Frequent somatic loss of BRCA1 in breast tumours from BRCA2 germ-line mutation carriers and vice versa

Breast cancer susceptibility genes BRCA1 and BRCA2 are tumour suppressor genes the alleles of which have to be inactivated before tumour development occurs. Hereditary breast cancers linked to germ-line mutations of BRCA1 and BRCA2 genes almost invariably show allelic imbalance (AI) at the respective loci. BRCA1 and BRCA2 are believed to take part in a common pathway in maintenance of genomic integrity in cells. We carried out AI and fluorescence in situ hybridization (FISH) analyses of BRCA2 in breast tumours from germ-line BRCA1 mutation carriers and vice versa. For comparison, 14 sporadic breast tumours were also studied. 8 of the 11 (73%) informative BRCA1 mutation tumours showed AI at the BRCA2 locus. 53% of these tumours showed a copy number loss of the BRCA2 gene by FISH. 5 of the 6 (83%) informative BRCA2 mutation tumours showed AI at the BRCA1 locus. Half of the tumours (4/8) showed a physical deletion of the BRCA1 gene by FISH. Combined allelic loss of both BRCA1 and BRCA2 gene was seen in 12 of the 17 (71%) informative hereditary tumours, whereas copy number losses of both BRCA genes was seen in only 4/14 (29%) sporadic control tumours studied by FISH. In conclusion, the high prevalence of AI at BRCA1 in BRCA2 mutation tumours and vice versa suggests that somatic events occurring at the other breast cancer susceptibility gene locus may be selected in the cancer development. The mechanism resulting in AI at these loci seems more complex than a physical deletion.   http://www.bjcancer.com © 2001 Cancer Research Campaig

Assessment of Abundance, Biomass and Production of the Lower Trophic Levels in the Eastern Basin of Lake Erie, 1994

The Lake Erie Biomonitoring (LEB) program conducted in 1994, focused on the eastern basin of the lake, resampling the same sites as in 1993. Nutrient conditions were similar in the two years. Responses differed between the stratified offshore and unstratified nearshore. At the offshore station, seasonal phytoplankton biomass was 56% higher in 1994 than in 1993 and apparently resulted from a reduction in grazing pressure by Dreissena. Dreissena biomass and their potential clearance rates at the offshore station were much lower in the spring of 1994 than in the spring of 1993 (2.5 vs. 14.9 m3·m·2·d·\u27), respectively. Despite this increase in phytoplankton biomass, chlorophyll (Chi) and phytoplankton photosynthesis (PP) were not significantly higher in 1994. Dinoflagellates, which have lower Chl:C and lower photosynthesis:Chl ratios than other groups of phytoplankton, accounted for much of the increase in biomass. Rotifer biomass decreased by 50% and zooplankton biomass by 40% between the two years. Calanoids were responsible for much of the decrease in zooplankton biomass. Composition also shifted towards larger bodied cladocerans, such as Daphnia and Bythotrephes, and away from Bosmina. This shift coincided with changes in predation pressure. Age-one smelt abundance was extremely high in 1993 and low in 1994, while the reverse was true of the YOY smelt. Age-one smelt consume mainly cladocerans and the YOY, copepods (REF). At the nearshore stations, seasonal PP and Chi were well below that expected given the total phosphorus (TP) concentration, indicating that Dreissena had an important impact on phytoplankton photosynthesis in this region. Low transparency due to suspended sediments also contributed to the low PP at station El. Zooplankton biomass was lower in 1994 than in 1993, and species composition and size shifted. Daphnia increased and calanoids and Bosmina decreased in the nearshore as in the offshore, presumably in response to changes in the smelt population. However, Bythotrephes decreased and rotifer biomass increased unlike in the offshore

Treatment as Prevention for Hepatitis C (TraP Hep C) - a nationwide elimination programme in Iceland using direct-acting antiviral agents

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesA nationwide programme for the treatment of all patients infected with hepatitis C virus (HCV) was launched in Iceland in January 2016. By providing universal access to direct-acting antiviral agents to the entire patient population, the two key aims of the project were to (i) offer a cure to patients and thus reduce the long-term sequelae of chronic hepatitis C, and (ii) to reduce domestic incidence of HCV in the population by 80% prior to the WHO goal of HCV elimination by the year 2030. An important part of the programme is that vast majority of cases will be treated within 36 months from the launch of the project, during 2016-2018. Emphasis is placed on early case finding and treatment of patients at high risk for transmitting HCV, that is people who inject drugs (PWID), as well as patients with advanced liver disease. In addition to treatment scale-up, the project also entails intensification of harm reduction efforts, improved access to diagnostic tests, as well as educational campaigns to curtail spread, facilitate early detection and improve linkage to care. With these efforts, Iceland is anticipated to achieve the WHO hepatitis C elimination goals well before 2030. This article describes the background and organization of this project. Clinical trial number: NCT02647879.Merck Astellas Gilead Gilead Sciences AbbVie BM

Improved Cortisol Exposure-Time Profile and Outcome in Patients with Adrenal Insufficiency: A Prospective Randomized Trial of a Novel Hydrocortisone Dual-Release Formulation.

Context:Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile.Objective:The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets.Design and Setting:We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers.Patients:The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM).Intervention:The same daily dose of hydrocortisone was administered as OD dual-release or TID.Main Outcome Measure:We evaluated cortisol pharmacokinetics.Results:Compared with conventional TID, OD provided a sustained serum cortisol profile 0-4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = -0.7 kg, P = 0.005), systolic blood pressure (difference = -5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: -2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = -0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004).Conclusion:The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM

La journée du souvenir André Prud'homme

The marine genus Pseudoalteromonas is known for its versatile biotechnological potential with respect to the production of antimicrobials and enzymes of industrial interest. We have sequenced the genomes of three Pseudoalteromonas sp. strains isolated from different deep sea sponges on the Illumina MiSeq platform. The isolates have been screened for various industrially important enzymes and comparative genomics has been applied to investigate potential relationships between the isolates and their host organisms, while comparing them to free-living Pseudoalteromonas spp. from shallow and deep sea environments. The genomes of the sponge associated Pseudoalteromonas strains contained much lower levels of potential eukaryotic-like proteins which are known to be enriched in symbiotic sponge associated microorganisms, than might be expected for true sponge symbionts. While all the Pseudoalteromonas shared a large distinct subset of genes, nonetheless the number of unique and accessory genes is quite large and defines the pan-genome as open. Enzymatic screens indicate that a vast array of enzyme activities is expressed by the isolates, including -galactosidase, -glucosidase, and protease activities. A -glucosidase gene from one of the Pseudoalteromonas isolates, strain EB27 was heterologously expressed in Escherichia coli and, following biochemical characterization, the recombinant enzyme was found to be cold-adapted, thermolabile, halotolerant, and alkaline active

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. Methods: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. Results: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. A Osorio1, R L Milne2, G Pita3, P Peterlongo4,5, T Heikkinen6, J Simard7, G Chenevix-Trench8, A B Spurdle8, J Beesley8, X Chen8, S Healey8, KConFab9, S L Neuhausen10, Y C Ding10, F J Couch11,12, X Wang11, N Lindor13, S Manoukian4, M Barile14, A Viel15, L Tizzoni5,16, C I Szabo17, L Foretova18, M Zikan19, K Claes20, M H Greene21, P Mai21, G Rennert22, F Lejbkowicz22, O Barnett-Griness22, I L Andrulis23,24, H Ozcelik24, N Weerasooriya23, OCGN23, A-M Gerdes25, M Thomassen25, D G Cruger26, M A Caligo27, E Friedman28,29, B Kaufman28,29, Y Laitman28, S Cohen28, T Kontorovich28, R Gershoni-Baruch30, E Dagan31,32, H Jernström33, M S Askmalm34, B Arver35, B Malmer36, SWE-BRCA37, S M Domchek38, K L Nathanson38, J Brunet39, T Ramón y Cajal40, D Yannoukakos41, U Hamann42, HEBON37, F B L Hogervorst43, S Verhoef43, EB Gómez García44,45, J T Wijnen46,47, A van den Ouweland48, EMBRACE37, D F Easton49, S Peock49, M Cook49, C T Oliver49, D Frost49, C Luccarini50, D G Evans51, F Lalloo51, R Eeles52, G Pichert53, J Cook54, S Hodgson55, P J Morrison56, F Douglas57, A K Godwin58, GEMO59,60,61, O M Sinilnikova59,60, L Barjhoux59,60, D Stoppa-Lyonnet61, V Moncoutier61, S Giraud59, C Cassini62,63, L Olivier-Faivre62,63, F Révillion64, J-P Peyrat64, D Muller65, J-P Fricker65, H T Lynch66, E M John67, S Buys68, M Daly69, J L Hopper70, M B Terry71, A Miron72, Y Yassin72, D Goldgar73, Breast Cancer Family Registry37, C F Singer74, D Gschwantler-Kaulich74, G Pfeiler74, A-C Spiess74, Thomas v O Hansen75, O T Johannsson76, T Kirchhoff77, K Offit77, K Kosarin77, M Piedmonte78, G C Rodriguez79, K Wakeley80, J F Boggess81, J Basil82, P E Schwartz83, S V Blank84, A E Toland85, M Montagna86, C Casella87, E N Imyanitov88, A Allavena89, R K Schmutzler90, B Versmold90, C Engel91, A Meindl92, N Ditsch93, N Arnold94, D Niederacher95, H Deißler96, B Fiebig97, R Varon-Mateeva98, D Schaefer99, U G Froster100, T Caldes101, M de la Hoya101, L McGuffog49, A C Antoniou49, H Nevanlinna6, P Radice4,5 and J Benítez1,3 on behalf of CIMB

BRCA2 gene mutations in families with aggregations of breast and stomach cancers

Stomach cancer ranks second to lung cancer in the global cancer burden. It is estimated that 25% of families meeting the criteria for hereditary diffuse gastric carcinoma (HDCG) will have germline mutations in the E-cadherin gene. Evidence suggests that stomach cancer might also be a malignant manifestation of other inherited predispositions to disease. Recently, it has been reported that the incidence of stomach cancer is significantly increased in BRCA2 gene mutation carriers. We analysed by direct sequencing the BRCA2 gene in 29 breast cancer patients derived from 29 families with an aggregation of at least one female breast cancer diagnosed before the age of 50 years and one male stomach cancer diagnosed before the age of 55 years. In all but one of these families at least one additional relative was also affected by a malignant tumour. We identified three frameshift mutations and three sequence variants – potentially missense mutations, in six unrelated patients representing 20.7% (six out of 29) of the families investigated. Our results confirm that BRCA2 gene mutations are also associated with familial aggregations of not only breast but also of stomach cancer. In comparison to the number of cancers expected in the study population compared to the general population there is an over-representation of several cancers with significant confidence intervals to suggest that the associations are real and not a selection artefact

Haplotype analysis suggest common founders in carriers of the recurrent BRCA2 mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families

BACKGROUND: The 3398delAAAAG mutation in BRCA2 was recently found to recur in breast and/or ovarian cancer families from the French Canadian population of Quebec, a population that has genetic attributes consistent with a founder effect. To characterize the contribution of this mutation in this population, this study established the frequency of this mutation in breast and ovarian cancer cases unselected for family history of cancer, and determined if mutation carriers shared a common ancestry. METHODS: The frequency was estimated by assaying the mutation in series of French Canadian breast cancer cases diagnosed before age 41 (n = 60) or 80 (n = 127) years of age, and ovarian cancer cases (n = 80) unselected for family history of cancer by mutation analysis. Haplotype analysis was performed to determine if mutation carriers shared a common ancestry. Members from 11 families were analyzed using six polymorphic microsatellite markers (cen-D13S260-D13S1699-D13S1698-D13S1697-D13S1701-D13S171-tel) spanning approximately a 3.6 cM interval at the chromosomal region 13q13.1, which contains BRCA2. Allele frequencies were estimated by genotyping 47 unaffected female individuals derived from the same population. Haplotype reconstruction of unaffected individuals was performed using the program PHASE. RESULTS: The recurrent BRCA2 mutation occurred in 1 of 60 (1.7%) women diagnosed with breast cancer before 41 years of age and one of 80 (1.3%) women with ovarian cancer. No mutation carriers were identified in the series of breast cancer cases diagnosed before age 80. Mutation carriers harboured one of two haplotypes, 7-3-9-3 – [3/4]-7, that varied with marker D13S1701 and which occurred at a frequency of 0.001. The genetic analysis of D13S1695, a polymorphic marker located approximately 0.3 cM distal to D13S171, did not favour a genetic recombination event to account for the differences in D13S1701 alleles within the haplotype. Although mutation carriers harbour genotypes that are frequent in the French Canadian population, neither mutation-associated haplotype was plausible in reconstructed haplotypes of 47 individuals of French Canadian descent. CONCLUSION: These results suggest that mutation carriers share a related ancestry; further supporting the concept that recurrent BRCA1 and BRCA2 mutations in the French Canadian population could be attributed to common founders. This finding provides further support for targeted screening of recurrent mutations in this population before large-scale mutation analyses are performed