2019 04 13;144(8):1962-1974. Epub 2018 Nov 13.

Inserm, Paris, France.

Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost-effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious-predicted variants in DNA repair genes in familial breast cancer (BC) in a well-characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC (N = 1,207), and general population controls (N = 1,199). Sequencing data were filtered for rare loss-of-function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2, ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI, MAST1, POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (OR = 17.4 vs. OR = 1.6; p = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious-predicted variants in PALB2, ATM and CHEK2 and to add MAST1, POLH, RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates.
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http://dx.doi.org/10.1002/ijc.31921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587727PMC
April 2019

Early Onset Multiple Primary Tumors in Atypical Presentation of Cowden Syndrome Identified by Whole-Exome-Sequencing.

Front Genet 2018 31;9:353. Epub 2018 Aug 31.

INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, Clermont-Ferrand, France.

A family with an aggregation of rare early onset multiple primary tumors has been managed in our oncogenetics department: the proband developed four early onset carcinomas between ages 31 and 33 years, including acral melanoma, bilateral clear cell renal carcinoma (RC), and follicular variant of papillary thyroid carcinoma. The proband's parent developed orbital lymphoma and small intestine mucosa-associated lymphoid tissue (MALT) lymphoma between 40 and 50 years old. Whole-exome-sequencing (WES) of the nuclear family (proband, parents, and sibling) identified in the proband a deleterious heterozygous mutation c.1003C > T (p.Arg335) in the phosphatase and tensin homolog () gene. Furthermore, WES allowed analysis of the nuclear family's genetic background, and identified deleterious variants in two candidate modifier genes: and . , a tumor suppressor gene, presents loss of expression in clear cell RC and is involved in proliferation of B cells. It could explain in part the phenotype of proband's parent and the occurrence of clear cell RC in the proband. Deleterious mutations in the gene are associated with melanoma invasion, and could explain the occurrence of melanoma in the proband. Cowden syndrome is a hereditary autosomal dominant disorder associated with increased risk of muco-cutaneous features, hamartomatous tumors, and cancer. This atypical presentation, including absence of muco-cutaneous lesions, four primary early onset tumors and bilateral clear cell RC, has not been described before. This encourages including the gene in panel testing in the context of early onset RC, whatever the histological subtype. Further studies are required to determine the implication of and in the severity of Cowden syndrome in our proband and occurrence of early onset MALT lymphoma in a parent.
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http://dx.doi.org/10.3389/fgene.2018.00353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127642PMC
August 2018

Exciting History of Tip60 and Its Companions in Carcinogenesis Across the Heterochromatin Landscapes.

OMICS 2018 09 14;22(9):626-628. Epub 2018 Aug 14.

1 Department of Oncogenetics, Centre Jean Perrin , CBRV, Clermont-Ferrand, France .

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http://dx.doi.org/10.1089/omi.2018.0122DOI Listing
September 2018