27 research outputs found
BRACAVENIR - impact of a psychoeducational intervention on expectations and coping in young women (aged 18â30 years) exposed to a high familial breast/ovarian cancer risk: study protocol for a randomized controlled trial
Genomic instability and telomere characteristics in breast cancer
Dans le cancer du sein, la recherche de nouveaux biomarqueurs, permettant de prĂ©dire la rĂ©ponse thĂ©rapeutique et de dĂ©terminer le pronostic dâune patiente, est importante pour adapter au mieux les traitements mais aussi pour amĂ©liorer la comprĂ©hension des phĂ©nomĂšnes physiopathologiques. Nous nous sommes particuliĂšrement intĂ©ressĂ©s aux cancers du sein traitĂ©s par chimiothĂ©rapie nĂ©oadjuvante. Nous avons Ă©tudiĂ©, dans des biopsies tumorales rĂ©alisĂ©es avant traitement et dans des rĂ©sidus tumoraux, Ă la fois les paramĂštres tĂ©lomĂ©riques et la rĂ©paration des lĂ©sions dâADN puisque ces 2 mĂ©canismes, lorsquâils sont dysfonctionnels, sont Ă lâorigine dâune forte instabilitĂ© gĂ©nomique. Nous avons corrĂ©lĂ©s ces paramĂštres Ă la rĂ©ponse Ă la chimiothĂ©rapie nĂ©oadjuvante et Ă la survie des patientes. Dans un 1er temps, nous avons montrĂ© que des tĂ©lomĂšres courts, une surexpression de la tĂ©lomĂ©rase (TERT) et une sous-expression dâune protĂ©ine impliquĂ©e dans diffĂ©rents mĂ©canismes de rĂ©paration de lâADN, ERCC1, sont des marqueurs de mauvais pronostic. La dysfonction simultanĂ©e des tĂ©lomĂšres et des mĂ©canismes de rĂ©paration de lâADN peut contribuer de façon synergique Ă la progression tumorale et Ă la rĂ©sistance thĂ©rapeutique. Nous avons ensuite Ă©tudiĂ© une population de tumeurs du sein triple nĂ©gatives. Nous avons montrĂ© que des tĂ©lomĂšres courts sont associĂ©s aux tumeurs les plus agressives et les plus rĂ©sistantes. De plus, une rĂ©sistance thĂ©rapeutique est retrouvĂ©e associĂ©e Ă une instabilitĂ© gĂ©nomique plus importante. Nous avons enfin analysĂ© les altĂ©rations gĂ©nomiques caractĂ©ristiques permettant dâidentifier le statut BRCA1-like. Le profil BRCA1-like est corrĂ©lĂ© Ă une rĂ©sistance thĂ©rapeutique et Ă une forte instabilitĂ© gĂ©nomique.Enfin, nous avons rĂ©alisĂ© une Ă©tude plus fondamentale visant Ă identifier les mĂ©canismes Ă lâorigine de la rĂ©activation de la tĂ©lomĂ©rase dans le cancer du sein. Nous avons dĂ©montrĂ© que la surexpression de TERT, dans le cancer du sein, nâest pas liĂ©e Ă la prĂ©sence de mutations somatiques activatrices mais plutĂŽt Ă celle de gain du locus TERT. Ces gains sont associĂ©s Ă une rĂ©sistance thĂ©rapeutique et un risque de rechute plus important. Enfin, la prĂ©sence de gain de TERT combinĂ©e Ă la surexpression de MYC, permet de dĂ©finir un sous groupe de trĂšs mauvais pronostique et pourrait ĂȘtre utilisĂ© pour Ă©valuer le risque de rĂ©cidives. Les paramĂštres tĂ©lomĂ©riques et lâinstabilitĂ© gĂ©nomique semblent donc ĂȘtre des biomarqueurs prĂ©dictifs de la rĂ©ponse Ă la chimiothĂ©rapie nĂ©oadjuvante dans le cancer du sein triple nĂ©gatif. Ces paramĂštres ont Ă©galement une forte valeur pronostique dans le cancer du sein en gĂ©nĂ©ral et pourraient ĂȘtre utilisĂ©s cliniquement comme biomarqueurs utiles au choix des traitements.In breast cancer, discovering new biomarkers, that can predict therapeutic response and prognosis, is important to find the best therapeutic options and improve our understanding of physiopathology. Our particular interest is in breast cancer treated by neoadjuvant chemotherapy (NCT). In pre-NCT biopsies and post-NCT tumors, we studied both telomeric parameters and DNA damage repair (DDR), because when these are dysfunctional, both result in high genomic instability. We correlated these parameters to neoadjuvant chemotherapy response and patient outcomes. First, we demonstrated that short telomeres, high telomerase (TERT) expression and low expression of ERCC1 (a protein involved in a number of DNA repair mechanisms) are markers of poor prognosis. Telomere and DDR dysfunction can contribute synergistically to tumor progression and chemoresistance. We then studied a triple negative breast cancer population. We demonstrated that short telomeres were associated with tumor aggressiveness and chemoresistance. Chemoresistance was also associated with high genomic instability. We analyzed genomic alterations specific to BRCA1-like status and demonstrated that BRCA1-like profile correlated with chemoresistance and high genomic instability. Finally, we performed a comprehensive study of telomerase reactivation in breast cancer. We demonstrated that high TERT expression in breast cancer is not associated with somatic enhancer mutations but more probably to TERT locus gains. These gains were correlated to chemoresistance and increased risk of relapse. TERT gain, combined with high MYC expression, was able to isolate a subgroup with a very poor prognosis, and this could be used to evaluate risk of relapse. Telomeric parameters and genomic instability seem to be predictive biomarkers for neoadjuvant chemotherapy response in triple negative breast cancer. These parameters also have strong prognostic value in breast cancer and could be used clinically as biomarkers for tailoring treatment
Recherche de microremaniements chez des patients atteints de leucodystrophie d'origine indéterminée par analyse chromosomique sur puces à ADN (ACPA)
Les leucodystrophies sont des maladies neurodĂ©gĂ©nĂ©ratives rares qui affectent la substance blanche, coeur de rĂ©seau de communication du systĂšme nerveux central, chez lesquelles, des microremaniements impliquant diffĂ©rents gĂšnes ont dĂ©jĂ Ă©tĂ© dĂ©crits (gĂšnes PLP1, MBP, Lamin B1), dĂ©montrant la sensibilitĂ© du processus de myĂ©linisation aux variations de dosage gĂ©nique. L'objectif principal de ce travail a Ă©tĂ© de rechercher des microremaniements chromosomiques dĂ©sĂ©quilibrĂ©s chez des patients prĂ©sentant une leucodystrophie d'origine indĂ©terminĂ©e. Une cohorte de 30 patients a Ă©tĂ© analysĂ©e par hybridation gĂ©nomique comparative sur puces oligonuclĂ©otides (Agilent 4x180K). Pour 17 patients, l'ensemble des remaniements identifiĂ©s a Ă©tĂ© retrouvĂ© dans les bases de donnĂ©es, dĂ©crits comme polymorphismes. Pour les 13 autres patients, les remaniements identifiĂ©s ont Ă©tĂ© confirmĂ© par QMF-PCR et une enquĂȘte familiale a Ă©tĂ© initiĂ©e lorsque les prĂ©lĂšvements des autres membres de la famille Ă©taient disponibles. Nous avons pu conclure Ă des remaniements pathogĂšnes pour 3 patients et probablement polymorphes pour 2 autres. Pour les 8 patients restants, il n'a pas Ă©tĂ© possible de statuer dĂ©finitivement sur la signification clinique de ces remaniements y compris chez les 3 patients pour lesquels des Ă©tudes d'expression et de biais d'inactivation du chromosome X ont Ă©tĂ© rĂ©alisĂ©es afin d'apporter des arguments en faveur de laur caractĂšre pathogĂšne ou bĂ©nin.CLERMONT FD-BCIU-SantĂ© (631132104) / SudocSudocFranceF
Early Onset Multiple Primary Tumors in Atypical Presentation of Cowden Syndrome Identified by Whole-Exome-Sequencing
International audienceA family with an aggregation of rare early onset multiple primary tumors has been managed in our oncogenetics department: the proband developed four early onset carcinomas between ages 31 and 33 years, including acral melanoma, bilateral clear cell renal carcinoma (RC), and follicular variant of papillary thyroid carcinoma. The proband's parent developed orbital lymphoma and small intestine mucosa-associated lymphoid tissue (MALT) lymphoma between 40 and 50 years old. Whole-exome-sequencing (WES) of the nuclear family (proband, parents, and sibling) identified in the proband a de novo deleterious heterozygous mutation c.1003C > T (p.Arg335â) in the phosphatase and tensin homolog (PTEN) gene. Furthermore, WES allowed analysis of the nuclear family's genetic background, and identified deleterious variants in two candidate modifier genes: CEACAM1 and MIB2. CEACAM1, a tumor suppressor gene, presents loss of expression in clear cell RC and is involved in proliferation of B cells. It could explain in part the phenotype of proband's parent and the occurrence of clear cell RC in the proband. Deleterious mutations in the MIB2 gene are associated with melanoma invasion, and could explain the occurrence of melanoma in the proband. Cowden syndrome is a hereditary autosomal dominant disorder associated with increased risk of muco-cutaneous features, hamartomatous tumors, and cancer. This atypical presentation, including absence of muco-cutaneous lesions, four primary early onset tumors and bilateral clear cell RC, has not been described before. This encourages including the PTEN gene in panel testing in the context of early onset RC, whatever the histological subtype. Further studies are required to determine the implication of CEACAM1 and MIB2 in the severity of Cowden syndrome in our proband and occurrence of early onset MALT lymphoma in a parent
Detection Rate and Spectrum of Pathogenic Variations in a Cohort of 83 Patients with Suspected Hereditary Risk of Kidney Cancer
International audienceHereditary predisposition to cancer affects about 3â5% of renal cancers. Testing criteria have been proposed in France for genetic testing of non-syndromic renal cancer. Our study explores the detection rates associated with our testing criteria. Using a comprehensive gene panel including 8 genes related to renal cancer and 50 genes related to hereditary predisposition to other cancers, we evaluated the detection rate of pathogenic variants in a cohort of 83 patients with suspected renal cancer predisposition. The detection rate was 7.2% for the renal cancer genes, which was 2.41-fold higher than the estimated 3% proportion of unselected kidney cases with inherited risk. Pathogenic variants in renal cancer genes were observed in 44.5% of syndromic cases, and in 2.7% of non-syndromic cases. Incidental findings were observed in CHEK2, MSH2, MUTYH and WRN. CHEK2 was associated with renal cancer (OR at 7.14; 95% CI 1.74â29.6; p < 0.003) in our study in comparison to the gnomAD control population. The detection rate in renal cancer genes was low in non-syndromic cases. Additional causal mechanisms are probably involved, and further research is required to find them. A study of the management of renal cancer risk for CHEK2 pathogenic variant carriers is needed
Feedback of extended panel sequencing in 1530 patients referred for suspicion of hereditary predisposition to adult cancers
International audienc
Analysis of 11 candidate genes in 849 adult patients with suspected hereditary cancer predisposition
International audienceHereditary predisposition to cancer concerns between 5% and 10% of cancers. The main genes involved in the most frequent syndromes (hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome) were identified in the 1990s. Exploration of their functional pathways then identified novel genes for hereditary predisposition to cancer, and candidate genes whose involvement remains unclear. To determine the contribution of truncating variants in 11 candidate genes (BARD1, FAM175A, FANCM, MLH3, MRE11A, PMS1, RAD50, RAD51, RAD51B, RINT1, and XRCC2) to cancer predisposition in a population of interest, panel sequencing was performed in 849 patients with a suspected hereditary predisposition to cancer for whom a diagnostic panel of 38 genes identified no causal mutation. Sixteen truncating variants were found in FANCM (n = 7), RINT1 (n = 4), RAD50 (n = 2), BARD1, PMS1, and RAD51B. FANCM (adjusted P-value: .03) and RINT1 (adjusted P-value: 0.04) were significantly associated with hereditary breast and ovarian cancer. However, further studies are required to determinate the risk of cancer, including the segregation of the variants in the families of our cases. No mutation was identified in RAD51, MRE11A, FAM175A, XRCC2, or MLH3. The involvement of these genes in the hereditary predisposition to cancer cannot be ruled out, although if it exists it is rare or does not seem to involve truncating variants
Case Series of 11 <i>CDH1</i> Families (47 Carriers) Including Incidental Findings, Signet Ring Cell Colon Cancer and Review of the Literature
Germline pathogenic variants in E-cadherin (CDH1) confer high risk of developing lobular breast cancer and diffuse gastric cancer (DGC). The cumulative risk of DGC in CDH1 carriers has been recently reassessed (from 40â83% by age 80 to 25â42%) and varies according to the presence and number of gastric cancers in the family. As there is no accurate estimate of the risk of gastric cancer in families without DGC, the International Gastric Cancer Linkage Consortium recommendation is not straightforward: prophylactic gastrectomy or endoscopic surveillance should be proposed for these families. The inclusion of CDH1 in constitutional gene panels for hereditary breast and ovarian cancer and for gastrointestinal cancers, recommended by the French Genetic and Cancer Consortium in 2018 and 2020, leads to the identification of families with lobular cancer without DGC but also to incidental findings of pathogenic variants. Management of CDH1 carriers in case of incidental findings is complex and causes dilemmas for both patients and providers. We report eleven families (47 CDH1 carriers) from our oncogenetic department specialized in breast and ovarian cancer, including four incidental findings. We confirmed that six families did not have diffuse gastric cancer in their medical records. We discuss the management of the risk of diffuse gastric cancer in Hereditary Lobular Breast Cancer (HLBC) through a family of 11 CDH1 carriers where foci were identified in endoscopic surveillance. We also report a new colon signet ring cancer case in a CDH1 carrier, a rare aggressive cancer included in CDH1-related malignancies
Additional file 1: of BRACAVENIR - impact of a psychoeducational intervention on expectations and coping in young women (aged 18ĂąÂÂ30 years) exposed to a high familial breast/ovarian cancer risk: study protocol for a randomized controlled trial
Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 checklist. (DOC 120 kb
Rare duplication of the CDC73 gene and atypical hyperparathyroidismâjaw tumor syndrome: A case report and review of the literature
International audienceBackgroundHyperparathyroidism jaw-tumor syndrome (HPT-JT) is the rarest familial cause of primary hyperparathyroidism, with an incidence <1/1000000, caused by a pathogenic variant in the CDC73 (or HRPT2) gene that encodes parafibromin, a protein involved in many cellular mechanisms. Patients with HPT-JT have a 15â20% of risk of developing parathyroid carcinoma, whereas it accounts for only 1% of all cases of primary hyperparathyroidism. Patients also develop jaw tumors in 30% of cases, kidney abnormalities in 15% of cases, and uterine tumors in 50% of patients.Case ReportHere are report two atypical cases of HPT-JT with variable expressivity in the same family. In front of an isolated primary hyperparathyroidism at 28âyears of age of incidental discovery following a weight gain, the propositus benefited a first-line panel by Next-Generation Sequencing of the genes involved in familial hyperparathyroidism: CaSR, CDC73, MEN1, and RET. Genetic testing revealed the presence of a pathogenic germline variation CDC73: c.687_688dup; p.Val230Glufs*28, found only in nine families in the literature and allowing the diagnosis of HPT-JT. Given a history of primary hyperparathyroidism at 52âyears and adenomyosis, the patient's mother also underwent a genetic analysis that found her daughter's variation and established her inherited trait.ConclusionIn view of the clinical and genotypic heterogeneity, we confirm the interest of using an extended gene panel for the diagnosis of familial primary hyperparathyroidism. CDC73 variations could be more frequent than described in the literature. The association of primary hyperparathyroidism with uterine involvement could be a new indication for analysis