BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Correction to: Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers.

After publication of the original article [1], we were notified that columns in Table 2 were erroneously displayed

Risk of a blood donation contaminated with hepatitis E virus entering the blood supply before the implementation of universal RNA screening in France

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Soumission chimique chez l'enfant : à propos d'un cas chez une fillette de 8 ans diagnostiqué en milieu hospitalier

Introduction : Nous rapportons le cas d'une fillette de 8 ans vue aux urgences d'un centre hospitalier. Patient et méthodes : À son entrée, la fillette marche difficilement, elle est euphorique et présente des hallucinations auditives. Un bilan toxicologique est demandé. Les dépistages immunologiques sanguins des différents psychotropes (barbituriques, benzodiazépines et tricycliques) et du paracétamol sont négatifs. Résultats : L'alcoolémie est positive (0,3 g/L). Un screening en CG/SM et CLHP/BD met en évidence de l'acide valproïque (140 mg/L). Discussion : Devant ces résultats étonnants pour une fillette de cet âge, nous contactons le pédiatre. Il nous apprend que l'enfant n'est pas traitée par antiépileptique. L'enfant raconte que, ne réussissant pas à s'endormir la nuit précédente, son beau-père lui aurait donné dans la nuit un comprimé blanc. Se réveillant une deuxième fois, il lui aurait fait à nouveau avaler 3 comprimés roses et 3 comprimés blancs avec une boisson au "mauvais goût". De nouveaux échantillons sanguin et urinaire sont envoyés pour dosage par CL/SM/SM des benzodiazépines et autres psychotropes utilisés dans les soumissions chimiques. Les résultats montrent la présence dans le sang et les urines de nordiazépam (5 et 3 ng/mL), d'alprazolam (3,5 et 11 ng/mL), d'oxazépam (23 ng/mL) et d'hydroxy-alprazolam (125 ng/mL) uniquement dans les urines. Conclusion : La mise en évidence d'acide valproïque par le screening et d'alcool dans le sérum a permis de donner l'alerte. La prise en charge hospitalière d'une telle situation à l'issue judiciaire doit être faite correctement. Une collaboration étroite avec les cliniciens s'avère indispensable (prélèvements de bonne qualité), et des techniques analytiques performantes type CL/SM/SM devront être nécessairement mises en œuvre

Insights on 21 Years of HBV Surveillance in Blood Donors in France

Hepatitis B virus (HBV) infection is the most frequent viral infection found in blood donors (BDs) in France. We analyzed the epidemiological and sero-molecular data on HBV infection gathered over the past two decades by the French haemovigilance surveillance network, blood screening laboratories, and the national reference center for transfusion infectious risks (NRC). Between 2000 and 2020, 6149 of the 58,160,984 donations (1.06/10,000) tested HBV positive, 98% of them from first-time blood donors (FTBDs). In addition, 2212 (0.0071%) of the 30,977,753 donations screened for HBV DNA tested DNA positive, of which 25 (1.1%) were positive only for this marker. HBV prevalence decreased by 2.8-fold and the residual risk for transfusion-transmitted HBV infection decreased 13-fold and was divided by 13. The major risk factor for HBV infection was the origin of donors (endemic country, 66.5%), followed by parenteral exposure (10.7%). In the whole HBV-positive BD population, genotype D was predominant (41.8%), followed by genotypes A (26.2%) and E (20.4%), reflecting the geographical origin of donors. The low and decreasing prevalence and incidence of HBV infection in French BDs, coupled with a screening strategy using three HBV markers (HBsAg, anti-HBc and DNA), ensures a high level of blood safety, further reinforced by the implementation of pathogen-reduction measures

Seven years (2015-2021) of blood donor screening for HEV-RNA in France: lessons and perspectives.

International audienceThe French health authorities are considering expanding the current selective HEV-RNA testing procedure to include all donations in order to further reduce transfusion-transmitted HEV infection. Data obtained from blood donors (BDs) tested for HEV-RNA between 2015 and 2021 were used to assess the most efficient nucleic acid testing (NAT) strategy

Crises convulsives inexpliquées chez un nouveau-né : évoquer le syndrome de Munchausen par procuration

Introduction : Nous rapportons le cas d’un nouveau-né hospitalisé en réanimation pour crises convulsives d’étiologie inconnue. Patient et méthodes : Pendant son hospitalisation, l’enfant présente 6 épisodes d’altération de la vigilance d’apparition brutale, des mouvements anormaux et une hypotonie. La mise en place d’une sonde naso-gastrique dans un but d’alimentation ramène un liquide épais de couleur violette. Un screening toxicologique en CG-SM et CLHP-BD est alors réalisé, avec dosage des molécules retrouvées par techniques spécifiques. D’autres prélèvements (sang, urines, aspiration gastrique, médicaments administrés, biberons, cheveux) sont effectués. Les cheveux sont analysés par CL-SM/SM pour recherche des psychotropes. Résultats : Du bromazépam, du phénobarbital, du diazépam et son métabolite, le nordiazépam sont identifiés dans le liquide violet alors que seuls le phénobarbital et le diazépam lui sont prescrits. L’analyse non segmentaire des cheveux prélevés 15 jours plus tard montre la présence de 5 psychotropes : diazépam : 18 pg/mg mais également bromazépam : 142 pg/mg, clobazam : 11 pg/mg, zolpidem : 276 pg/mg et cyamémazine : 110 pg/mg n’appartenant pas à son traitement. Discussion : Les épisodes de somnolence rythmés par la venue des parents et la mise en évidence d’une solution violette dans le contenu gastrique a alerté les cliniciens sur un possible syndrome de Munchausen par procuration, forme particulière de maltraitance. Les résultats des analyses toxicologiques semblent conforter leur suspicion. Conclusion : Un signalement a conduit à un placement de l’enfant. La prise en charge médicale de cette situation à l’issue judiciaire doit être menée correctement et en étroite collaboration avec le biologiste toxicologue