Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH): study protocol

Background: Young women presenting with breast cancer are more likely to have a genetic predisposition to the disease than breast cancer patients in general. A genetic predisposition is known to increase the risk of new primary breast (and other) cancers. It is unclear from the literature whether genetic status should be taken into consideration when planning adjuvant treatment in a young woman presenting with a first primary breast cancer. The primary aim of the POSH study is to establish whether genetic status influences the prognosis of primary breast cancer independently of known prognostic factors. Methods/design: The study is a prospective cohort study recruiting 3,000 women aged 40 years or younger at breast cancer diagnosis; the recruiting period covers 1st June 2001 to 31st December 2007. Written informed consent is obtained at study entry. Family history and known epidemiological risk data are collected by questionnaire. Clinical information about diagnosis, treatment and clinical course is collected and blood is stored. Follow up data are collected annually after the first year. An additional recruitment category includes women aged 41 to 50 years who are found to be BRCA1 or BRCA2 gene carriers and were diagnosed with their first breast cancer during the study recruiting period. Discussion: Power estimates were based on 10% of the cohort carrying a BRCA1 gene mutation. Preliminary BRCA1 and BRCA2 mutation analysis in a pilot set of study participants confirms we should have 97% power to detect a difference of 10% in event rates between gene carriers and sporadic young onset cases. Most of the recruited patients (>80%) receive an anthracycline containing adjuvant chemotherapy regimen making planned analyses more straightforward

A method for the allocation of sequencing resources in genotyped livestock populations

International audienceAbstractBackgroundThis paper describes a method, called AlphaSeqOpt, for the allocation of sequencing resources in livestock populations with existing phased genomic data to maximise the ability to phase and impute sequenced haplotypes into the whole population.MethodsWe present two algorithms. The first selects focal individuals that collectively represent the maximum possible portion of the haplotype diversity in the population. The second allocates a fixed sequencing budget among the families of focal individuals to enable phasing of their haplotypes at the sequence level. We tested the performance of the two algorithms in simulated pedigrees. For each pedigree, we evaluated the proportion of population haplotypes that are carried by the focal individuals and compared our results to a variant of the widely-used key ancestors approach and to two haplotype-based approaches. We calculated the expected phasing accuracy of the haplotypes of a focal individual at the sequence level given the proportion of the fixed sequencing budget allocated to its family.ResultsAlphaSeqOpt maximises the ability to capture and phase the most frequent haplotypes in a population in three ways. First, it selects focal individuals that collectively represent a larger portion of the population haplotype diversity than existing methods. Second, it selects focal individuals from across the pedigree whose haplotypes can be easily phased using family-based phasing and imputation algorithms, thus maximises the ability to impute sequence into the rest of the population. Third, it allocates more of the fixed sequencing budget to focal individuals whose haplotypes are more frequent in the population than to focal individuals whose haplotypes are less frequent. Unlike existing methods, we additionally present an algorithm to allocate part of the sequencing budget to the families (i.e. immediate ancestors) of focal individuals to ensure that their haplotypes can be phased at the sequence level, which is essential for enabling and maximising subsequent sequence imputation.ConclusionsWe present a new method for the allocation of a fixed sequencing budget to focal individuals and their families such that the final sequenced haplotypes, when phased at the sequence level, represent the maximum possible portion of the haplotype diversity in the population that can be sequenced and phased at that budget

Androgen receptor expression predicts breast cancer survival: the role of genetic and epigenetic events

Background: Breast cancer outcome, including response to therapy, risk of metastasis and survival, is difficult to predict using currently available methods, highlighting the urgent need for more informative biomarkers. Androgen receptor (AR) has been implicated in breast carcinogenesis however its potential to be an informative biomarker has yet to be fully explored. In this study, AR protein levels were determined in a cohort of 73 Grade III invasive breast ductal adenocarcinomas

SnoRNA Snord116 (Pwcr1/MBII-85) Deletion Causes Growth Deficiency and Hyperphagia in Mice

Prader-Willi syndrome (PWS) is the leading genetic cause of obesity. After initial severe hypotonia, PWS children become hyperphagic and morbidly obese, if intake is not restricted. Short stature with abnormal growth hormone secretion, hypogonadism, cognitive impairment, anxiety and behavior problems are other features. PWS is caused by lack of expression of imprinted genes in a ∼4 mb region of chromosome band 15q11.2. Our previous translocation studies predicted a major role for the C/D box small nucleolar RNA cluster SNORD116 (PWCR1/HBII-85) in PWS. To test this hypothesis, we created a ∼150 kb deletion of the >40 copies of Snord116 (Pwcr1/MBII-85) in C57BL/6 mice. Snord116del mice with paternally derived deletion lack expression of this snoRNA. They have early-onset postnatal growth deficiency, but normal fertility and lifespan. While pituitary structure and somatotrophs are normal, liver Igf1 mRNA is decreased. In cognitive and behavior tests, Snord116del mice are deficient in motor learning and have increased anxiety. Around three months of age, they develop hyperphagia, but stay lean on regular and high-fat diet. On reduced caloric intake, Snord116del mice maintain their weight better than wild-type littermates, excluding increased energy requirement as a cause of hyperphagia. Normal compensatory feeding after fasting, and ability to maintain body temperature in the cold indicate normal energy homeostasis regulation. Metabolic chamber studies reveal that Snord116del mice maintain energy homeostasis by altered fuel usage. Prolonged mealtime and increased circulating ghrelin indicate a defect in meal termination mechanism. Snord116del mice, the first snoRNA deletion animal model, reveal a novel role for a non-coding RNA in growth and feeding regulation

Treatment options for patients with triple-negative breast cancer

Breast cancer is a heterogeneous disease composed of different subtypes, characterized by their different clinicopathological characteristics, prognoses and responses to treatment. In the past decade, significant advances have been made in the treatment of breast cancer sensitive to hormonal treatments, as well as in patients whose malignant cells overexpress or amplify HER2. In contrast, mainly due to the lack of molecular targets, little progress has been made in the treatment of patients with triple-negative breast cancer. Recent improved understanding of the natural history, pathophysiology, and molecular features of triple-negative breast cancers have provided new insights into management and therapeutic strategies for women affected with this entity. Ongoing and planned translational clinical trials are likely to optimize and improve treatment of women with this disease

A transcriptomic analysis of gene expression in the venom gland of the snake Bothrops alternatus (urutu)

<p>Abstract</p> <p>Background</p> <p>The genus <it>Bothrops </it>is widespread throughout Central and South America and is the principal cause of snakebite in these regions. Transcriptomic and proteomic studies have examined the venom composition of several species in this genus, but many others remain to be studied. In this work, we used a transcriptomic approach to examine the venom gland genes of <it>Bothrops alternatus</it>, a clinically important species found in southeastern and southern Brazil, Uruguay, northern Argentina and eastern Paraguay.</p> <p>Results</p> <p>A cDNA library of 5,350 expressed sequence tags (ESTs) was produced and assembled into 838 contigs and 4512 singletons. BLAST searches of relevant databases showed 30% hits and 70% no-hits, with toxin-related transcripts accounting for 23% and 78% of the total transcripts and hits, respectively. Gene ontology analysis identified non-toxin genes related to general metabolism, transcription and translation, processing and sorting, (polypeptide) degradation, structural functions and cell regulation. The major groups of toxin transcripts identified were metalloproteinases (81%), bradykinin-potentiating peptides/C-type natriuretic peptides (8.8%), phospholipases A₂(5.6%), serine proteinases (1.9%) and C-type lectins (1.5%). Metalloproteinases were almost exclusively type PIII proteins, with few type PII and no type PI proteins. Phospholipases A₂were essentially acidic; no basic PLA₂were detected. Minor toxin transcripts were related to L-amino acid oxidase, cysteine-rich secretory proteins, dipeptidylpeptidase IV, hyaluronidase, three-finger toxins and ohanin. Two non-toxic proteins, thioredoxin and double-specificity phosphatase Dusp6, showed high sequence identity to similar proteins from other snakes. In addition to the above features, single-nucleotide polymorphisms, microsatellites, transposable elements and inverted repeats that could contribute to toxin diversity were observed.</p> <p>Conclusions</p> <p><it>Bothrops alternatus </it>venom gland contains the major toxin classes described for other <it>Bothrops </it>venoms based on trancriptomic and proteomic studies. The predominance of type PIII metalloproteinases agrees with the well-known hemorrhagic activity of this venom, whereas the lower content of serine proteases and C-type lectins could contribute to less marked coagulopathy following envenoming by this species. The lack of basic PLA₂agrees with the lower myotoxicity of this venom compared to other <it>Bothrops </it>species with these toxins. Together, these results contribute to our understanding of the physiopathology of envenoming by this species.</p

Biased-corrected richness estimates for the Amazonian tree flora

Amazonian forests are extraordinarily diverse, but the estimated species richness is very much debated. Here, we apply an ensemble of parametric estimators and a novel technique that includes conspecific spatial aggregation to an extended database of forest plots with up-to-date taxonomy. We show that the species abundance distribution of Amazonia is best approximated by a logseries with aggregated individuals, where aggregation increases with rarity. By averaging several methods to estimate total richness, we confirm that over 15,000 tree species are expected to occur in Amazonia. We also show that using ten times the number of plots would result in an increase to just ~50% of those 15,000 estimated species. To get a more complete sample of all tree species, rigorous field campaigns may be needed but the number of trees in Amazonia will remain an estimate for years to come