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1. Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants

Author: Richard Gallon, Carlijn Brekelmans, Marie Martin, Vincent Bours, Esther Schamschula, Albert Amberger, Martine Muleris, Chrystelle Colas, Jeroen Dekervel, Gert De Hertogh, Jérôme Coupier, Orphal Colleye, Edith Sepulchre, John Burn, Hilde Brems, Eric Legius, and Katharina Wimmer
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are distinct cancer syndromes caused, respectively, by mono- and bi-allelic germline mismatch repair (MMR) variants. LS predisposes to mainly gastrointestinal and genitourinary cancers in adulthood. CMMRD predisposes to brain, haematological, and LS-spectrum cancers from childhood. Two suspected LS patients with first cancer diagnosis aged 27 or 38 years were found to be homozygous for an MMR (likely) pathogenic variant, MSH6 c.3226C>T (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G>A (p.(Glu102=)). MLH1 c.306G>A was shown to cause leaky exon 3 skipping. The apparent genotype-phenotype conflict was resolved by detection of constitutional microsatellite instability in both patients, a hallmark feature of CMMRD. A hypomorphic effect of these and other variants found in additional late onset CMMRD cases, identified by literature review, likely explains a LS-like phenotype. CMMRD testing in carriers of compound heterozygous or homozygous MMR VUS may find similar cases and novel hypomorphic variants. Individualised management of mono- and bi-allelic carriers of hypomorphic MMR variants is needed until we better characterise the associated phenotypes.
Published: 2024
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2. Male breast cancer: No evidence for mosaic BRCA1 promoter methylation involvement

Author: Mathias Schwartz, Sabrina Ibadioune, Sophie Vacher, Marie-Charlotte Villy, Olfa Trabelsi-Grati, Jessica Le Gall, Sandrine M. Caputo, Hélène Delhomelle, Mathilde Warcoin, Virginie Moncoutier, Christine Bourneix, Nadia Boutry-Kryza, Antoine De Pauw, Marc-Henri Stern, Bruno Buecher, Emmanuelle Mouret-Fourme, Chrystelle Colas, Dominique Stoppa-Lyonnet, Julien Masliah-Planchon, Lisa Golmard, and Ivan Bieche
Subjects: HBOC syndrome, Breast neoplasm, Genetic testing, Homologous recombination, DNA methylation, Epigenomics, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Breast cancers (BC) are rare in men and are often caused by constitutional predisposing factors. In women, mosaic BRCA1 promoter methylations (MBPM) are frequent events, detected in 4–8% of healthy subjects. This constitutional epimutation increases risk of early-onset and triple-negative BC. However, the role of MBPM in male BC predisposition has never been assessed. We screened 40 blood samples from men affected by BC, and performed extensive tumour analysis on MBPM-positive patients. We detected two patients carrying MBPM. Surprisingly, tumour analysis revealed that neither of these two male BCs were caused by the constitutional BRCA1 epimutations carried by the patients.
Published: 2024
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3. Clinical implications of incorporating genetic and non-genetic risk factors in CanRisk-based breast cancer risk prediction

Author: Anja Tüchler, Antoine De Pauw, Corinna Ernst, Amélie Anota, Inge M.M. Lakeman, Julia Dick, Nienke van der Stoep, Christi J. van Asperen, Monika Maringa, Natalie Herold, Britta Blümcke, Robert Remy, Anke Westerhoff, Denise J. Stommel-Jenner, Eléonore Frouin, Lisa Richters, Lisa Golmard, Nadine Kütting, Chrystelle Colas, Barbara Wappenschmidt, Kerstin Rhiem, Peter Devilee, Dominique Stoppa-Lyonnet, Rita K. Schmutzler, and Eric Hahnen
Subjects: Breast cancer, Genetic testing, Hereditary breast and ovarian cancer syndrome, Cancer prevention, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Background: Breast cancer (BC) risk prediction models consider cancer family history (FH) and germline pathogenic variants (PVs) in risk genes. It remains elusive to what extent complementation with polygenic risk score (PRS) and non-genetic risk factor (NGRFs) data affects individual intensified breast surveillance (IBS) recommendations according to European guidelines. Methods: For 425 cancer-free women with cancer FH (mean age 40·6 years, range 21–74), recruited in France, Germany and the Netherlands, germline PV status, NGRFs, and a 306 variant-based PRS (PRS306) were assessed to calculate estimated lifetime risks (eLTR) and estimated 10-year risks (e10YR) using CanRisk. The proportions of women changing country-specific European risk categories for IBS recommendations, i.e. ≥20 % and ≥30 % eLTR, or ≥5 % e10YR were determined. Findings: Of the women with non-informative PV status, including PRS306 and NGRFs changed clinical recommendations for 31·0 %, (57/184, 20 % eLTR), 15·8 % (29/184, 30 % eLTR) and 22·4 % (41/183, 5 % e10YR), respectively whereas of the women tested negative for a PV observed in their family, clinical recommendations changed for 16·7 % (25/150), 1·3 % (2/150) and 9·5 % (14/147). No change was observed for 82 women with PVs in high-risk genes (BRCA1/2, PALB2). Combined consideration of eLTRs and e10YRs identified BRCA1/2 PV carriers benefitting from IBS
Published: 2024
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4. Diagnostic chest X-rays and breast cancer risk among women with a hereditary predisposition to breast cancer unexplained by a BRCA1 or BRCA2 mutation

Author: Maximiliano Ribeiro Guerra, Juliette Coignard, Séverine Eon-Marchais, Marie-Gabrielle Dondon, Dorothée Le Gal, Juana Beauvallet, Noura Mebirouk, Muriel Belotti, Olivier Caron, Marion Gauthier-Villars, Isabelle Coupier, Bruno Buecher, Alain Lortholary, Jean-Pierre Fricker, Paul Gesta, Catherine Noguès, Laurence Faivre, Pascaline Berthet, Elisabeth Luporsi, Capucine Delnatte, Valérie Bonadona, Christine M. Maugard, Pascal Pujol, Christine Lasset, Michel Longy, Yves-Jean Bignon, Claude Adenis-Lavignasse, Laurence Venat-Bouvet, Hélène Dreyfus, Laurence Gladieff, Isabelle Mortemousque, Séverine Audebert-Bellanger, Florent Soubrier, Sophie Giraud, Sophie Lejeune-Dumoulin, Jean-Marc Limacher, Jean Chiesa, Anne Fajac, Anne Floquet, François Eisinger, Julie Tinat, Sandra Fert-Ferrer, Chrystelle Colas, Thierry Frebourg, Francesca Damiola, Laure Barjhoux, Eve Cavaciuti, Sylvie Mazoyer, Anne Tardivon, Fabienne Lesueur, Dominique Stoppa-Lyonnet, and Nadine Andrieu
Subjects: Breast cancer, X-ray exposure, Low dose, High-risk population, DNA repair genes, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Diagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation. Methods We evaluated the effect of chest X-rays from diagnostic medical procedures in a dataset composed of 1552 BC cases identified through French family cancer clinics and 1363 unrelated controls. Participants reported their history of X-ray exposures in a detailed questionnaire and were tested for 113 DNA repair genes. Logistic regression and multinomial logistic regression models were used to assess the association with BC. Results Chest X-ray exposure doubled BC risk. A 3% increased BC risk per additional exposure was observed. Being 20 years old or younger at first exposure or being exposed before first full-term pregnancy did not seem to modify this risk. Birth after 1960 or carrying a rare likely deleterious coding variant in a DNA repair gene other than BRCA1/2 modified the effect of chest X-ray exposure. Conclusion Ever/never chest X-ray exposure increases BC risk 2-fold regardless of age at first exposure and, by up to 5-fold when carrying 3 or more rare variants in a DNA repair gene. Further studies are needed to evaluate other DNA repair genes or variants to identify those which could modify radiation sensitivity. Identification of subpopulations that are more or less susceptible to ionizing radiation is important and potentially clinically relevant.
Published: 2021
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5. No Overt Clinical Immunodeficiency Despite Immune Biological Abnormalities in Patients With Constitutional Mismatch Repair Deficiency

Author: Victoria K. Tesch, Hanna IJspeert, Andrea Raicht, Daniel Rueda, Nerea Dominguez-Pinilla, Luis M. Allende, Chrystelle Colas, Thorsten Rosenbaum, Denisa Ilencikova, Hagit N. Baris, Michaela H. M. Nathrath, Manon Suerink, Danuta Januszkiewicz-Lewandowska, Iman Ragab, Amedeo A. Azizi, Soeren S. Wenzel, Johannes Zschocke, Wolfgang Schwinger, Matthias Kloor, Claudia Blattmann, Laurence Brugieres, Mirjam van der Burg, Katharina Wimmer, and Markus G. Seidel
Subjects: primary immunodeficiency, hyper-IgM syndrome, DNA repair defect, mismatch repair, somatic hypermutation, class-switch recombination, Immunologic diseases. Allergy, RC581-607
Abstract: Immunoglobulin class-switch recombination (CSR) and somatic hypermutations (SHMs) are prerequisites for antibody and immunoglobulin receptor maturation and adaptive immune diversity. The mismatch repair (MMR) machinery, consisting of homologs of MutSα, MutLα, and MutSβ (MSH2/MSH6, MLH1/PMS2, and MSH2/MSH3, respectively) and other proteins, is involved in CSR, primarily acting as a backup for nonhomologous end-joining repair of activation-induced cytidine deaminase-induced DNA mismatches and, furthermore, in addition to error-prone polymerases, in the repair of SHM-induced DNA breaks. A varying degree of antibody formation defect, from IgA or selective IgG subclass deficiency to common variable immunodeficiency and hyper-IgM syndrome, has been detected in a small number of patients with constitutional mismatch repair deficiency (CMMRD) due to biallelic loss-of-function mutations in one of the MMR genes (PMS2, MSH6, MLH1, or MSH2). To elucidate the clinical relevance of a presumed primary immunodeficiency (PID) in CMMRD, we systematically collected clinical history and laboratory data of a cohort of 15 consecutive, unrelated patients (10 not previously reported) with homozygous/compound heterozygous mutations in PMS2 (n = 8), MSH6 (n = 5), and MLH1 (n = 2), most of whom manifested with typical malignancies during childhood. Detailed descriptions of their genotypes, phenotypes, and family histories are provided. Importantly, none of the patients showed any clinical warning signs of PID (infections, immune dysregulation, inflammation, failure to thrive, etc.). Furthermore, we could not detect uniform or specific patterns of laboratory abnormalities. The concentration of IgM was increased in 3 out of 12, reduced in 3 out of 12, and normal in 6 out of 12 patients, while concentrations of IgG and IgG subclasses, except IgG4, and of IgA, and specific antibody formation were normal in most. Class-switched B memory cells were reduced in 5 out of 12 patients, and in 9 out of 12 also the CD38hiIgM− plasmablasts were reduced. Furthermore, results of next generation sequencing-based analyses of antigen-selected B-cell receptor rearrangements showed a significantly reduced frequency of SHM and an increased number of rearranged immunoglobulin heavy chain (IGH) transcripts that use IGHG3, IGHG1, and IGHA1 subclasses. T cell subsets and receptor repertoires were unaffected. Together, neither clinical nor routine immunological laboratory parameters were consistently suggestive of PID in these CMMRD patients, but previously shown abnormalities in SHM and rearranged heavy chain transcripts were confirmed.
Published: 2018
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6. APCgermline pathogenic variants and epithelial ovarian cancer: causal or coincidental findings?

Author: Roseline Vibert, Jessica Le Gall, Bruno Buecher, Emmanuelle Mouret-Fourme, Guillaume Bataillon, Véronique Becette, Olfa Trabelsi-Grati, Virginie Moncoutier, Catherine Dehainault, Jennifer Carriere, Mathias Schwartz, Voreak Suybeng, Ivan Bieche, Chrystelle Colas, Anne Vincent-Salomon, Dominique Stoppa-Lyonnet, and Lisa Golmard
Subjects: Genetics, Genetics (clinical)
Abstract: APCgermline pathogenic variants result in predisposition to familial adenomatous polyposis and extraintestinal tumours such as desmoid fibromatosis, medulloblastomas and thyroid cancers. They have also been recently involved in ovarian microcystic stromal tumours.APCinactivation has been described at the tumour level in epithelial ovarian cancers (EOCs). Here, we report the identification ofAPCgermline pathogenic variants in two patients diagnosed with premenopausal EOC in early 30s, with no other pathogenic variant detected in the known ovarian cancer predisposing genes. Subsequent tumour analysis showed neither a second hit ofAPCinactivation nor β-catenin activation. Both tumours did not have a homologous recombination (HR) deficiency, pointing towards the implication of other genes than those involved in HR.APCmay contribute to the carcinogenesis of EOC in a multifactorial context. Further studies are required to clarify the role ofAPCin predisposition to EOC.
Published: 2022
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7. First estimates of diffuse gastric cancer risks for carriers of CTNNA1 germline pathogenic variants

Author: Marie Coudert, Youenn Drouet, Hélène Delhomelle, Magali Svrcek, Patrick R Benusiglio, Florence Coulet, Dana Farengo Clark, Bryson W Katona, Liselotte P van Hest, Lizet E van der Kolk, Annemieke Cats, Jolanda M van Dieren, Bita Nehoray, Thomas Slavin, Isabel Spier, Robert Hüneburg, Silvana Lobo, Carla Oliveira, Lise Boussemart, Laure Masson, Jean Chiesa, Mathias Schwartz, Bruno Buecher, Lisa Golmard, Anne-Marie Bouvier, Valérie Bonadona, Dominique Stoppa-lyonnet, Christine Lasset, Chrystelle Colas, Human genetics, and CCA - Cancer biology and immunology
Subjects: Genetics, Genetics (clinical)
Abstract: BackgroundPathogenic variants (PV) ofCTNNA1are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate diffuse gastric cancer (DGC) risks for carriers of germlineCTNNA1PV.MethodsData from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A ‘leave-one-out’ strategy was used to evaluate estimate uncertainty.ResultsThirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers ofCTNNA1PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL.ConclusionThis is the largest series ofCTNNA1families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion ofCTNNA1in germline testing panels.
Published: 2022
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8. Lynch syndrome: influence of additional susceptibility variants on cancer risk

Author: Roseline Vibert, Jasmine Hasnaoui, Alexandre Perrier, Alexandra Lefebvre, Chrystelle Colas, Marion Dhooge, Noémie Basset, Albain Chansavang, Camille Desseignes, Alex Duval, Solenne Farelly, Nadim Hamzaoui, Pierre Laurent-Puig, Julie Metras, Diane Moliere, Martine Muleris, Jeanne Netter, Mehdi Touat, Franck Bielle, Karim Labreche, Romain Nicolle, Géraldine Perkins, Mathilde Warcoin, Florence Coulet, and Patrick R. Benusiglio
Subjects: Genetics, Genetics (clinical)
Published: 2023
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9. Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency

Author: Richard Gallon, Rachel Phelps, Christine Hayes, Laurence Brugieres, Léa Guerrini-Rousseau, Chrystelle Colas, Martine Muleris, Neil A.J. Ryan, D. Gareth Evans, Hannah Grice, Emily Jessop, Annabel Kunzemann-Martinez, Lilla Marshall, Esther Schamschula, Klaus Oberhuber, Amedeo A. Azizi, Hagit Baris Feldman, Andreas Beilken, Nina Brauer, Triantafyllia Brozou, Karin Dahan, Ugur Demirsoy, Benoît Florkin, William Foulkes, Danuta Januszkiewicz-Lewandowska, Kristi J. Jones, Christian P. Kratz, Stephan Lobitz, Julia Meade, Michaela Nathrath, Hans-Jürgen Pander, Claudia Perne, Iman Ragab, Tim Ripperger, Thorsten Rosenbaum, Daniel Rueda, Tomasz Sarosiek, Astrid Sehested, Isabel Spier, Manon Suerink, Stefanie-Yvonne Zimmermann, Johannes Zschocke, Gillian M. Borthwick, Katharina Wimmer, John Burn, Michael S. Jackson, and Mauro Santibanez-Koref
Subjects: Constitutional Mutation Burden, Hepatology, Pediatric Cancer, Gastroenterology, Functional Test, Replication Error Repair
Abstract: BACKGROUND & AIMS: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood.METHODS: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls.RESULTS: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor.CONCLUSIONS: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk.
Published: 2023
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10. Preimplantation genetic testing in patients with genetic susceptibility to cancer

Author: Marie-Charlotte Villy, Nelly Frydman, Céline Moutou, Gaëlle Thierry, Jade Raad, Chrystelle Colas, Julie Steffann, Julie Metras, Nathalie Chabbert-Buffet, Yann Parc, Stéphane Richard, and Patrick R. Benusiglio
Subjects: Cancer Research, Oncology, Genetics, Genetics (clinical)
Abstract: Data on preimplantation genetic testing (PGT-M) in patients with genetic susceptibility to cancer are scarce in the literature, while there is, in our experience, a growing familiarity with assisted reproduction techniques (ART) among pathogenic variant heterozygotes. We performed a retrospective multicenter study of PGT-M outcomes among French patients with genetic susceptibility to cancer. Our objectives were to collect data on this complex issue, and to help cancer geneticists counsel their patients of reproductive age. We also wanted to increase awareness regarding PGT-M among cancer genetics professionals. Patients from three university hospital cancer genetics clinics who had requested PGT-M between 2000 and 2019 were included retrospectively. Data were extracted from medical records. Patients were then contacted directly to collect missing and up-to-date information. Out of 41 eligible patients, 28 agreed explicitly to participate when contacted and were therefore included. They carried PV in VHL (n = 9), APC (n = 8), CDH1 (n = 5), STK11 (n = 2), AXIN2, BRCA1, MEN1, and FH (n = 1). Seven patients were denied PGT-M based on multidisciplinary team meetings or subsequently by the ART hospital teams, two changed their minds, and two were yet to start the process. PGT-M was successful in seven patients (25%), with a mean age at PGT-M request of 27. Most had von Hippel-Lindau. PGT-M failed in the remaining ten, with a mean age at PGT-M request of 32. The main reason for failure was non-implantation of the embryo. Of these, four patients were pursuing PGT-M at the time of last contact. PGT-M outcomes in patients with cancer susceptibility syndromes were satisfactory. These patients should be informed about PGT-M more systematically, which would imply greater awareness among cancer genetics professionals regarding ART. Our series was not representative of cancer susceptibility syndromes in general; the predominance of cases with syndromes characterized by early-onset, highly penetrant disease is explained by the restrictive French guidelines.
Published: 2022
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11. Data from Breast Cancer Risk Associated with Estrogen Exposure and Truncating Mutation Location in BRCA1/2 Carriers

Author: Nadine Andrieu, Christine Lasset, Julie Tinat, Chrystelle Colas, Christine M. Maugard, Laurence Venat-Bouvet, Dominique Leroux, Elisabeth Luporsi, Alain Lortholary, Laurence Gladieff, Véronique Mari, François Eisinger, Paul Gesta, Laurence Faivre, Pascal Pujol, Isabelle Coupier, Olivier Caron, Pascaline Berthet, Jean-Pierre Fricker, Valérie Bonadona, Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Emmanuelle Mouret-Fourme, Catherine Noguès, and Julie Lecarpentier
Abstract: Background: Mutations in BRCA1/2 confer a high risk of breast cancer, but literature values of this risk vary. A genotype–phenotype correlation has been found in both genes, and the effect of reproductive factors differs according to mutation location. Therefore, we hypothesize that such a variation may exist for other factors related to estrogen exposure.Methods: We used a weighted Cox regression model to assess variation in breast cancer risk with these factors using location of mutation in homogeneous breast cancer risk region of BRCA1/2 in the GENEPSO study.Results: We found that late age at menarche reduced breast cancer risk by 31% and that among BRCA1 carriers, a long or a short menstrual cycle increased risk (by 65% and 73%, respectively). Among premenopausal women, overweight was associated with a 45% decrease in risk whereas underweight was associated with an increased risk (HR, 2.40). A natural menopause, mainly after age 50, was associated with a high breast cancer risk (HR, 2.46), and a significant interaction between menopause status and the location of mutations was found leading up to 10% variation in absolute risk according to the age at menopause.Conclusions: As observed in the general population, a late menarche, a long or a short menstrual cycle, over- or underweight, and being postmenopausal were associated with breast cancer risk in BRCA1/2 carriers. The association with the menopause was observed only when the mutation was located in the “high-risk” zones.Impact: Taking into account modifier factors, location of mutation might be important for the clinical management of BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 24(4); 698–707. ©2015 AACR.
Published: 2023
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12. Supplementary Figure 1 from Breast Cancer Risk Associated with Estrogen Exposure and Truncating Mutation Location in BRCA1/2 Carriers

Author: Nadine Andrieu, Christine Lasset, Julie Tinat, Chrystelle Colas, Christine M. Maugard, Laurence Venat-Bouvet, Dominique Leroux, Elisabeth Luporsi, Alain Lortholary, Laurence Gladieff, Véronique Mari, François Eisinger, Paul Gesta, Laurence Faivre, Pascal Pujol, Isabelle Coupier, Olivier Caron, Pascaline Berthet, Jean-Pierre Fricker, Valérie Bonadona, Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Emmanuelle Mouret-Fourme, Catherine Noguès, and Julie Lecarpentier
Abstract: Supplementary Figure 1: Representation of BRCA1 and BRCA2 major functional and risk domains (location of codons)
Published: 2023
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13. Supplementary Tables from Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by Using BRCA2 Exon 3 as a Model System

Author: Alexandra Martins, Shyam K. Sharan, Pascaline Gaildrat, Thierry Frebourg, Claude Houdayer, Dominique Stoppa-Lyonnet, Angela R. Solano, Laurence Venat-Bouvet, Chrystelle Colas, Séverine Audebert-Bellanger, Fátima Vaz, Pascal Pujol, Danièle Muller, Hélène Larbre, Violaine Bourdon, Françoise Bonnet-Dorion, Myriam Vezain, Daniela Di Giacomo, Aurélie Drouet, Omar Soukarieh, Eileen Southon, Susan Reid, Linda Cleveland, Marine Guillaud-Bataille, Capucine Delnatte, Nadia Boutry-Kryza, Mélanie Léoné, Françoise Révillion, Laëtitia Meulemans, Alice Fiévet, Gaia Castelain, Julie Hauchard, Virginie Caux-Moncoutier, Sophie Krieger, Julie Rondeaux, Teresa Sullivan, Sandrine M. Caputo, and Hélène Tubeuf
Abstract: Supp Tables S1-S6 (including variant classification, bioinformatics predictions versus experimental data, primer sequences, summary of biological, clinical, tumoral, familial and multifactorial data, and description of statistical analysis approaches)
Published: 2023
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14. Data from Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by Using BRCA2 Exon 3 as a Model System

Author: Alexandra Martins, Shyam K. Sharan, Pascaline Gaildrat, Thierry Frebourg, Claude Houdayer, Dominique Stoppa-Lyonnet, Angela R. Solano, Laurence Venat-Bouvet, Chrystelle Colas, Séverine Audebert-Bellanger, Fátima Vaz, Pascal Pujol, Danièle Muller, Hélène Larbre, Violaine Bourdon, Françoise Bonnet-Dorion, Myriam Vezain, Daniela Di Giacomo, Aurélie Drouet, Omar Soukarieh, Eileen Southon, Susan Reid, Linda Cleveland, Marine Guillaud-Bataille, Capucine Delnatte, Nadia Boutry-Kryza, Mélanie Léoné, Françoise Révillion, Laëtitia Meulemans, Alice Fiévet, Gaia Castelain, Julie Hauchard, Virginie Caux-Moncoutier, Sophie Krieger, Julie Rondeaux, Teresa Sullivan, Sandrine M. Caputo, and Hélène Tubeuf
Abstract: BRCA2 is a clinically actionable gene implicated in breast and ovarian cancer predisposition that has become a high priority target for improving the classification of variants of unknown significance (VUS). Among all BRCA2 VUS, those causing partial/leaky splicing defects are the most challenging to classify because the minimal level of full-length (FL) transcripts required for normal function remains to be established. Here, we explored BRCA2 exon 3 (BRCA2e3) as a model for calibrating variant-induced spliceogenicity and estimating thresholds for BRCA2 haploinsufficiency. In silico predictions, minigene splicing assays, patients' RNA analyses, a mouse embryonic stem cell (mESC) complementation assay and retrieval of patient-related information were combined to determine the minimal requirement of FL BRCA2 transcripts. Of 100 BRCA2e3 variants tested in the minigene assay, 64 were found to be spliceogenic, causing mild to severe RNA defects. Splicing defects were also confirmed in patients' RNA when available. Analysis of a neutral leaky variant (c.231T>G) showed that a reduction of approximately 60% of FL BRCA2 transcripts from a mutant allele does not cause any increase in cancer risk. Moreover, data obtained from mESCs suggest that variants causing a decline in FL BRCA2 with approximately 30% of wild-type are not pathogenic, given that mESCs are fully viable and resistant to DNA-damaging agents in those conditions. In contrast, mESCs producing lower relative amounts of FL BRCA2 exhibited either null or hypomorphic phenotypes. Overall, our findings are likely to have broader implications on the interpretation of BRCA2 variants affecting the splicing pattern of other essential exons.Significance:These findings demonstrate that BRCA2 tumor suppressor function tolerates substantial reduction in full-length transcripts, helping to determine the pathogenicity of BRCA2 leaky splicing variants, some of which may not increase cancer risk.
Published: 2023
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15. Hereditary cancer predispositions: Comparison of multigene panel sequencing on fresh‐frozen breast/ovarian tumor versus blood

Author: Mathias Schwartz, Virginie Moncoutier, Adrien Peytral, Jessica Le Gall, Voreak Suybeng, Mélanie Pagès, Julien Masliah‐Planchon, Olfa Trabelsi‐Grati, Samia Melaabi, Céline Callens, Ivan Bièche, Hélène Delhomelle, Antoine De Pauw, Claire Saule, Emmanuelle Mouret‐Fourme, Marion Gauthier‐Villars, Bruno Buecher, Chrystelle Colas, Dominique Stoppa‐Lyonnet, and Lisa Golmard
Subjects: Genetics, Genetics (clinical)
Published: 2023
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16. Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes

Author: José Garcia-Pelaez, Rita Barbosa-Matos, Silvana Lobo, Alexandre Dias, Luzia Garrido, Sérgio Castedo, Sónia Sousa, Hugo Pinheiro, Liliana Sousa, Rita Monteiro, Joaquin J Maqueda, Susana Fernandes, Fátima Carneiro, Nádia Pinto, Carolina Lemos, Carla Pinto, Manuel R Teixeira, Stefan Aretz, Svetlana Bajalica-Lagercrantz, Judith Balmaña, Ana Blatnik, Patrick R Benusiglio, Maud Blanluet, Vincent Bours, Hilde Brems, Joan Brunet, Daniele Calistri, Gabriel Capellá, Sergio Carrera, Chrystelle Colas, Karin Dahan, Robin de Putter, Camille Desseignés, Elena Domínguez-Garrido, Conceição Egas, D Gareth Evans, Damien Feret, Eleanor Fewings, Rebecca C Fitzgerald, Florence Coulet, María Garcia-Barcina, Maurizio Genuardi, Lisa Golmard, Karl Hackmann, Helen Hanson, Elke Holinski-Feder, Robert Hüneburg, Mateja Krajc, Kristina Lagerstedt-Robinson, Conxi Lázaro, Marjolijn J L Ligtenberg, Cristina Martínez-Bouzas, Sonia Merino, Geneviève Michils, Srdjan Novaković, Ana Patiño-García, Guglielmina Nadia Ranzani, Evelin Schröck, Inês Silva, Catarina Silveira, José L Soto, Isabel Spier, Verena Steinke-Lange, Gianluca Tedaldi, María-Isabel Tejada, Emma R Woodward, Marc Tischkowitz, Nicoline Hoogerbrugge, Carla Oliveira, Institut Català de la Salut, [Garcia-Pelaez J] Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal. Faculty of Medicine, University of Porto, Porto, Portugal. Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal. Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal. [Barbosa-Matos R, Lobo S] Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal. Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal. Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal. Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal. [Dias A] Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal. Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal. Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal. [Garrido L] Centro Hospitalar Universitário São João, Porto, Portugal. [Castedo S] Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal. Faculty of Medicine, University of Porto, Porto, Portugal. Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal. Centro Hospitalar Universitário São João, Porto, Portugal. Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal. European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Porto, Portugal. [Balmaña J] Vall d'Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. ERN GENTURIS, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias gástricas [ENFERMEDADES], Genotype, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], enfermedades de la piel y tejido conjuntivo::enfermedades de la piel::enfermedades de la mama [ENFERMEDADES], Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Mutation, Missense, Breast Neoplasms, All institutes and research themes of the Radboud University Medical Center, Germ Cells/pathology, Antigens, CD, Stomach Neoplasms, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Humans, Genetic Predisposition to Disease, Genotip, Càncer, Germ-Line Mutation, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], Cancer, Retrospective Studies, Breast Neoplasms/epidemiology, Cadherins/genetics, Antigens, CD/genetics, Stomach Neoplasms/epidemiology, Cadherins, Pedigree, Fenotip, Carcinoma, Lobular, Germ Cells, Phenotype, Oncology, Aparell digestiu - Càncer - Aspectes genètics, Mama - Càncer - Aspectes genètics, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Stomach Neoplasms [DISEASES], Female
Abstract: Genotype; Cancer phenotypes; Genetic tumour Genotip; Fenotips del càncer; Tumor genètic Genotipo; Fenotipos del cáncer; Tumor genético Background Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype–phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. Methods This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype–phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. Findings From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1–93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66–57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18–29·39], p=0·0017) and gastric cancer (7·81 [2·03–29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). Interpretation CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. Funding European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme. European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.
Published: 2023
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17. AXIN2 germline testing in a French cohort validates pathogenic variants as a rare cause of predisposition to colorectal polyposis and cancer

Author: Julie Leclerc, Marie Beaumont, Roseline Vibert, Stéphane Pinson, Catherine Vermaut, Cathy Flament, Tonio Lovecchio, Lucie Delattre, Christophe Demay, Florence Coulet, Erell Guillerm, Nadim Hamzaoui, Patrick R. Benusiglio, Afane Brahimi, François Cornelis, Hélène Delhomelle, Sandra Fert‐Ferrer, Benjamin P. J. Fournier, Alain Hovnanian, Clémentine Legrand, Alain Lortholary, David Malka, Florence Petit, Jean‐Christophe Saurin, Sophie Lejeune, Chrystelle Colas, Marie‐Pierre Buisine, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Physiopathologie orale moléculaire = Molecular Oral Pathophysiology [CRC], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Genetic skin diseases : from disease mechanism to therapies (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Wnt signaling pathway, Cancer Research, colorectal cancer susceptibility, [SDV]Life Sciences [q-bio], Genetics, oligodontia, adenomatous polyposis
Abstract: International audience; Only a few patients with germline AXIN2 variants and colorectal adenomatous polyposis or cancer have been described, raising questions about the actual contribution of this gene to colorectal cancer (CRC) susceptibility. To assess the clinical relevance for AXIN2 testing in patients suspected of genetic predisposition to CRC, we collected clinical and molecular data from the French Oncogenetics laboratories analyzing AXIN2 in this context. Between 2004 and June 2020, 10 different pathogenic/likely pathogenic AXIN2 variants were identified in 11 unrelated individuals. Eight variants were from a consecutive series of 3322 patients, which represents a frequency of 0.24%. However, loss‐of‐function AXIN2 variants were strongly associated with genetic predisposition to CRC as compared with controls (odds ratio: 11.89, 95% confidence interval: 5.103–28.93). Most of the variants were predicted to produce an AXIN2 protein devoid of the SMAD3‐binding and DIX domains, but preserving the β‐catenin‐binding domain. Ninety‐one percent of the AXIN2 variant carriers who underwent colonoscopy had adenomatous polyposis. Forty percent of the variant carriers developed colorectal or/and other digestive cancer. Multiple tooth agenesis was present in at least 60% of them. Our report provides further evidence for a role of AXIN2 in CRC susceptibility, arguing for AXIN2 testing in patients with colorectal adenomatous polyposis or cancer.
Published: 2022
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18. Lynch syndrome: influence of additional susceptibility variants on cancer risk

Author: Roseline VIBERT, Jasmine Hasnaoui, Alexandra Lefebvre, Chrystelle Colas, Marion Dhooge, Noemie Basset, Albain Chansavang, Camille Desseignes, Alex Duval, Solenne Farelly, Nadim Hamzaoui, Pierre Laurent-Puig, Julie Metras, Diane Moliere, Martine Muleris, Jeanne Netter, Romain Nicolle, Géraldine Perkins, Alexandre Perrier, Mathilde Warcoin, Florence Coulet, and Patrick Benusiglio
Abstract: Some patients with Lynch syndrome (LS) have extreme phenotypes, i.e. cancer before the recommended screening age, or cancer for which there are no screening guidelines. We made the hypothesis that additional germline variants in cancer susceptibility genes (CSG) could explain some of these phenotypes. We compared the prevalence of additional CSG variants in LS patients with a cancer diagnosis before age 30 (early-onset, EO group) and after 40 (usual-onset, UO group). While there was no overall difference, we did find an excess of pathogenic variants and variants of unknown significance in EO cases when only gastrointestinal CSG were considered (OR 2.25; 95%CI: 1.01–5.06, p-value = 0.04). Four EO cases stood out: two with POLE/POLD1 variants in the key exonuclease domain, one with a BMPR1A duplication and one with an EPCAM deletion. Additional germline variants should be considered in future screening recommendations, as they might influence cancer risk.
Published: 2022
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19. Association and performance of polygenic risk scores for breast cancer among French women presenting or not a familial predisposition to the disease

Author: Yue Jiao, Thérèse Truong, Séverine Eon-Marchais, Noura Mebirouk, Sandrine M. Caputo, Marie-Gabrielle Dondon, Mojgan Karimi, Dorothée Le Gal, Juana Beauvallet, Édith Le Floch, Claire Dandine-Roulland, Delphine Bacq-Daian, Robert Olaso, Juliette Albuisson, Séverine Audebert-Bellanger, Pascaline Berthet, Valérie Bonadona, Bruno Buecher, Olivier Caron, Mathias Cavaillé, Jean Chiesa, Chrystelle Colas, Marie-Agnès Collonge-Rame, Isabelle Coupier, Capucine Delnatte, Antoine De Pauw, Hélène Dreyfus, Sandra Fert-Ferrer, Marion Gauthier-Villars, Paul Gesta, Sophie Giraud, Laurence Gladieff, Lisa Golmard, Christine Lasset, Sophie Lejeune-Dumoulin, Mélanie Léoné, Jean-Marc Limacher, Alain Lortholary, Élisabeth Luporsi, Véronique Mari, Christine M. Maugard, Isabelle Mortemousque, Emmanuelle Mouret-Fourme, Sophie Nambot, Catherine Noguès, Cornel Popovici, Fabienne Prieur, Pascal Pujol, Nicolas Sevenet, Hagay Sobol, Christine Toulas, Nancy Uhrhammer, Dominique Vaur, Laurence Venat, Anne Boland-Augé, Pascal Guénel, Jean-François Deleuze, Dominique Stoppa-Lyonnet, Nadine Andrieu, and Fabienne Lesueur
Subjects: Cancer Research, Oncology
Abstract: Three partially overlapping breast cancer polygenic risk scores (PRS) comprising 77, 179 and 313 SNPs have been proposed for European-ancestry women by the Breast Cancer Association Consortium (BCAC) for improving risk prediction in the general population. However, the effect of these SNPs may vary from one country to another and within a country because of other factors.To assess their associated risk and predictive performance in French women from (1) the CECILE population-based case-control study, (2) BRCA1 or BRCA2 (BRCA1/2) pathogenic variant (PV) carriers from the GEMO study, and (3) familial breast cancer cases with no BRCA1/2 PV and unrelated controls from the GENESIS study.All three PRS were associated with breast cancer in all studies, with odds ratios per standard deviation varying from 1.7 to 2.0 in CECILE and GENESIS, and hazard ratios varying from 1.1 to 1.4 in GEMO. The predictive performance of PRSOur results are in line with previous validation studies in the general population and in BRCA1/2 PV carriers. Additionally, we showed that PRS may be of clinical utility for women with a strong family history of breast cancer and no BRCA1/2 PV, and for those carrying a predicted PV in a moderate-risk gene like ATM, CHEK2 or PALB2.
Published: 2022

20. Co-occurrence of germline BRCA1 and CDH1 pathogenic variants

Author: Dominique Lamarque, Lisa Golmard, Gilles Marx, Emmanuelle Mouret-Fourme, Marie-Charlotte Villy, Etienne Rouleau, Dominique Stoppa-Lyonnet, Nasrine Callet, Véronique Becette, and Chrystelle Colas
Subjects: 0301 basic medicine, Proband, Genetics, medicine.medical_specialty, Daughter, business.industry, media_common.quotation_subject, Genetic counseling, Cancer, medicine.disease, Germline, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Medicine, Medical genetics, business, Genetics (clinical), Aunt, media_common
Abstract: Introduction: We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description: The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary breast cancer.Results: A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified.Conclusion: This complex situation is challenging for genetic counselling and management of at-risk individuals.
Published: 2020
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21. Disease expression in juvenile polyposis syndrome: a retrospective survey on a cohort of 221 European patients and comparison with a literature-derived cohort of 473 SMAD4/BMPR1A pathogenic variant carriers

Author: Maurizio Genuardi, Robert Blatter, Benjamin Tschupp, Hans F. A. Vasen, Karl Heinimann, Fiona Lalloo, Gabriela Moeslein, D. Gareth Evans, Robert Hüneburg, Frederik J. Hes, Laura Renkonen-Sinisalo, Inge Bernstein, Stefan Aretz, Chrystelle Colas, Isabel Spier, Andrew Latchford, Nicoletta Resta, Heikki Järvinen, Dora Varvara, HUS Abdominal Center, II kirurgian klinikka, Department of Surgery, University of Helsinki, Helsinki University Hospital Area, Clinical sciences, Medical Genetics, University Hospital Basel [Basel], University of Basel (Unibas), University Hospital Bonn, Aalborg University [Denmark] (AAU), Unité fonctionnelle d'Oncogénétique et Angiogénétique Moléculaire [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Institut Curie [Paris], University of Manchester [Manchester], Fondazione 'Policlinico Universitario A. Gemelli' [Rome], Università cattolica del Sacro Cuore [Roma] (Unicatt), Leiden University Medical Center (LUMC), Universität Witten Herdecke, and University of Bari Aldo Moro (UNIBA)
Subjects: 0301 basic medicine, polyposis, 030105 genetics & heredity, PHENOTYPE, Settore MED/03 - GENETICA MEDICA, SMAD4, Surveys and Questionnaires, Genetics(clinical), Juvenile polyposis syndrome, Telangiectasia, Genetics (clinical), Smad4 Protein, Intestinal Polyposis, Stomach, 1184 Genetics, developmental biology, physiology, genotype–phenotype correlation, syndrome, PREVALENCE, GENOTYPE, 3. Good health, juvenile polyposis syndrome, medicine.anatomical_structure, Cohort, medicine.symptom, Adult, medicine.medical_specialty, Anemia, [SDV.CAN]Life Sciences [q-bio]/Cancer, colorectal cancer, genotype-phenotype correlation, Article, hereditary hemorrhagic telangiectasia, 03 medical and health sciences, Neoplastic Syndromes, Hereditary, Internal medicine, medicine, Humans, Bone Morphogenetic Protein Receptors, Type I, Germ-Line Mutation, BMPR1A, Retrospective Studies, MUTATIONS, business.industry, Cancer, Retrospective cohort study, medicine.disease, digestive system diseases, DELETIONS, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, business
Abstract: International audience; Purpose: Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases.Methods: We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature.Results: We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%).Conclusion: This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.
Published: 2020
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22. Cancer Risks Associated With

Author: Shuai, Li, Valentina, Silvestri, Goska, Leslie, Timothy R, Rebbeck, Susan L, Neuhausen, John L, Hopper, Henriette Roed, Nielsen, Andrew, Lee, Xin, Yang, Lesley, McGuffog, Michael T, Parsons, Irene L, Andrulis, Norbert, Arnold, Muriel, Belotti, Åke, Borg, Bruno, Buecher, Saundra S, Buys, Sandrine M, Caputo, Wendy K, Chung, Chrystelle, Colas, Sarah V, Colonna, Jackie, Cook, Mary B, Daly, Miguel, de la Hoya, Antoine, de Pauw, Hélène, Delhomelle, Jacqueline, Eason, Christoph, Engel, D Gareth, Evans, Ulrike, Faust, Tanja N, Fehm, Florentia, Fostira, George, Fountzilas, Megan, Frone, Vanesa, Garcia-Barberan, Pilar, Garre, Marion, Gauthier-Villars, Andrea, Gehrig, Gord, Glendon, David E, Goldgar, Lisa, Golmard, Mark H, Greene, Eric, Hahnen, Ute, Hamann, Helen, Hanson, Tiara, Hassan, Julia, Hentschel, Judit, Horvath, Louise, Izatt, Ramunas, Janavicius, Yue, Jiao, Esther M, John, Beth Y, Karlan, Sung-Won, Kim, Irene, Konstantopoulou, Ava, Kwong, Anthony, Laugé, Jong Won, Lee, Fabienne, Lesueur, Noura, Mebirouk, Alfons, Meindl, Emmanuelle, Mouret-Fourme, Hannah, Musgrave, Joanne, Ngeow Yuen Yie, Dieter, Niederacher, Sue K, Park, Inge Sokilde, Pedersen, Juliane, Ramser, Susan J, Ramus, Johanna, Rantala, Muhammad U, Rashid, Florian, Reichl, Julia, Ritter, Andreas, Rump, Marta, Santamariña, Claire, Saule, Gunnar, Schmidt, Rita K, Schmutzler, Leigha, Senter, Saba, Shariff, Christian F, Singer, Melissa C, Southey, Dominique, Stoppa-Lyonnet, Christian, Sutter, Yen, Tan, Soo Hwang, Teo, Mary Beth, Terry, Mads, Thomassen, Marc, Tischkowitz, Amanda E, Toland, Diana, Torres, Ana, Vega, Sebastian A, Wagner, Shan, Wang-Gohrke, Barbara, Wappenschmidt, Bernhard H F, Weber, Drakoulis, Yannoukakos, Amanda B, Spurdle, Douglas F, Easton, Georgia, Chenevix-Trench, Laura, Ottini, and Antonis C, Antoniou
Subjects: BRCA2 Protein, Male, Ovarian Neoplasms, Risk, Heterozygote, BRCA1 Protein, Infant, Newborn, Breast Neoplasms, Breast Neoplasms, Male, Pancreatic Neoplasms, Mutation, Humans, Female, Genetic Predisposition to Disease
Abstract: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) inWe used data from 3,184In addition to female breast and ovarian cancers
Published: 2022

23. Diagnostic chest X-rays and breast cancer risk among women with a hereditary predisposition to breast cancer unexplained by a BRCA1 or BRCA2 mutation

Author: Michel Longy, Christine Maugard, Elisabeth Luporsi, Capucine Delnatte, Séverine Eon-Marchais, Marion Gauthier-Villars, Juana Beauvallet, Noura Mebirouk, Muriel Belotti, Alain Lortholary, Sophie Lejeune-Dumoulin, Christine Lasset, Isabelle Mortemousque, Yves-Jean Bignon, François Eisinger, Sylvie Mazoyer, Valérie Bonadona, Jean-Marc Limacher, Anne Tardivon, Paul Gesta, Sandra Fert-Ferrer, Fabienne Lesueur, Dorothée Le Gal, Jean Chiesa, Florent Soubrier, Pascaline Berthet, Laurence Faivre, Bruno Buecher, Nadine Andrieu, Juliette Coignard, Julie Tinat, Thierry Frebourg, Isabelle Coupier, Sophie Giraud, Laure Barjhoux, Catherine Noguès, Séverine Audebert-Bellanger, Claude Adenis-Lavignasse, Chrystelle Colas, Maximiliano Ribeiro Guerra, Laurence Venat-Bouvet, Eve Cavaciuti, Anne Floquet, Pascal Pujol, Francesca Damiola, Anne Fajac, Jean-Pierre Fricker, Hélène Dreyfus, Dominique Stoppa-Lyonnet, Marie-Gabrielle Dondon, Laurence Gladieff, Olivier Caron, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Federal University of Juiz de Fora (UFIJ), Institut Gustave Roussy (IGR), AP-HP. Université Paris Saclay, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Catherine-de-Sienne [Nantes] (CCS), Centre Paul Strauss, CRLCC Paul Strauss, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Hôpital de Mercy, Centre René Gauducheau, CRLCC René Gauducheau, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Bergonié [Bordeaux], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Ramsay Générale de Santé - Hôpital Privé La Louvière, Hôpital Dupuytren [CHU Limoges], Institut Sainte Catherine [Avignon], hôpital couple-enfant [CHU Grenoble Alpes], Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Morvan [Brest], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Groupement Hospitalier Lyon-Est (GHE), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Hôpital pasteur [Colmar], Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU de Bordeaux Pellegrin [Bordeaux], Centre Hospitalier Métropole Savoie [Chambéry], Hôpital René HUGUENIN (Saint-Cloud), CHU Rouen, Normandie Université (NU), Hôpital Edouard Herriot [CHU - HCL], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), MINES ParisTech - École nationale supérieure des mines de Paris, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), COLO, Mouniati, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Adult, Risk, Oncology, medicine.medical_specialty, DNA Repair, DNA repair, [SDV]Life Sciences [q-bio], Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, X-ray exposure, Logistic regression, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Surgical oncology, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Risk factor, RC254-282, High-risk population, Pregnancy, DNA repair genes, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, Middle Aged, medicine.disease, 3. Good health, Radiography, [SDV] Life Sciences [q-bio], Low dose, 030220 oncology & carcinogenesis, Mutation, Female, business, Research Article
Abstract: Background Diagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation. Methods We evaluated the effect of chest X-rays from diagnostic medical procedures in a dataset composed of 1552 BC cases identified through French family cancer clinics and 1363 unrelated controls. Participants reported their history of X-ray exposures in a detailed questionnaire and were tested for 113 DNA repair genes. Logistic regression and multinomial logistic regression models were used to assess the association with BC. Results Chest X-ray exposure doubled BC risk. A 3% increased BC risk per additional exposure was observed. Being 20 years old or younger at first exposure or being exposed before first full-term pregnancy did not seem to modify this risk. Birth after 1960 or carrying a rare likely deleterious coding variant in a DNA repair gene other than BRCA1/2 modified the effect of chest X-ray exposure. Conclusion Ever/never chest X-ray exposure increases BC risk 2-fold regardless of age at first exposure and, by up to 5-fold when carrying 3 or more rare variants in a DNA repair gene. Further studies are needed to evaluate other DNA repair genes or variants to identify those which could modify radiation sensitivity. Identification of subpopulations that are more or less susceptible to ionizing radiation is important and potentially clinically relevant.
Published: 2021
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24. High yield of surveillance in patients diagnosed with constitutional mismatch repair deficiency

Author: Zeinab Ghorbanoghli, Mariëtte van Kouwen, Birgitta Versluys, Delphine Bonnet, Christine Devalck, Julie Tinat, Danuta Januszkiewicz-Lewandowska, Consuelo Calvino Costas, Edouard Cottereau, James C H Hardwick, Katharina Wimmer, Laurence Brugieres, Chrystelle Colas, and Hans F A Vasen
Subjects: genetic predisposition to disease, Genetics, germ-line mutation, Genetics (clinical)
Abstract: BackgroundConstitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessively inherited syndrome that is caused by biallelic pathogenic variants of the mismatch repair genes. It is characterised by the development of multiple tumours in the first and second decade of life including brain, gastrointestinal and haematological tumours often resulting in early death. In order to improve the prognosis of these patients, the European collaborative group ‘care for CMMRD’ developed a surveillance programme in 2014 and established a registry of patients with CMMRD in Paris. The aim of the study was to evaluate the outcome of this programme.MethodsTwenty-two patients with a definitive diagnosis of CMMRD and with at least one follow-up study were selected from the registry. Medical data on the outcome of surveillance were collected from these patients.ResultsDuring a mean follow-up of 4 years, the programme detected eight malignant tumours including three brain tumours, three upper gastrointestinal cancers and two colorectal cancers. Most tumours could successfully be treated. In addition, many adenomas were detected in the duodenum, and colorectum and subsequently removed. Seven patients developed a symptomatic malignancy, including two brain tumours, one small bowel cancer and four haematological malignancies. At the end of the follow-up, 16 out of 22 patients (73%) who participated in the surveillance programme were still alive.ConclusionThe study suggests a beneficial effect of surveillance of the digestive tract and brains.
Published: 2022
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25. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Daniel R. Barnes, Matti A. Rookus, Lesley McGuffog, Goska Leslie, Thea M. Mooij, Joe Dennis, Nasim Mavaddat, Julian Adlard, Munaza Ahmed, Kristiina Aittomäki, Nadine Andrieu, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Katarzyna Białkowska, Amie M. Blanco, Marinus J. Blok, Bernardo Bonanni, Susanne E. Boonen, Åke Borg, Aniko Bozsik, Angela R. Bradbury, Paul Brennan, Carole Brewer, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Lise Lotte Christensen, Wendy K. Chung, Kathleen B.M. Claes, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Antonis Antoniou, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D. Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-ren Ong, Lucy Side, Aoife O’Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Mary B. Daly, Miguel de la Hoya, Robin de Putter, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Cecilia M. Dorfling, Martine Dumont, Bent Ejlertsen, Christoph Engel, Lenka Foretova, Florentia Fostira, Michael Friedlander, Eitan Friedman, Patricia A. Ganz, Judy Garber, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Anna González-Neira, Mark H. Greene, Daphne Gschwantler-Kaulich, Eric Hahnen, Ute Hamann, Julia Hentschel, Frans B.L. Hogervorst, Maartje J. Hooning, Judit Horvath, Chunling Hu, Peter J. Hulick, Evgeny N. Imyanitov, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Catherine Noguès, Claudine Isaacs, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Karin Kast, Torben A. Kruse, Ava Kwong, Yael Laitman, Conxi Lazaro, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jennifer T. Loud, Jan Lubiński, Phuong L. Mai, Siranoush Manoukian, Hanne E.J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Austin Miller, Marco Montagna, Semanti Mukherjee, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Finn Cilius Nielsen, Liene Nikitina-Zake, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Laura Papi, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Bernard Peissel, Ana Peixoto, Paolo Peterlongo, Georg Pfeiler, Karolina Prajzendanc, Miquel Angel Pujana, Paolo Radice, Juliane Ramser, Susan J. Ramus, Johanna Rantala, Gad Rennert, Harvey A. Risch, Mark Robson, Karina Rønlund, Ritu Salani, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy E. Side, Christian F. Singer, Thomas P. Slavin, Penny Soucy, Melissa C. Southey, Amanda B. Spurdle, Doris Steinemann, Zoe Steinsnyder, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Darcy L. Thull, Silvia Tognazzo, Amanda E. Toland, Alison H. Trainer, Nadine Tung, Elizabeth J. van Rensburg, Ana Vega, Jeroen Vierstraete, Gabriel Wagner, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Siddhartha Yadav, Xin Yang, Drakoulis Yannoukakos, Dario Zimbalatti, Kenneth Offit, Mads Thomassen, Fergus J. Couch, Rita K. Schmutzler, Jacques Simard, Douglas F. Easton, Antonis C. Antoniou, Pediatric surgery, Human genetics, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Amsterdam Reproduction & Development (AR&D), Apollo - University of Cambridge Repository, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Chapel Allerton Hospital, Great Ormond Street Hospital for Children [London] (GOSH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Mount Sinai Hospital [Toronto, Canada] (MSH), University of Toronto (University of Toronto), Christian-Albrechts University of Kiel, The University of Texas M.D. Anderson Cancer Center [Houston], Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], CIBER de Enfermedades Raras (CIBERER), Spanish National Cancer Research Center (CNIO), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Pomeranian Medical University [Szczecin] (PUM), University of California (UC), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], European Institute of Oncology IRCCS [Milan, Italy] (EIO), Zealand University Hospital [Roskilde, Denmark], Lund University [Lund], National Institute of Oncology [Budapest, Hungary], Abramson Cancer Center [philadelphia], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Royal Devon & Exeter Hospital, Exeter, UK, Catalan Institute of Oncology [Barcelone, Espagne], Huntsman Cancer Institute [Salt Lake City], University of Utah, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Pisa University Hospital, Peter MacCallum Cancer Centre [Melbourne, Australie], University of Melbourne, Aarhus University Hospital, Columbia University [New York], Ghent University Hospital, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Sheffield Children's NHS Foundation Trust, Fox Chase Cancer Center, Queen Elizabeth University Hospital (Glasgow), Centre hospitalier universitaire de Nantes (CHU Nantes), Leiden University Medical Center (LUMC), Beckman Research Institute of the City of Hope, Abramson Cancer Center, University of Pretoria [South Africa], Centre Hospitalier Universitaire de Québec Research Center [Canada], Royal Marsden NHS Foundation Trust, Copenhagen University Hospital, Leipzig University, University of Manchester [Manchester], Manchester Academic Health Science Centre (MAHSC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Masaryk Memorial Cancer Institute (MMCI), Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety (INRASTES), National Center for Scientific Research 'Demokritos' (NCSR), NHMRC Clinical Trials Centre [Camperdown NSW 2050, Australie], Chaim Sheba Medical Center, Tel Aviv University (TAU), Jonsson Comprehensive Cancer Center, University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Dana-Farber Cancer Institute [Boston], University of Würzburg, Rigshospitalet [Copenhagen], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Hospices Civils de Lyon (HCL), University of Kansas [Kansas City], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Medizinische Universität Wien = Medical University of Vienna, University of Cologne, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Lancashire NHS Foundation Trust, University Hospital Leipzig, Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Mayo Clinic, NorthShore University HealthSystem [Evanston, IL, USA], The University of Chicago Medicine [Chicago], N. N. Petrov Institute of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Guy's and St Thomas' NHS Foundation Trust [London, UK], Peter MacCallum Cancer Center, East Melbourne, Peter MacCallum Cancer Center, Vilnius University [Vilnius], The State Scientific Research Institute Nature Research Centre, Vilnius, Lithuania, Stanford University School of Medicine [CA, USA], Memorial Sloane Kettering Cancer Center [New York], Cedars-Sinai Medical Center, Technische Universität Dresden = Dresden University of Technology (TU Dresden), University Medical Center [Utrecht], Odense University Hospital [Odense, Denmark], The Hong Kong Hereditary Breast Cancer Family Registry, The University of Hong Kong (HKU), Hong Kong Sanatorium and Hospital [Hong Kong] (HKSH), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), David Geffen School of Medicine [Los Angeles], Fondation MINES ParisTech, Karolinska Institutet [Stockholm], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Amsterdam UMC - Amsterdam University Medical Center, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Radboud University Medical Center [Nijmegen], Roswell Park Cancer Institute [Buffalo], Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], University of Toronto, University Health Network, University Hospital Düsseldorf, Latvian Biomedical Research and Study Centre [Rīga], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), University of Chicago, Birmingham Women's and Children's NHS Foundation Trust, Cambridge University Hospitals - NHS (CUH), Charité Campus Virchow-Klinikum (CVK), Università degli Studi di Firenze = University of Florence (UniFI), Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), Seoul National University [Seoul] (SNU), QIMR Berghofer Medical Research Institute, Aalborg University [Denmark] (AAU), IRCCS Istituto Nazionale dei Tumori [Milano], Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Klinikum rechts der Isar [Munich, Germany], University of New South Wales [Sydney] (UNSW), Garvan Institute of medical research, Technion Faculty of Medicine [Haifa, Israel], Yale School of Medicine [New Haven, Connecticut] (YSM), Vejle Hospital [Danemark], Ohio State University [Columbus] (OSU), Centre de lutte contre le cancer Paul-Strauss, Institut de Cancérologie de Strasbourg Europe (ICANS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Kansas Medical Center [Kansas City, KS, USA], Princess Anne Hospital, City of Hope Comprehensive Cancer Center [Duarte], Monash University [Clayton], Cancer Council Victoria [Melbourne, VIC, Australia], Hannover Medical School [Hannover] (MHH), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Heidelberg University Hospital [Heidelberg], Institute of Biomedical Sciences Abel Salazar - ICBAS [Porto, Portugal], Malaysia and University Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya [Kuala Lumpur, Malaisie], University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), McGill University = Université McGill [Montréal, Canada], Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), Instituto de Investigaciones Sanitarias, Universidade de Santiago de Compostela [Spain] (USC ), Universiteit Gent = Ghent University (UGENT), Oxford University Hospitals NHS Trust, University of Oxford, Universitätsklinikum Ulm - University Hospital of Ulm, University Hospital of Cologne [Cologne], Mayo Clinic [Rochester], Collaborators : Pascaline Berthet, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Julian Adlard, Munaza Ahmed, Antonis Antoniou, Daniel Barrowdale, Paul Brennan, Carole Brewer, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-Ren Ong, Lucy Side, Aoife O'Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Peter Devilee, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Nadine Andrieu, Catherine Noguès, Dupuis, Christine, Institut Català de la Salut, [Barnes DR, McGuffog L, Leslie G, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Rookus MA, Mooij TM] The Netherlands Cancer Institute, Department of Epidemiology (PSOE), Amsterdam, The Netherlands. [Balmaña J] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Barnes, Daniel [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Dennis, Joe [0000-0003-4591-1214], Mavaddat, Nasim [0000-0003-0307-055X], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Universiteit Leiden, Roswell Park Cancer Institute [Buffalo] (RPCI), Medical Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, University of Helsinki, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Pomeranian Medical University, University of California, University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], University of Leipzig [Leipzig, Allemagne], Masaryk Memorial Cancer Institute (RECAMO), Tel Aviv University [Tel Aviv], University of California-University of California, University of Münster, Amsterdam UMC, Technical University of Munich (TUM), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Garvan Institute of Medical Research [Sydney, Australia], Yale University School of Medicine, Vejle Hospital, University of Kansas Medical Center [Lawrence], Université Paris Descartes (Paris 5), University of Malaya [Kuala Lumpur, Malaisie], Universiteit Gent = Ghent University [Belgium] (UGENT), and University of Oxford [Oxford]
Subjects: 0301 basic medicine, Oncology, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], [SDV]Life Sciences [q-bio], Càncer d'ovari, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], MODIFIERS, Diàtesi, SUSCEPTIBILITY, Carcinoma, Ovarian Epithelial, PRS, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Medicine and Health Sciences, Medicine, Genetics(clinical), genetics, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, education.field_of_study, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], BRCA1 Protein, Hazard ratio, Absolute risk reduction, 1184 Genetics, developmental biology, physiology, article, ASSOCIATION, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], ddc, 3. Good health, [SDV] Life Sciences [q-bio], ovarian cancer, 030220 oncology & carcinogenesis, Female, Cohort study, medicine.medical_specialty, Heterozygote, Population, 3122 Cancers, Single-nucleotide polymorphism, Breast Neoplasms, MUTATION CARRIERS, Ovaris - Càncer - Aspectes genètics, Càncer de mama, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, Ovarian cancer, BRCA1/2, Internal medicine, Humans, Genetic Predisposition to Disease, education, Retrospective Studies, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], BRCA2 Protein, IDENTIFICATION, business.industry, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], Retrospective cohort study, ALLELES, medicine.disease, BRCA1, BRCA2, MODEL, PATHOLOGY, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, 3111 Biomedicine, business
Abstract: Contains fulltext : 229292.pdf (Publisher’s version ) (Open Access) PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10(-72)). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10(-22)) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10(-12)) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Published: 2020
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26. Tumor BRCA testing can reveal a high tumor mutational burden related to POLE pathogenic variants

Author: Lisa Golmard, O. Trabelsi Grati, Elodie Girard, Guillaume Bataillon, Ivan Bièche, Julien Masliah-Planchon, Dominique Stoppa-Lyonnet, Samia Melaabi, Chrystelle Colas, J. Le Gall, Marie-Charlotte Villy, and Anne Vincent-Salomon
Subjects: Large tumor, business.industry, medicine.medical_treatment, Obstetrics and Gynecology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunotherapy, Brca testing, Gynecology and obstetrics, Oncogenetics, Oncology, POLE, medicine, Cancer research, RG1-991, Routine clinical practice, Tumor BRCA testing, business, RC254-282
Abstract: Objective Tumors harboring a POLE pathogenic variant, associated with high tumor mutational burden, are good candidates for immunotherapy. However, POLE pathogenic variants are not currently screened in routine clinical practice. Can these tumors be identified by means of an already available test? Methods We describe seven tumors harboring a POLE pathogenic variant, among eight patients with tumors harboring multiple BRCA1/2 variants (from 4 to 20). All patients were managed at Institut Curie, Paris. Five patients were selected because of unexpected tumor BRCA testing results with multiple variants and another three patients were selected because of a POLE pathogenic variant detected by large tumor testing. We looked for other tumor variants by Next-Generation Sequencing in tumors harboring multiple BRCA1/2 variants, and for multiple BRCA1/2 variants in tumors harboring a POLE pathogenic variant. Results Four of the five tumors selected because of multiple BRCA1/2 variants exhibited a POLE pathogenic variant, and all three tumors selected for POLE pathogenic variants exhibited multiple BRCA1/2 variants. Conclusions Tumor BRCA testing could be a way to detect tumors harboring a highly mutagenic POLE pathogenic variant.
Published: 2021

27. TUMOSPEC: A Nation-Wide Study of Hereditary Breast and Ovarian Cancer Families with a Predicted Pathogenic Variant Identified through Multigene Panel Testing

Author: Celine Garrec, Monique Mozelle-Nivoix, Jérôme Lemonnier, Etienne Rouleau, Tan Dat Nguyen, Dominique Vaur, Elodie Lacaze, Sarah Bonnet-Boissinot, Sophie Nambot, Jean Chiesa, Sophie Giraud, Dominique Stoppa-Lyonnet, Michel Longy, Alain Lortholary, Jean-Marc Rey, Olivier Caron, Christine Lasset, Claude Houdayer, Christine Maugard, Virginie Bubien, Véronique Mari, Marie-Emmanuelle Morin-Meschin, Nadine Andrieu, Nancy Uhrhammer, Louise Crivelli, Hélène Dreyfus, Vincent Goussot, Stephanie Chieze-Valéro, Nicolas Sevenet, Lisa Golmard, Séverine Eon-Marchais, Mathilde Martinez, Isabelle Coupier, Marie-Gabrielle Dondon, Odile Béra, Paul Vilquin, Capucine Delnatte, Odile Cohen-Haguenauer, Cornel Popovici, Christine Toulas, Laurence Gladieff, Marie-Agnès Collonge-Rame, Chrystelle Colas, Paul Gesta, Catherine Noguès, Fanny Brayotel, Audrey Mailliez, Fabienne Lesueur, Julie Tinat, Marie Bidart, Yves-Jean Bignon, Florence Coulet, Nadia Boutry-Kryza, Fabienne Prieur, Juana Beauvallet, Philippe Denizeau, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôtel-Dieu de Nantes, CHU Rouen, Normandie Université (NU), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jean Godinot [Reims], UNICANCER, Centre Eugène Marquis (CRLCC), Institut de Cancérologie de Strasbourg Europe (ICANS), Centre Paul Strauss, CRLCC Paul Strauss, Institut Bergonié [Bordeaux], Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Genetic and Immunology Medical Institute (GIMI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), CHU de Saint-Étienne Hôpital Nord [Saint Etienne], Hôpital Nord (Saint Etienne), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), CHU Bordeaux [Bordeaux], Centre Catherine-de-Sienne [Nantes] (CCS), Hôpital privé du Confluent [Nantes], Institut Sainte Catherine [Avignon], hôpital couple-enfant [CHU Grenoble Alpes], Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier de Troyes, Hospices Civils de Lyon (HCL), Groupement Hospitalier Lyon-Est (GHE), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Groupe Hospitalier du Havre, CHU de la Martinique [Fort de France], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CRLCC René Gauducheau, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre médical de Bligny, Onco-génétique, Département de médecine oncologique [Gustave Roussy], COLO, Mouniati, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine génomique et d’immunothérapie (Genomic and Immunotherapy Medical Institute) (institut GIMI), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Lille-UNICANCER, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-FHU TRANSLAD (CHU de Dijon), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_specialty, Sequencing data, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 030105 genetics & heredity, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Care plan, Internal medicine, Epidemiology, medicine, RC254-282, Genetic testing, medicine.diagnostic_test, business.industry, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, genetic predisposition to breast and ovarian cancer, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Oncology, 030220 oncology & carcinogenesis, multigene panels, Cancer risk, Ovarian cancer, business, cancer risk estimate, penetrance of pathogenic variants
Abstract: Simple Summary TUMOSPEC was designed for estimating the risk of cancer for carriers of a predicted pathogenic variant (PPV) in a gene usually tested in a hereditary breast and ovarian cancer context. Index cases are enrolled consecutively among patients who undergo genetic testing as part of their care plan in France. First- and second-degree relatives and cousins of PPV carriers are invited to participate whether they are affected by cancer or not, and are tested for the familial PPV. Genetic, clinical, family and epidemiological data are centralized at the coordinating centre. The three-year feasibility study included 4431 prospective index cases, with 19.1% of them carrying a PPV. This showed that the study logistics are well adapted to clinical and laboratory constraints, and collaboration between partners (clinicians, biologists, coordinating centre and participants) is smooth. Hence, TUMOSPEC is being pursued, with the aim of optimizing clinical management guidelines specific to each gene. Abstract Assessment of age-dependent cancer risk for carriers of a predicted pathogenic variant (PPV) is often hampered by biases in data collection, with a frequent under-representation of cancer-free PPV carriers. TUMOSPEC was designed to estimate the cumulative risk of cancer for carriers of a PPV in a gene that is usually tested in a hereditary breast and ovarian cancer context. Index cases are enrolled consecutively among patients who undergo genetic testing as part of their care plan in France. First- and second-degree relatives and cousins of PPV carriers are invited to participate whether they are affected by cancer or not, and genotyped for the familial PPV. Clinical, family and epidemiological data are collected, and all data including sequencing data are centralized at the coordinating centre. The three-year feasibility study included 4431 prospective index cases, with 19.1% of them carrying a PPV. When invited by the coordinating centre, 65.3% of the relatives of index cases (5.7 relatives per family, on average) accepted the invitation to participate. The study logistics were well adapted to clinical and laboratory constraints, and collaboration between partners (clinicians, biologists, coordinating centre and participants) was smooth. Hence, TUMOSPEC is being pursued, with the aim of optimizing clinical management guidelines specific to each gene.
Published: 2021
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28. Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study

Author: Lieske H. Schrijver, Antonis C. Antoniou, Håkan Olsson, Thea M. Mooij, Marie-José Roos-Blom, Leyla Azarang, Julian Adlard, Munaza Ahmed, Daniel Barrowdale, Rosemarie Davidson, Alan Donaldson, Ros Eeles, D. Gareth Evans, Debra Frost, Alex Henderson, Louise Izatt, Kai-Ren Ong, Valérie Bonadona, Isabelle Coupier, Laurence Faivre, Jean-Pierre Fricker, Paul Gesta, Klaartje van Engelen, Agnes Jager, Fred H. Menko, Marian J.E. Mourits, Christian F. Singer, Yen Y. Tan, Lenka Foretova, Marie Navratilova, Rita K. Schmutzler, Carolina Ellberg, Anne-Marie Gerdes, Trinidad Caldes, Jacques Simard, Edith Olah, Anna Jakubowska, Johanna Rantala, Ana Osorio, John L. Hopper, Kelly-Anne Phillips, Roger L. Milne, Mary Beth Terry, Catherine Noguès, Christoph Engel, Karin Kast, David E. Goldgar, Flora E. van Leeuwen, Douglas F. Easton, Nadine Andrieu, Matti A. Rookus, Lilian Laborde, Pauline Pontois, Emanuelle Breysse, Margot Berline, Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Chrystelle Colas, Olivier Caron, Emmanuelle Mouret-Fourme, Claire Saule, Christine Lasset, Sophie Dussard, Pascaline Berthet, Elisabeth Luporsi, Véronique Mari, Laurence Gladieff, Stéphanie Chieze-Valéro, Jessica Moretta, Hagay Sobol, François Eisinger, Cornel Popovici, Michel Longy, Louise Grivelli, Florent Soubrier, Patrick Benusiglio, Pascal Pujol, Carole Corsini, Marie-Emmanuelle Morin-Meschin, Alain Lortholary, Claude Adenis, Audrey Maillez, Tan Dat Nguyen, Capucine Delnatte, Caroline Abadie, Julie Tinat, Isabelle Tennevet, Christine Maugard, Yves-Jean Bignon, Mathilde Gay Bellile, Clotilde Penet, Hélène Dreyfus, Odile Cohen-Haguenauer, Brigitte Gilbert, Laurence Venat-Bouvet, Dominique Leroux, Clémentine Legrand, Hélène Zattara-Cannoni, Valérie Layet, Elodie Lacaze, Sandra Fert-Ferrer, Odile Bera, Brigitte Gilbert-Dussardier, David Tougeron, Hakima Lallaoui, M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, M.K. Schmidt, D.J. Jenner, J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, I.A. Boere, C.J. van Asperen, P. Devilee, R.B. van der Luijt, T.C.T.E.F. van Cronenburg, M.R. Wevers, A.R. Mensenkamp, M.G.E.M. Ausems, M.J. Koudijs, I. van de Beek, K. van Engelen, J.J.P. Gille, E.B. Gómez García, M.J. Blok, M. de Boer, L.P.V. Berger, A.H. van der Hout, M.J.E. Mourits, G.H. de Bock, S. Siesling, J. Verloop, E.C. van den Broek, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Human genetics, Epidemiology and Data Science, Cancer Center Amsterdam, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Paul Strauss, CRLCC Paul Strauss, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Aix Marseille Université (AMU), Institut Curie [Paris], Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL), Human Genetics, APH - Methodology, APH - Quality of Care, Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, MUMC+: DA KG Lab Centraal Lab (9), Michel-Avella, Amandine, Medical Oncology, and Clinical Genetics
Subjects: endocrine system diseases, [SDV]Life Sciences [q-bio], MESH: Proportional Hazards Models, Cohort Studies, fetal growth restriction, small for gestational age, MESH: BRCA2 Protein, EPITHELIAL OVARIAN-CANCER, Medicine, pharma-ceutical treatment, MESH: Cohort Studies, Original Research, oral contraceptives, risk, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], MESH: Middle Aged, obstetrics, Obstetrics, BRCA1 Protein, Hazard ratio, MESH: Genetic Predisposition to Disease, Obstetrics and Gynecology, Oral/administration & dosage, Contraceptives, pregnancy complica-tions, MESH: Follow-Up Studies, Contraceptives, Oral/administration & dosage, Middle Aged, BRCA2 Protein/genetics, drug therapy, [SDV] Life Sciences [q-bio], Europe, MESH: Ovarian Neoplasms, ovarian cancer, SURVIVAL, Female, epidemiology, Ovarian Neoplasms/epidemiology, pregnancy, MESH: Contraceptives, Oral, preterm delivery, legislative framework, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Cohort study, HORMONAL FACTORS, Adult, preterm labor, medicine.medical_specialty, preterm premature rupture of membranes, MESH: Mutation, Population, REPRODUCTIVE RISK-FACTORS, retrospective, clinical trials with pregnant women, MUTATION CARRIERS, BREAST, Europe/epidemiology, research and development, preeclampsia, Breast cancer, multivariate, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, observational, education, MESH: BRCA1 Protein, Proportional Hazards Models, Retrospective Studies, BRCA2 Protein, MESH: Humans, survival bias, treatment during pregnancy, Proportional hazards model, business.industry, Retrospective cohort study, MESH: Adult, MESH: Retrospective Studies, medicine.disease, BRCA1, BRCA2, drug development, Confidence interval, placental transfer, Gynecology, obstetrical syndromes, Mutation, BRCA1 Protein/genetics, MESH: Europe, business, Ovarian cancer, MESH: Female, Contraceptives, Oral, Follow-Up Studies
Abstract: Contains fulltext : 237895.pdf (Publisher’s version ) (Open Access) BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with 10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; P(trend)=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.
Published: 2021
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29. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study

Author: Seçil Aksoy, Michael O. Woods, Heinric Williams, Bruno Buecher, Finlay A. Macrae, Lotte N. Krogh, Jay Qiu, Wan K.W. Juhari, Jan T. Lowery, Anne-Marie Gerdes, Magnus von Knebel Doeberitz, Luigi Ricciardiello, Karsten Schulmann, Jose Luis Soto, Kristina Lagerstedt-Robinson, Kiwamu Akagi, Raj Ramesar, Uffe Birk Jensen, Angel Alonso, Robert Hüneburg, Olivier Caron, Michel Longy, Jan Lubinski, Kate Green, Annabel Goodwin, D. Gareth Evans, Julie Wods, Leigha Senter, Matthew F. Kalady, Mark Clendenning, Barbara A. Leggett, Ravindran Ankathil, Swati G. Patel, Julian Barwell, Katherine M. Tucker, Grant Lee, Pascaline Berthet, Dawn M. Nixon, Sonia S. Kupfer, Naohiro Tomita, Susan Parry, Trinidad Caldés, Robert W. Haile, Edenir Inêz Palmero, Karin Alvarez, Cassandra B. Nichols, Mark A. Jenkins, N. Jewel Samadder, Loic LeMarchand, John Burn, Francisco Lopez, Rodney J. Scott, Pierre Laurent-Puig, Julie Arnold, Christina Therkildsen, Hans K. Schackert, Pilar Garre, Reinhard Buettner, Adriana Della Valle, Patricia Esperon, Wolff Schmiegel, Karl Heinimann, Inge Bernstein, Matthias Kloor, Nicoline Hoogerbrugge, Rui Manuel Reis, Fränzel J.B. Van Duijnhoven, Christoph Engel, Mohd Nizam Zahary, Sylviane Olschwang, Sapna Syngal, Valérie Bonadona, Nicholas Pachter, Matilde Navarro, Albert de la Chapelle, Beate Betz, Jukka-Pekka Mecklin, Catherine Noguès, Elena M. Stoffel, Toni T. Seppälä, Chrystelle Colas, Anneke Lucassen, Allan D. Spigelman, Youenn Drouet, Elisa J. Cops, Uri Ladabaum, Steve Thibodeau, Jeffrey N. Weitzel, Fiona Lalloo, Patrick J. Morrison, Maurizio Genuardi, Kohji Tanakaya, Patrick M. Lynch, Frederik J. Hes, William D. Foulkes, Carmen Guillén-Ponce, Jenny von Salomé, Emilia Rogoża-Janiszewska, Andrew Latchford, John L. Hopper, Carrie Snyder, Verónica Barca-Tierno, Gabriela Möslein, Lauren M. Gima, Melissa C. Southey, Paul A. James, Marion Dhooge, Claudia Perne, Steven Gallinger, Heather Hampel, Amanda B. Spurdle, Ingrid Winship, Emmanuelle Fourme, Rish K. Pai, Daniela Turchetti, Marta Pineda, Jürgen Weitz, James Hill, Daniel D. Buchanan, Carlos A. Vaccaro, Noralane M. Lindor, Rachel Pearlman, Pål Møller, Christian P. Strassburg, Jane C. Figueiredo, Aída Falcón de Vargas, Silke Zachariae, Karolin Bucksch, Joanne Ngeow, Silke Redler, Henrik Okkels, Maija R.J. Kohonen-Corish, Hans F. A. Vasen, Verena Steinke-Lange, Roselyne Guimbaud, Deepak Vangala, Isabelle Coupier, Nils Rahner, Berrin Tunca, Sanne W. Bajwa-ten Broeke, Niels de Wind, Sophie Lejeune, José Gaston Guillem, Karin Wadt, Polly A. Newcomb, Elke Holinski-Feder, Florencia Neffa, Rodrigo Santa Cruz Guindalini, Paul E. Wise, Julian R. Sampson, Graham Casey, Lene Juel Rasmussen, Rolf H. Sijmons, Tadeusz Dębniak, Ann-Sofie Backman, Joji Utsunomiya, Melyssa Aronson, Aung Ko Win, Yves-Jean Bignon, Judy W. C. Ho, Robyn L. Ward, Mev Dominguez-Valentin, Karolina Malińska, Elizabeth E. Half, John-Paul Plazzer, Marjolijn J. L. Ligtenberg, Rachel Austin, Nicola K. Poplawski, Marcia Cruz-Correa, Nagahide Matsubara, Charlotte Kvist Lautrup, Thomas Hansen, Tatsuro Yamaguchi, Thomas John, David J. Amor, Ilana Solomon, Yun-Hee Choi, Meghan J. van Wanzeele, Rakefet Shtoyerman, Vanessa Huntley, Maartje Nielsen, Deborah Neklason, Kevin J. Monahan, Gülçin Tezcan, Stefan Aretz, Talya Boisjoli, Sophie Giraud, Thierry Frebourg, Christophe Rosty, Heike Görgens, Lone Sunde, Allyson Templeton, Jacob Nattermann, Mala Pande, Joan Brunet, Nancy Uhrhammer, James M. Church, Florencia Spirandelli, Laurent Briollais, James G. Dowty, Jeanette C. Reece, Rachel Susman, Fay Kastrinos, Kirsi Pylvänäinen, Gabriel Capellá, Helène Schuster, Min H. Chew, Markus Loeffler, Christine Lasset, Michael J. Hall, Capuccine Delnatte, Floor A. Duijkers, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Digital Precision Cancer Medicine (iCAN), ATG - Applied Tumor Genomics, HUS Abdominal Center, Clinical sciences, Medical Genetics, Win A.K., Dowty J.G., Reece J.C., Lee G., Templeton A.S., Plazzer J.-P., Buchanan D.D., Akagi K., Aksoy S., Alonso A., Alvarez K., Amor D.J., Ankathil R., Aretz S., Arnold J.L., Aronson M., Austin R., Backman A.-S., Bajwa-ten Broeke S.W., Barca-Tierno V., Barwell J., Bernstein I., Berthet P., Betz B., Bignon Y.-J., Boisjoli T., Bonadona V., Briollais L., Brunet J., Bucksch K., Buecher B., Buettner R., Burn J., Caldes T., Capella G., Caron O., Casey G., Chew M.H., Choi Y.-H., Church J., Clendenning M., Colas C., Cops E.J., Coupier I., Cruz-Correa M., de la Chapelle A., de Wind N., Debniak T., Della Valle A., Delnatte C., Dhooge M., Dominguez-Valentin M., Drouet Y., Duijkers F.A., Engel C., Esperon P., Evans D.G., Falcon de Vargas A., Figueiredo J.C., Foulkes W., Fourme E., Frebourg T., Gallinger S., Garre P., Genuardi M., Gerdes A.-M., Gima L.M., Giraud S., Goodwin A., Gorgens H., Green K., Guillem J., Guillen-Ponce C., Guimbaud R., Guindalini R.S.C., Half E.E., Hall M.J., Hampel H., Hansen T.V.O., Heinimann K., Hes F.J., Hill J., Ho J.W.C., Holinski-Feder E., Hoogerbrugge N., Huneburg R., Huntley V., James P.A., Jensen U.B., John T., Juhari W.K.W., Kalady M., Kastrinos F., Kloor M., Kohonen-Corish M.R., Krogh L.N., Kupfer S.S., Ladabaum U., Lagerstedt-Robinson K., Lalloo F., Lasset C., Latchford A., Laurent-Puig P., Lautrup C.K., Leggett B.A., Lejeune S., LeMarchand L., Ligtenberg M., Lindor N., Loeffler M., Longy M., Lopez F., Lowery J., Lubinski J., Lucassen A.M., Lynch P.M., Malinska K., Matsubara N., Mecklin J.-P., Moller P., Monahan K., Morrison P.J., Nattermann J., Navarro M., Neffa F., Neklason D., Newcomb P.A., Ngeow J., Nichols C., Nielsen M., Nixon D.M., Nogues C., Okkels H., Olschwang S., Pachter N., Pai R.K., Palmero E.I., Pande M., Parry S., Patel S.G., Pearlman R., Perne C., Pineda M., Poplawski N.K., Pylvanainen K., Qiu J., Rahner N., Ramesar R., Rasmussen L.J., Redler S., Reis R.M., Ricciardiello L., Rogoza-Janiszewska E., Rosty C., Samadder N.J., Sampson J.R., Schackert H.K., Schmiegel W., Schulmann K., Schuster H., Scott R., Senter L., Seppala T.T., Shtoyerman R., Sijmons R.H., Snyder C., Solomon I.B., Soto J.L., Southey M.C., Spigelman A., Spirandelli F., Spurdle A.B., Steinke-Lange V., Stoffel E.M., Strassburg C.P., Sunde L., Susman R., Syngal S., Tanakaya K., Tezcan G., Therkildsen C., Thibodeau S., Tomita N., Tucker K.M., Tunca B., Turchetti D., Uhrhammer N., Utsunomiya J., Vaccaro C., van Duijnhoven F.J.B., van Wanzeele M.J., Vangala D.B., Vasen H.F.A., von Knebel Doeberitz M., von Salome J., Wadt K.A.W., Ward R.L., Weitz J., Weitzel J.N., Williams H., Winship I., Wise P.E., Wods J., Woods M.O., Yamaguchi T., Zachariae S., Zahary M.N., Hopper J.L., Haile R.W., Macrae F.A., Moslein G., and Jenkins M.A.
Subjects: 0301 basic medicine, Proband, Oncology, Male, Heredity, DNA mismatch repair, [SDV]Life Sciences [q-bio], SUSCEPTIBILITY, Settore MED/03 - GENETICA MEDICA, 0302 clinical medicine, Residence Characteristics, Risk Factors, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], PMS2, ComputingMilieux_MISCELLANEOUS, MLH1, Age Factors, Middle Aged, Penetrance, Lynch syndrome, 3. Good health, Pedigree, Phenotype, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis, Female, Adult, medicine.medical_specialty, PENETRANCE, congenital, hereditary, and neonatal diseases and abnormalities, GENES, 3122 Cancers, colorectal cancer, BREAST, Risk Assessment, 03 medical and health sciences, Sex Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Retrospective Studies, business.industry, MUTATIONS, Cancer, medicine.disease, digestive system diseases, MSH2, MSH6, MODEL, INDIVIDUALS, 030104 developmental biology, Lynch Syndrome, Gene-Environment Interaction, business
Abstract: Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.
Published: 2021
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30. Abstract P1-09-07: Breast cancer characteristics and outcomes in patients with TP53 germline mutation

Author: F-C Bidard, Dominique Stoppa-Lyonnet, Luc Cabel, M Tran, Chrystelle Colas, A De Pauw, L Bozec, Florence Lerebours, Marion Lavigne, Delphine Loirat, A Vincent-Salomon, Valérie Laurence, and Marion Gauthier-Villars
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Breast cancer, Germline mutation, business.industry, Internal medicine, Medicine, In patient, business, medicine.disease
Abstract: Introduction Li-Fraumeni syndrome (LFS) resulting from monoallelic germline TP53 gene mutation is a rare hereditary cancer predisposition. Breast cancer (BC) is the most common cancer among women with TP53 germline mutation with a risk ranging from 49% to 85% by the age of 60 years old. Most of these cancers are early onset. Few patients' cases have been reported so far in the literature. Our aim was to describe the medical history of a cohort of LFS women diagnosed with BC recruited from a single institution. The characteristics combined were genetic alteration diagnosis, tumor characteristics, treatment, outcome, and LFS associated cancers. Methods We retrospectively identified breast cancer patients with TP53 germline mutation from the Institut Curie (Paris, France) database and described their cancer characteristics and medical history. Results From 1989 to 2015, 25 patients affected with BC (31 tumors) and TP53 germline mutation carrier were identified, with a median follow up of 6.5 years. Median age at BC diagnosis was 30.5 years. All patients were women. 33% had a previously identified TP53 mutation in their family. 70% of them had BC as their first cancer event. 60% of the patients presented with another LFS associated cancer or non-related cancers: osteosarcoma (22%), glioblastoma (18%), pulmonary carcinoma (13%), gastric linitis plastica (9%), malignant hemopathy (9%), soft tissue sarcoma (9%), adrenocortical carcinoma (4%), ovarian cystadenocarcinoma (4%), renal tumor (4%), choroid plexus carcinoma (4%). 92% of the breast tumors were ductal carcinoma (28% DCIS and 64% IDC), 7% were sarcoma (1 phyllodesarcoma, 1 pleiomorphic liposarcoma); there were no lobular carcinoma. Among the IDC, 50% were HER2 positive, 72% were hormone-receptor positive. Most patients had a mastectomy (64%), and most of them received radiation (55%). However, when TP53 mutation had been identified prior to the treatment, none of the patients received radiotherapy (5 patients). Most patients received chemotherapy (70%) (37% in neoadjuvant setting, 33% in adjuvant setting, 25% for metastatic setting). 40% of the patients received hormone therapy (37% as adjuvant treatment, 7% for metastatic disease) Most of the patients did not relapse from BC (75%). Overall, only 17% of the patients had metastatic BC. To date, 12 patients of our series have died (48%), 6 patients (24%) from other LFS-associated cancers and 4 patients from BC (16%). Conclusion To the best of our knowledge, this descriptive series is the largest study of tumor characteristics and medical history of LFS-women with BC, the most frequent cancer among women with TP53 germline mutation. It confirms the higher HER2 overexpression rate observed in LFS-patients BC, as suggested in the literature and showed a high rate of DCIS at initial presentation. Most of the patients developed other LFS-associated cancers. In depth molecular analysis of these BC will be performed in order to gain insight into their biological specificities and to adapt the therapeutic management of this poor prognosis syndrome. Citation Format: Tran M, Loirat D, Colas C, Bozec L, Laurence V, Lerebours F, Cabel L, Bidard F-C, Stoppa-Lyonnet D, Vincent-Salomon A, Gauthier-Villars M, Lavigne M, De Pauw A. Breast cancer characteristics and outcomes in patients with TP53 germline mutation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-07.
Published: 2019
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31. Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach

Author: Marie-Noëlle Bonnet-Dupeyron, Helene Dreyfus, Nadia Boutry-Kryza, Cornel Popovici, Laurent Castera, Nancy Uhrhammer, Anthony Laugé, Yves-Jean Bignon, Hélène Delhomelle, Alice Fiévet, Christophe Guy, Noémie Bronnec, Bruno Buecher, Fabienne Prieur, Sophie Demontety, Vincent Goussot, Emmanuelle Mouret-Fourme, Claire Saule, Helene Zattara, Sarah Malsa, Paul Gesta, Cindy Meira, Erell Guillerm, Isabelle Turbiez, Agathe Ricou, Mélanie Léoné, Pierre Vande Perre, Sarab Lizard, Pascaline Berthet, Norbert Lignon, Adrien Buisson, Anne-Marie Birot, Philippe Denizeau, Etienne Rouleau, Odile Cohen-Haguenauer, Veronica Goldbarg, Virginie Moncoutier, Charlotte Benigni, Emmanuelle Barouk-Simonet, Flavie Boulouard, Caroline Jacquot-Sawka, Alice Yvard, Hakima Lallaoui, Veronica Cusin, Angélina Legros, Muriel Belotti, Christine Maugard, Marine Guillaud-Bataille, Jean-Marc Limacher, Marion Gauthier-Villars, Louise Crivelli, Afane Brahimi, Odile Cabaret, Ophelie Bertrand, Michel Longy, Gabrielle Le Guyadec, Doriane Livon, Amelie Bloucard, Dominique Stoppa-Lyonnet, Capucine Delnatte, Caroline Lecerf, Jennifer Carriere, Virginie Guibert, Véronique Mari, Anne-Sophie Allary, Florence Coulet, Françoise Bonnet, Paul Vilquin, Noémie Basset, Khadija Abidallah, Pierre Macquere, Nicolas Derive, Manon Boulaire, Stephanie Chieze-Valéro, Marine Le Mentec, Mathilde Gay-Bellile, Anne-Laure Conoy, Henri Margot, Pierre Devulder, Mathias Schwartz, Isabelle Tennevet, Stéphane Bézieau, Francesca Damiola, Violaine Bourdon, Audrey Mailliez, Zoe Nevière, Nicolas Viellard, Laurence Venat, Antoine De Pauw, Brigitte Bressac-de Paillerets, Agnès Hardouin, Sofiane Lacoste, Sandra Fert-Ferrer, Maud Privat, Helene Larbre, Dominique Vaur, Etienne Muller, Françoise Revillion, Clémentine Legrand, Rosette Lidereau, Laurence Gladieff, Sabine Raad, Jean Chiesa, Diane Molière, Ahmed Bouras, Nicolas Sevenet, Patrick R. Benusiglio, Sophie Giraud, Christine Toulas, Voreak Suybeng, Florine Oca, Tetsuro Noguchi, Catherine Dehainault, Sophie Lejeune, Céline Heude, Catherine Dubois d’Enghein, Thien-vu Nguyen Minh Tuan, Olivier Caron, Mathilde Warcoin, Christine Lasset, Claude Houdayer, Jessica Moretta-Serra, Julie Tinat, Hagay Sobol, Natalie Jones, Fanny Brayotel, Anne Fajac, Virginie Bubien, Maud Blanluet, Jean-Marc Rey, Anne Durlach, Sandrine M. Caputo, Isabelle Coupier, Fatoumata Simaga, Sophie Krieger, Catherine Noguès, Fabrice Airaud, Robin Fouillet, Celine Garrec, Valérie Bonadona, Julie Menjard, Bérengère Legendre, Chrystelle Colas, Christelle Berthemin, Camille Cohen, Caroline Abadie, Olivier Ingster, Audrey Remenieras, Anaïs Dupré, Jessica Le Gall, Lisa Golmard, Marie Bidart, Henrique Tenreiro, J Bombled, Marie-Charlotte Villy, Marie-Agnès Collonge-Rame, Sophie Dussart, Alain Lortholary, Lucie Salle, Samira Fekairi, Service de Génétique Oncologique, Institut Curie [Paris], Université Paris sciences et lettres (PSL), Département de Biologie des Tumeurs, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Références Cancers Rares (PREDIR), INCA, Institut national du cancer [Boulogne] (INCA), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Centre Hospitalier Universitaire de Reims (CHU Reims), dormoy, valerian, Unité fonctionnelle de neurogénétique moléculaire et cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
Subjects: Cosegregation, Genotype, [SDV]Life Sciences [q-bio], Breast Neoplasms, Biology, Article, 03 medical and health sciences, Likely benign, Genetics, medicine, Humans, Clinical significance, Genetic Predisposition to Disease, Genetic Testing, Uncertain significance, Gene, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), 030304 developmental biology, BRCA2 Protein, Ovarian Neoplasms, 0303 health sciences, Cancer predisposition, BRCA1 Protein, 030305 genetics & heredity, Cancer, Genetic Variation, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Classification methods, Female
Abstract: Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs. The classification method was a multifactorial model combining different associations between VUSs and cancer, including cosegregation data. At this time, among the 653 variants selected, 101 (15%) distinct variants shared by 1,624 families were classified as pathogenic/likely pathogenic or benign/likely benign by the COVAR study. Sixty-six of the 101 (65%) variants classified by COVAR would have remained VUSs without cosegregation data. Of note, among the 34 variants classified as pathogenic by COVAR, 16 remained VUSs or likely pathogenic when following the ACMG/AMP variant classification guidelines. Although the initiation and organization of cosegregation analyses require a considerable effort, the growing number of available genetic tests results in an increasing number of families sharing a particular variant, and thereby increases the power of such analyses. Here we demonstrate that variant cosegregation analyses are a powerful tool for the classification of variants in the BRCA1/2 breast-ovarian cancer predisposition genes.
Published: 2021
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32. Cancer predisposition and germline CTNNA1 variants

Author: Lisa Golmard, Robert Hüneburg, Silvana Lobo, Carla Oliveira, Lise Boussemart, Isabel Spier, Florence Coulet, Stefan Aretz, Chrystelle Colas, and Patrick R. Benusiglio
Subjects: Proband, Heterozygote, Germline, Frameshift mutation, CDH1, Breast cancer, Gene Frequency, Antigens, CD, Stomach Neoplasms, Genetics, Medicine, Humans, Genetic Predisposition to Disease, Genetics (clinical), Germ-Line Mutation, biology, business.industry, Cancer, General Medicine, medicine.disease, Cadherins, Pedigree, Phenotype, biology.protein, Age of onset, Hereditary diffuse gastric cancer, business, alpha Catenin
Abstract: Hereditary Diffuse Gastric Cancer (HDGC) is a cancer predisposing syndrome mainly caused by germline inactivating variants in CDH1, encoding E-cadherin. Early-onset diffuse gastric cancer (DGC) and/or invasive lobular breast cancer (LBC) are the main phenotypes in CDH1-associated HDGC. CTNNA1, encoding for α-E-catenin, and E-cadherin-partner in the adherens junction complex, has been recently classified as a HDGC predisposing gene. Nevertheless, little is known about CTNNA1 tumor spectrum in variant carriers and variant-type associated causality. Herein, we systematically reviewed the literature searching for CTNNA1 germline variants carriers, further categorized them according to HDGC clinical criteria (HDGC vs non-HDGC), collected phenotypes, classified variants molecularly and according to CDH1 ACMG/AMP guidelines and performed genotype-phenotype analysis. We found 41 families carrying CTNNA1 germline variants encompassing in total 105 probands and relatives. All probands from 13 HDGC families presented DGC and their average age of onset was 40 ± 17 years; 10/13 (77%) HDGC families carried a pathogenic (P) variant. Most probands from 28 non-HDGC families developed unspecified-BC, as well as most of their relatives; 4/28 (14%) carried a P variant, 16/28 (57%) carried a likely pathogenic (LP) variant, 7/28 (25%) carried variants of unknown significance (VUS) and 1/28 (4%) carried a likely benign variant. Regardless of clinical criteria, 97% (32/33) of probands and relatives from P variant-carrier families had DGC/unspecified-GC. In LP variant-carrier families, 82% (28/34) of probands and relatives had unspecified-BC. Only 2/105 individuals had LBC. A cluster of frameshift and nonsense variants was found in CTNNA1 last exon of non-HDGC families and classified as VUS. In conclusion, current available data confirms an association of CTNNA1 P variants with early-onset DGC, but not with LBC. We demonstrate that in ascertained cohorts, CTNNA1 P variants explain2% of HDGC families and support the use of ACMG/AMP CDH1 specific variant curation guidelines, while no specific guidelines are developed for CTNNA1 variant classification. Moreover, we demonstrated that truncating variants at the CTNNA1 NMD-incompetent last exon have limited deleteriousness, and that CTNNA1 LP variants have lower actionability than CDH1 LP variants. Current knowledge supports considering only CTNNA1 P variants as clinically actionable in HDGC carrying families.
Published: 2021

33. EPCO-03. GLIOMA ONCOGENESIS IN THE CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY (CMMRD) SYNDROME

Author: Laurence Brugières, Jacques Grill, Nadim Hamzaoui, Martine Muleris, Tiphaine Adam de Beaumais, Odile Cabaret, Philippe Denizeau, Franck Bourdeaut, David Castel, Jane Merlevede, Felipe Andreiuolo, Chrystelle Colas, Cécile Faure-Conter, Stéphanie Puget, Pascale Varlet, Thomas Blauwblomme, Etienne Rouleau, Léa Guerrini-Rousseau, Marie-Anne Debily, and Kevin Beccaria
Subjects: Cancer Research, business.industry, Cancer, 26th Annual Meeting & Education Day of the Society for Neuro-Oncology, medicine.disease, medicine.disease_cause, Oncology, Glioma, medicine, Cancer research, MISMATCH REPAIR DEFICIENCY, DNA mismatch repair, Neurology (clinical), Carcinogenesis, business, Exome sequencing, Protein overexpression, Glioblastoma
Abstract: PURPOSE Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40NS SNV/Mb, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.
Published: 2021
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34. Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms

Author: Pierre Hirsch, Barbara Schmaltz-Panneau, Jean-Henri Bourhis, Caroline Deswarte, Christophe Marzac, Christine Bellanné-Chantelot, Jean-Baptiste Micol, Christine Delaunay-Darivon, Flore Sicre de Fontbrune, Hélène Guermouche, Albert Najman, William Vainchenker, Céline Lemaitre, Jean-Côme Meniane, Eolia Brissot, Florence Pasquier, Philippe Pellet, Gwendoline Leroy, François Delhommeau, Patrick R. Benusiglio, Samy Chraibi, Isabelle Plo, Olivier Caron, Pascal Fuseau, Simona Lapusan, Pascale Cony-Makhoul, Odile Bera, Chrystelle Colas, Jean Pegliasco, Graciela Rabadan Moraes, and Françoise Isnard
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, Myeloid, Adolescent, DNA Copy Number Variations, Vesicular Transport Proteins, Autophagy-Related Proteins, Biology, Germline, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene Duplication, Gene duplication, medicine, Biomarkers, Tumor, Humans, Gene, Dominance (genetics), Aged, Retrospective Studies, Chromosomes, Human, Pair 14, Myeloproliferative Disorders, Essential thrombocythemia, Myeloid leukemia, Hematology, Middle Aged, medicine.disease, Prognosis, Repressor Proteins, Survival Rate, Haematopoiesis, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, Germ Cells, Oncology, 030220 oncology & carcinogenesis, Case-Control Studies, Myelodysplastic Syndromes, Mutation, Cancer research, Female, Disease Susceptibility, Clonal Hematopoiesis, Follow-Up Studies
Abstract: The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.
Published: 2021

35. Duodenal adenomas and cancer in MUTYH-associated polyposis: an international cohort study

Author: Andrew Latchford, A. Alonso Sanchez, Patrick M. Lynch, Matthew Mort, Joanna J Hurley, Maria Teresa Ricci, E. Meuser, Marco Vitellaro, Hannah West, A. Backman, Yann Parc, Susan K. Clark, M. R. Aznárez, Frederik J. Hes, Sunil Dolwani, O. Vinet, H. Leon Brito, Maureen E. Mork, Chrystelle Colas, M. Navarro Garcia, S. Gonzalez Romero, Sarah-Jane Walton, Hala Jundi, Gabriel Capellá, S. Kelland, Zeinab Ghorbanoghli, K van der Tuin, Hans F. A. Vasen, Julian R. Sampson, Jan Björk, Evelien Dekker, Jean-Christophe Saurin, Eduardo Vilar, Laura E. Thomas, M. Gonn, Maartje Nielsen, Clinical sciences, Medical Genetics, Gastroenterology and Hepatology, APH - Quality of Care, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Adult, Male, medicine.medical_specialty, Duodenum, Gastroenterology, DNA Glycosylases, Familial adenomatous polyposis, Adenomatous Polyps, Young Adult, Duodenal Neoplasms, Internal medicine, Prevalence, medicine, Humans, Genetics(clinical), Prospective Studies, Intestinal Mucosa, Endoscòpia, Polyposis, Càncer, Duodenoscopy, Aged, Cancer, Aged, 80 and over, Hepatology, Spigelman Stage, business.industry, MUTYH-Associated Polyposis, Endoscopy, Middle Aged, medicine.disease, digestive system diseases, Estudi de casos, Female, Case studies, business, Cohort study
Abstract: Although duodenal adenomas and cancer appear to occur significantly less frequently in autosomal recessive MUTYH-associated polyposis (MAP) than in autosomal dominant familial adenomatous polyposis (FAP),1 current guidelines recommend similar endoscopic surveillance for both disorders.2-4 This involves gastro-duodenoscopy starting at 25 to 35 years of age and repeated at intervals determined by Spigelman staging based on the number, size, histological type and degree of dysplasia of adenomas, and by ampullary staging. Case reports of duodenal cancers in MAP suggest that they may develop in the absence of advanced Spigelman stage benign disease and even without coexisting adenomas.1 Recent molecular analyses suggest thatMAPduodenal adenomashave a higher mutational burden than FAP adenomas and are more likely to harbor oncogenic drivermutations, such as those in KRAS.5 These apparent differences in the biology and natural history of duodenal polyposis in FAP and MAP challenge the assumption that the same surveillance should be applied in both conditions.
Published: 2021
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36. Overview of hereditary breast and ovarian cancer (HBOC) guidelines across Europe

Author: David Humberto Marmolejo, Mark Yu Zheng Wong, Svetlana Bajalica-Lagercrantz, Marc Tischkowitz, Judith Balmaña, Attila Balázs Patócs, Pierre Chappuis, Chrystelle Colas, Maurizio Genuardi, Maria Haanpää, Hildegunn Hoberg Vetti, Nicoline Hoogerbrugge, Arvids Irmejs, Tiina Kahre, Barbara Klink, Mateja Krajc, Tamara Hussong Milagre, Robin de Putter, Verena Steinke-Lange, Karin Wadt, and Katharina Wimmer
Subjects: Oncology, medicine.medical_specialty, PALB2, medicine.medical_treatment, Breast Neoplasms, Germline, Breast cancer, Internal medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, skin and connective tissue diseases, CHEK2, Mastectomy, Genetics (clinical), Genetic testing, Ovarian Neoplasms, medicine.diagnostic_test, business.industry, General Medicine, medicine.disease, Europe, Female, Age of onset, Ovarian cancer, business
Abstract: Item does not contain fulltext Hereditary breast and ovarian cancer (HBOC) is a syndrome defined by an increased risk of developing breast and/or ovarian cancer most commonly due to germline disease-causing variants in the BRCA1 and BRCA2 genes, but also other causative genes such as PALB2, ATM and CHEK2. As genetic testing becomes more prevalent and new clinical data emerge, updates of national guidelines are required to incorporate these advances in our knowledge. The aim of this work is to review the guidelines for HBOC genetic testing and clinical surveillance across European countries, mostly affiliated to the European Reference Network (ERN) for Genetic Tumor Risk Syndroms (GENTURIS). Young onset breast cancer (BC), triple negative phenotype, or bilateral BC are considered as criteria for genetic testing in all, with differences in age limits. Testing of invasive epithelial non-mucinous ovarian cancer is also universally accepted. While breast magnetic resonance imaging (MRI) is consistently recommended in high-risk individuals, age of onset for mammograms differ between 30 and 40 years. Risk-reducing mastectomy is commonly offered as an option, while risk-reducing salpingo-oophorectomy is universally recommended. The largest differences are observed with respect to ovarian surveillance prior to risk-reducing salpingo-oophorectomy and in breast surveillance for carriers of non-BRCA1/2 genes. These differences in national guidelines reflect the variations in clinical consensus that may be reached in the absence of consistent evidence for some recommendations.
Published: 2021
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37. The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Author: GEMO Study Collaborators, EMBRACE Collaborators, OCGN Investigators, HEBON Investigators, kConFab Investigators, IMM (Inge) Lakeman, Alexandra J. van den Broek, Juliën A.M. Vos, Daniel R. Barnes, Julian Adlard, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Banu K. Arun, Judith Balmaña, Daniel Barrowdale, Javier Benitez, Ake Borg, Trinidad Caldés, Maria A. Caligo, W.K. (Kuan) Chung, Kathleen B.M. Claes, Emmanuelle Barouk-Simonet, Muriel Belotti, Pascaline Berthet, Yves Jean Bignon, Valérie Bonadona, Brigitte Bressac-de Paillerets, Bruno Buecher, Sandrine Caputo, O (Olivier) Caron, Laurent Castera, Virginie Caux-Moncoutier, Chrystelle Colas, Marie Agnès Collonge-Rame, Isabelle Coupier, Antoine de Pauw, Capucine Delnatte, Camille Elan, Laurence Faivre, Sandra Fert Ferrer, Marion Gauthier-Villars, Paul Gesta, Sophie Giraud, J.M. (Margriet) Collee, CW (Christoph) Engel, M.J. (Maartje) Hooning, B.A.M. (Annette) Heemskerk - Gerritsen, A. (Antoinette) Hollestelle, A. (Agnes) Jager, L.B. (Linetta) Koppert, AG (Mieke) Kriege, A.M.W. (Ans) van den Ouweland, C.H.M. (Carolien) van Deurzen, H.C. (Lena) van Doorn, GEMO Study Collaborators, EMBRACE Collaborators, OCGN Investigators, HEBON Investigators, kConFab Investigators, IMM (Inge) Lakeman, Alexandra J. van den Broek, Juliën A.M. Vos, Daniel R. Barnes, Julian Adlard, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Banu K. Arun, Judith Balmaña, Daniel Barrowdale, Javier Benitez, Ake Borg, Trinidad Caldés, Maria A. Caligo, W.K. (Kuan) Chung, Kathleen B.M. Claes, Emmanuelle Barouk-Simonet, Muriel Belotti, Pascaline Berthet, Yves Jean Bignon, Valérie Bonadona, Brigitte Bressac-de Paillerets, Bruno Buecher, Sandrine Caputo, O (Olivier) Caron, Laurent Castera, Virginie Caux-Moncoutier, Chrystelle Colas, Marie Agnès Collonge-Rame, Isabelle Coupier, Antoine de Pauw, Capucine Delnatte, Camille Elan, Laurence Faivre, Sandra Fert Ferrer, Marion Gauthier-Villars, Paul Gesta, Sophie Giraud, J.M. (Margriet) Collee, CW (Christoph) Engel, M.J. (Maartje) Hooning, B.A.M. (Annette) Heemskerk - Gerritsen, A. (Antoinette) Hollestelle, A. (Agnes) Jager, L.B. (Linetta) Koppert, AG (Mieke) Kriege, A.M.W. (Ans) van den Ouweland, C.H.M. (Carolien) van Deurzen, and H.C. (Lena) van Doorn
Abstract: Purpose: To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313b
Published: 2021
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38. HGG-41. Glioma oncogenesis in the constitutional mismatch repair deficiency (CMMRD) syndrome

Author: Lea Guerrini-Rousseau, Jane Merlevede, Philippe Denizeau, Felipe Andrejuolo, Pascale Varlet, Stephanie Puget, Kevin Beccaria, Thomas Blauwblomme, Odile Cabaret, Nadim Hamzaoui, Franck Bourdeaut, Cecile Faure-Conter, Martine Muleris, Chrystelle Colas, Tiphaine Adam de Beaumais, David Castel, Etienne Rouleau, Laurence Brugieres, Jacques Grill, and Marie-Anne Debily
Subjects: Cancer Research, Oncology, Neurology (clinical)
Abstract: PURPOSE: Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS: A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS: Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION: CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.
Published: 2022
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39. EPID-04. PREDCAP, the French registry of predisposition to pediatric cancers

Author: Lea Guerrini-Rousseau, Pauline Hoarau, Gaelle Bougeard, Lisa Golmard, Chrystelle Colas, Marion Gauthier-Villars, Claude Houdayer, Thierry Frebourg, Franck Bourdeaut, and Laurence Brugieres
Subjects: Cancer Research, Oncology, Neurology (clinical)
Abstract: A pathogenic or likely pathogenic variant (PV) in a major cancer predisposition gene is identified in almost 10% of children or young adults who developed a cancer, regardless of their family history. This incidence may increase by the development of wide tumor sequencing programs leading to identify germline PVs in cancer patients and new cancer predisposition syndromes (CPS) associated with childhood cancers. Due to the rarity of each CPS, we still lack information about phenotype associated with most CPS especially cancer risks according to age as well as tumor characteristics and response to treatment. Within the French genetic multidisciplinary network involving pediatric oncologists, oncogeneticists and researchers, we have created a clinico-molecular registry for pediatric-CPS according to data protection regulation. The PREDCAP database collects clinical, genetic and molecular data from patients who developed pediatric tumors associated with a CPS, both retrospectively and prospectively. It includes a mandatory set of data on clinical phenotype, tumor characteristics (including treatment and outcome), family data and results of genetic analyses, with annual data updates. Interoperability with existing databases is planned, allowing for pooling of data collection and management. Aims of PREDCAP registry are to obtain reliable clinical and molecular data on pediatric CPS with a simplified and effective access. By collecting all available data on a large number of patients thanks to international collaborations, we hope to improve the knowledge on rare CPS, in particular, to better define the tumor spectrum and the penetrance of PVs, to analyze the specificity of tumors associated with these germline PVs. With this tool, we wish to facilitate future projects using structured and centralized data, associated with a virtual bank of available tumor and constitutional DNA, to evaluate and improve the relevance of management recommendations established for each syndrome.
Published: 2022
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40. Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group

Author: Rose B. McGee, Arun Rangaswami, Chrystelle Colas, Melyssa Aronson, Andrew Y Shuen, Heather Hampel, Kory Jasperson, William D. Foulkes, Yael Goldberg, Laurence Brugières, Uri Tabori, Martine Muleris, Kami Wolfe Schneider, Hagit Baris Feldman, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université Paris-Saclay
Subjects: 0301 basic medicine, medicine.medical_specialty, Consensus, [SDV]Life Sciences [q-bio], Clinical manifestation, medicine.disease_cause, DNA Mismatch Repair, 03 medical and health sciences, 0302 clinical medicine, Neoplastic Syndromes, Hereditary, Heredity, Genetics, PMS2, Medicine, Humans, Intensive care medicine, Genetics (clinical), Genetic testing, Mismatch Repair Endonuclease PMS2, medicine.diagnostic_test, business.industry, Brain Neoplasms, International working group, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Moderate evidence, MISMATCH REPAIR DEFICIENCY, Position paper, business, Colorectal Neoplasms
Abstract: BackgroundConstitutional mismatch repair deficiency syndrome (CMMRD) is the most aggressive cancer predisposition syndrome associated with multiorgan cancers, often presenting in childhood. There is variability in age and presentation of cancers and benign manifestations mimicking neurofibromatosis type 1. Genetic testing may not be informative and is complicated by pseudogenes associated with the most commonly associated gene, PMS2. To date, no diagnostic criteria exist. Since surveillance and immune-based therapies are available, establishing a CMMRD diagnosis is key to improve survival.MethodsIn order to establish a robust diagnostic path, a multidisciplinary international working group, with representation from the two largest consortia (International Replication Repair Deficiency (IRRD) consortium and European Consortium Care for CMMRD (C4CMMRD)), was formed to establish diagnostic criteria based on expertise, literature review and consensus.ResultsThe working group established seven diagnostic criteria for the diagnosis of CMMRD, including four definitive criteria (strong evidence) and three likely diagnostic criteria (moderate evidence). All criteria warrant CMMRD surveillance. The criteria incorporate germline mismatch repair results, ancillary tests and clinical manifestation to determine a diagnosis. Hallmark cancers for CMMRD were defined by the working group after extensive literature review and consultation with the IRRD and C4CMMRD consortia.ConclusionsThis position paper summarises the evidence and rationale to provide specific guidelines for CMMRD diagnosis, which necessitates appropriate surveillance and treatment.
Published: 2020
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41. National recommendations of the French Genetics and Cancer Group - Unicancer on the modalities of multi-genes panel analyses in hereditary predispositions to tumors of the digestive tract

Author: Bruno Buecher, Christine Lasset, Carole Corsini, Christine Maugard, Pascaline Berthet, Nadine Andrieu, Odile Cohen-Haguenauer, Catherine Noguès, Olivier Caron, Marion Dhooge, Sophie Dussart, Chrystelle Colas, Antoine De Pauw, Valérie Bonadona, Stéphanie Baert-Desurmont, Cornel Popovici, Capucine Delnatte, Jessica Moretta-Serra, Dominique Leroux, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Gustave Roussy (IGR), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre Léon Bérard [Lyon], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Institut Curie [Paris], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, CRLCC René Gauducheau, CHU Grenoble, CHU Strasbourg, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), Mines Paris - PSL (École nationale supérieure des mines de Paris), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Dupuis, Christine, and UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité)
Subjects: 0301 basic medicine, Candidate gene, Gene panel, Recommendations, Genetic counseling, [SDV]Life Sciences [q-bio], Predisposition, Context (language use), 030105 genetics & heredity, MLH1, 03 medical and health sciences, MUTYH, Pancreatic cancer, Biomarkers, Tumor, Genetics, Humans, Medicine, Gastrointestinal tumors, Genetic Testing, Genetics (clinical), Gastrointestinal Neoplasms, business.industry, Clinical management, Academies and Institutes, Cancer, General Medicine, medicine.disease, 3. Good health, MSH6, [SDV] Life Sciences [q-bio], 030104 developmental biology, Practice Guidelines as Topic, France, business
Abstract: International audience; In case of suspected hereditary predisposition to digestive cancers, next-generation sequencing can analyze simultaneously several genes associated with an increased risk of developing these tumors. Thus, "Gastro Intestinal" (GI) gene panels are commonly used in French molecular genetic laboratories. Lack of international recommendations led to disparities in the composition of these panels and in the management of patients. To harmonize practices, the Genetics and Cancer Group (GGC)-Unicancer set up a working group who carried out a review of the literature for 31 genes of interest in this context and established a list of genes for which the estimated risks associated with pathogenic variant seemed sufficiently reliable and high for clinical use. Pancreatic cancer susceptibility genes have been excluded. This expertise defined a panel of 14 genes of confirmed clinical interest and relevant for genetic counseling: APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SMAD4 and STK11. The reasons for the exclusion of the others 23 genes have been discussed. The paucity of estimates of the associated tumor risks led to the exclusion of genes, in particular CTNNA1, MSH3 and NTHL1, despite their implication in the molecular pathways involved in the pathophysiology of GI cancers. A regular update of the literature is planned to up-grade this panel of genes in case of new data on candidate genes. Genetic and epidemiological studies and international collaborations are needed to better estimate the risks associated with the pathogenic variants of these genes either selected or not in the current panel.
Published: 2020
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42. Molecular tumor testing in patients with Lynch-like syndrome reveals a de novo mosaic variant of a mismatch repair gene transmitted to offspring

Author: Florence Coulet, Erell Guillerm, Armelle Bardier-Dupas, Noémie Basset, Chrystelle Colas, and Magali Svrcek
Subjects: Male, congenital, hereditary, and neonatal diseases and abnormalities, Somatic cell, Offspring, Colon, Genetic counseling, Biology, MLH1, Brief Communication, Germline, 03 medical and health sciences, Genetics, medicine, Humans, Genetics (clinical), 0303 health sciences, Mosaicism, 030305 genetics & heredity, Microsatellite instability, nutritional and metabolic diseases, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Pedigree, MSH2, Mutation, DNA mismatch repair, Female, MutL Protein Homolog 1
Abstract: In Lynch-like syndrome, patients have tumors with microsatellite instability but no germline pathogenic variant in mismatch repair genes or somatic methylation of the MLH1 promoter. Identification of the mechanism that causes these tumors is crucial for guiding screening of the patients and their relatives. Double somatic hits are the usual explanation for these cases; however, we have previously reported a de novo mosaic pathogenic variant in a patient with Lynch-like syndrome. Using tumoral NGS analysis of a series of 16 patients with Lynch-like syndrome, we found six patients with double somatic hits, including one patient with mosaicism of a de novo pathogenic variant in MSH2. This variant was transmitted to the patient's offspring, which has significant implications for genetic counseling.
Published: 2020

43. Calibration of pathogenicity due to variant-induced leaky splicing defects by using BRCA2 exon 3 as a model system

Author: Gaia Castelain, Capucine Delnatte, Pascaline Gaildrat, Myriam Vezain, Laëtitia Meulemans, Nadia Boutry-Kryza, Teresa Sullivan, Dominique Stoppa-Lyonnet, Julie Hauchard, Pascal Pujol, Thierry Frebourg, Séverine Audebert-Bellanger, Daniela Di Giacomo, Danièle Muller, Aurélie Drouet, Hélène Tubeuf, Susan W. Reid, Julie Rondeaux, Mélanie Léoné, Violaine Bourdon, Françoise Bonnet-Dorion, Françoise Révillion, Hélène Larbre, Shyam K. Sharan, Omar Soukarieh, Sandrine M. Caputo, Alice Fiévet, Laurence Venat-Bouvet, Virginie Caux-Moncoutier, Alexandra Martins, Fátima Vaz, Angela R. Solano, Claude Houdayer, Eileen Southon, Chrystelle Colas, Marine Guillaud-Bataille, Linda Cleveland, Sophie Krieger, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche de l'Institut Curie [Paris], Institut Curie [Paris], Université Paris sciences et lettres (PSL), National Cancer Institute Frederick, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Hospices Civils de Lyon (HCL), Centre hospitalier universitaire de Nantes (CHU Nantes), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Jean Godinot [Reims], UNICANCER, Centre Paul Strauss, CRLCC Paul Strauss, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Hôpital Dupuytren [CHU Limoges], Centro de Educación Médica e Investigaciones Clínicas (CEMIC), and This work was funded by a translational research grant from the French National Cancer Institute and the Direction Générale de l’Offre des Soins (INCa/DGOS, AAP/CFB/CI), by the OpenHealth Institute, the Groupement des Entreprises Fran¸caises dans la Lutte contre le Cancer (Gefluc), the Fédération Hospitalo-Universitaire (FHU) Normandy Centre for Genomic and Personalized Medicine (NGP), the European Union and Region Normandie as well as by the Intramural Research Program from the Center for Cancer Research of the NCI, NIH. Europe gets involved in Normandie with European Regional Development Fund (ERDF). H. Tubeuf was funded by a CIFRE PhD fellowship (#2015/0335) from the French Association Nationale de la Recherche et de la Technologie (ANRT) in the context of a public–private partnership between INSERM and Interactive Biosoftware and by two short-term fellowship from EMBO (#3436) and Cancéropôle Nord-Ouest. J. Hauchard and G. Castelain were sponsored by the French INCa.
Subjects: 0301 basic medicine, Cancer Research, endocrine system diseases, In silico, Genes, BRCA2, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Biology, MESH: Protein Isoforms, Article, 03 medical and health sciences, Exon, Mice, 0302 clinical medicine, Protein-fragment complementation assay, Animals, Humans, Protein Isoforms, MESH: Animals, Genetic Predisposition to Disease, skin and connective tissue diseases, Gene, MESH: Mice, Genetics, Ovarian Neoplasms, MESH: Humans, MESH: Alternative Splicing, MESH: Genetic Predisposition to Disease, RNA, Exons, MESH: Ovarian Neoplasms, Alternative Splicing, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, RNA splicing, Female, Haploinsufficiency, MESH: Exons, MESH: Female, MESH: Breast Neoplasms, MESH: Genes, BRCA2, Minigene
Abstract: BRCA2 is a clinically actionable gene implicated in breast and ovarian cancer predisposition that has become a high priority target for improving the classification of variants of unknown significance (VUS). Among all BRCA2 VUS, those causing partial/leaky splicing defects are the most challenging to classify because the minimal level of full-length (FL) transcripts required for normal function remains to be established. Here, we explored BRCA2 exon 3 (BRCA2e3) as a model for calibrating variant-induced spliceogenicity and estimating thresholds for BRCA2 haploinsufficiency. In silico predictions, minigene splicing assays, patients' RNA analyses, a mouse embryonic stem cell (mESC) complementation assay and retrieval of patient-related information were combined to determine the minimal requirement of FL BRCA2 transcripts. Of 100 BRCA2e3 variants tested in the minigene assay, 64 were found to be spliceogenic, causing mild to severe RNA defects. Splicing defects were also confirmed in patients' RNA when available. Analysis of a neutral leaky variant (c.231T>G) showed that a reduction of approximately 60% of FL BRCA2 transcripts from a mutant allele does not cause any increase in cancer risk. Moreover, data obtained from mESCs suggest that variants causing a decline in FL BRCA2 with approximately 30% of wild-type are not pathogenic, given that mESCs are fully viable and resistant to DNA-damaging agents in those conditions. In contrast, mESCs producing lower relative amounts of FL BRCA2 exhibited either null or hypomorphic phenotypes. Overall, our findings are likely to have broader implications on the interpretation of BRCA2 variants affecting the splicing pattern of other essential exons. Significance: These findings demonstrate that BRCA2 tumor suppressor function tolerates substantial reduction in full-length transcripts, helping to determine the pathogenicity of BRCA2 leaky splicing variants, some of which may not increase cancer risk.
Published: 2020
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44. Report of the fifth meeting of the European Consortium 'Care for CMMRD' (C4CMMRD), Leiden, The Netherlands, July 6th 2019

Author: M le Mentec, Chrystelle Colas, Marta Pineda, Richard Gallon, Hans F. A. Vasen, Zeinab Ghorbanoghli, Laurence Brugières, Manon Suerink, Katharina Wimmer, Clara Ruiz-Ponte, Yael Goldberg, James C. H. Hardwick, E M A Bleiker, Martine Muleris, Tim Ripperger, Patrick R. Benusiglio, Matthias Kloor, CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0303 health sciences, Cancer Research, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], MEDLINE, Review, Human genetics, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, Epidemiology, Genetics, medicine, business, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2020
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45. Direct-to-consumer misleading information on cancer risks calls for an urgent clarification of health genetic testing performed by commercial companies

Author: Antoine De Pauw, Dominique Stoppa-Lyonnet, Mathias Schwartz, Chrystelle Colas, Lisa Golmard, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Paris (UP)
Subjects: Adult, Male, 0301 basic medicine, Cancer Research, Drug Industry, media_common.quotation_subject, Genetic counseling, [SDV]Life Sciences [q-bio], Predictive medicine, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Direct-To-Consumer Screening and Testing, Neoplasms, Health care, medicine, Humans, Quality (business), Genetic Testing, Diagnostic Errors, Genetic testing, media_common, Incidental Findings, medicine.diagnostic_test, Genome, Human, Information Dissemination, business.industry, Medical practice, Sequence Analysis, DNA, 3. Good health, 030104 developmental biology, Oncology, Risk analysis (engineering), 030220 oncology & carcinogenesis, Business, Relevant information
Abstract: Direct-to-consumer (DTC) commercial companies offer genetic tests that are presented as allowing individuals the opportunity to increase their capacities to be in charge of their own healthcare managements. DTC companies deny performing medical tests, yet they provide data based on sequencing multigene panel or whole exome. This contradiction allows these companies to escape the requirements of a regulated medical practice that guarantees the quality of the tests, as well as the information and support for tested individuals. Herein, we illustrate the lack of such requirements by analysing the bad experience of a young man who dealt with DTC health genetic testing companies. There is an emergency for DTC testing to be either deprived of any medically relevant information, or carried out in a legally regulated medical framework.
Published: 2020
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46. La polypose associée à MUTYH : synthèse et actualisation des recommandations françaises établies en 2012 sous l’égide de l’Institut national du cancer (INCa)

Author: Yves-Jean Bignon, Jean-Christophe Saurin, Delphine Bonnet, Valérie Bonadona, Stéphanie Baert-Desurmont, Antoine De Pauw, Olivier Caron, Chrystelle Colas, Florence Coulet, Bruno Buecher, Marion Dhooge, Marie-Pierre Buisine, Audrey Remenieras, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Centre Léon Bérard [Lyon], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), Université de Lyon, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut Gustave Roussy (IGR), Département de Génétique [Institut Curie, Paris] (Unité de Pharmacogénomique), Institut Curie [Paris], Mucines Epitheliales : du Gene a la Fonction, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), MARine Biodiversity Exploitation and Conservation (UMR MARBEC), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut de Recherche pour le Développement (IRD), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Equipe 8, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'oncogénétique, Unité fonctionnelle d'Oncogénétique et Angiogénétique Moléculaire [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Fédération Francophone de la Cancérologie Digestive, FFCD
Subjects: medicine.medical_specialty, MUTYH, Colorectal cancer, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Digestive System Neoplasms, Panel de gènes de prédisposition aux cancers colorectaux, DNA Glycosylases, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Polypose adénomateuse colorectale, Genotype, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Allele, Colorectal adenomatous polyposis, Multigene panel, Alleles, Genetics (clinical), 030304 developmental biology, Family Health, 0303 health sciences, business.industry, Molecular genetic testing, MUTYH-Associated Polyposis, Academies and Institutes, Cancer, Gène MUTYH, General Medicine, medicine.disease, 3. Good health, Molecular analysis, Phenotype, Adenomatous Polyposis Coli, 030220 oncology & carcinogenesis, Family medicine, Practice Guidelines as Topic, Hereditary colorectal cancer, France, Colorectal Neoplasms, business
Abstract: International audience; 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.
Published: 2020
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47. INCIDENCE OF COLORECTAL NEOPLASIA AMONG YOUNG PATIENTS WITH LYNCH SYNDROME IN CORRELATION WITH THE TYPE OF MUTATION: RESULTS OF THE LARGEST PARIS AREA COHORT

Author: Elia Samaha, V Cusin, Géraldine Perkins, S Chaussade, R Benamouzig, J Netter-Cotti, E Coffin, E Perez Cuadrado, Aziz Zaanan, M. Dhooge, Olivier Caron, Y Parc, P Laurent Puig, Guillaume Perrod, Jerôme Bellanger, David Malka, C Lekhal, Christophe Cellier, Chrystelle Colas, and Bruno Buecher
Subjects: Correlation, medicine.medical_specialty, business.industry, Incidence (epidemiology), Internal medicine, Mutation (genetic algorithm), Cohort, medicine, medicine.disease, business, Gastroenterology, Lynch syndrome
Published: 2020
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48. Co-occurrence of germline

Author: Marie-Charlotte, Villy, Emmanuelle, Mouret-Fourme, Lisa, Golmard, Véronique, Becette, Nasrine, Callet, Gilles, Marx, Chrystelle, Colas, Dominique, Lamarque, Etienne, Rouleau, and Dominique, Stoppa-Lyonnet
Subjects: Aged, 80 and over, Neoplasms, Multiple Primary, Antigens, CD, Stomach Neoplasms, Genes, BRCA1, Humans, Breast Neoplasms, Female, Cadherins, Medical History Taking, Germ-Line Mutation, Pedigree
Abstract: We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in bothA large deletion ofThis complex situation is challenging for genetic counselling and management of at-risk individuals.
Published: 2020

49. Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas

Author: Marie-Bernadette Delisle, Anne-Isabelle Bertozzi-Salomon, Marc Polivka, Hélène Zattara, Aurore Surun, Laurence Brugières, Fabienne Prieur, Franck Bourdeaut, Alexandre Vasiljevic, Pierre Leblond, Pascale Varlet, Nicolas André, Françoise Desseigne, Dominique Figarella-Branger, Eric Sariban, Rosine Guimbaud, Christelle Dufour, Cécile Faure-Conter, Claire Alapetite, Florence Coulet, Léa Guerrini-Rousseau, Chrystelle Colas, François Doz, Sandra Raimbault, Claude-Alain Maurage, Brigitte Lacour, Claire Berger, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], and Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: Adult, Male, Cancer Research, Adolescent, Adenomatous polyposis coli, [SDV]Life Sciences [q-bio], Adenomatous Polyposis Coli Protein, Context (language use), medulloblastoma, Germline, Thyroid carcinoma, WNT, 03 medical and health sciences, 0302 clinical medicine, Gardner Syndrome, Medicine, Humans, Cerebellar Neoplasms, Child, Gardner syndrome, Osteoma, neoplasms, Germ-Line Mutation, beta Catenin, 030304 developmental biology, Retrospective Studies, Medulloblastoma, 0303 health sciences, biology, business.industry, Wnt signaling pathway, Editorials, medicine.disease, familial adenomatosis polyposis, 3. Good health, nervous system diseases, APC, stomatognathic diseases, Oncology, Adenomatous Polyposis Coli, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female, Neurology (clinical), business
Abstract: Background Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description. Methods We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae. Results Medulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1–28 y). Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant triton in the radiation field, which caused the only cancer-related death in our series. Conclusions Medulloblastomas associated with an APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.
Published: 2020
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50. Endometrial cancer may be part of the MUTYH-associated polyposis cancer spectrum

Author: Anne Vincent-Salomon, Dominique Stoppa-Lyonnet, Marie-Charlotte Villy, Bruno Buecher, Chrystelle Colas, Julien Masliah-Planchon, and Clément Beaulaton
Subjects: Endometrial cancer, MUTYH-Associated Polyposis, Cancer, General Medicine, Middle Aged, Biology, medicine.disease, medicine.disease_cause, Germline, DNA Glycosylases, Endometrial Neoplasms, Endometrium, Germline mutation, Adenomatous Polyposis Coli, Loss of Function Mutation, MUTYH, Mutation, Genetics, Cancer research, medicine, Humans, Female, KRAS, Carcinogenesis, Genetics (clinical)
Abstract: The MUTYH gene encodes a DNA glycosylase that prevents G:C→T:A transversions. Patients with biallelic pathogenic germline MUTYH variants develop an adenomatous polyposis called MUTYH-associated polyposis (MAP). Endometrial cancers have been reported in patients with MAP, but the role of MUTYH loss of function in the oncogenesis remains unclear. We report for the first time a case of endometrial carcinoma with excess of G:C→T:A transversions in a 61-year-old patient with MAP. Single nucleotide variants of interest, Tumor Mutational Burden (TMB) and somatic mutation profile were obtained from Next-Generation Sequencing (NGS). The Tumor-Infiltrating Lymphocyte (TIL) level and immune infiltrate phenotype were assessed. The endometrial cancer had a high TMB (31.5 variants/Mb) with enrichment in G:C→T:A transversions and the presence of a driver pathogenic variant c.34G>T, p.(Gly12Cys) in KRAS, suggesting a role of MUTYH loss of function in oncogenesis. MUTYH loss of function could be involved in endometrial cancer in patients with MAP.
Published: 2022
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