The Angelina Jolie effect : how high celebrity profile can have a major impact on provision of cancer related services

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Acknowledgements We acknowledge the support of the Genesis Breast Cancer Prevention Appeal and Breast Cancer Campaign, which funds the FH02 study. DGE is a NIHR Senior investigator. FH02 Study Group, Family History Clinics providing data is as follows, Edinburgh: Lynda Luke, Lesley Smart; St Barts, London: Vian Salih, Ilyena Froud; Grantham: Nicky Turner, Natarajan Vaithilingam; Leighton Hospital Crewe: Tracey Hales, Samantha Bennion; LondonDerry: Celia Diver-Hall, Jackie McGee; Nottingham: Douglas MacMillan; Nicky Scott; Bath: Diana Dalgleish, Alison Smith; Coventry: Celia Lewis; Royal Marsden Hospital, London: Janet self, Gerald Gui; Derby: Mark Sibbering, Samantha Crockett; City Hospital, Birmingham: Simerjit Rai, Harriet Goddard; Genesis Prevention Centre, Manchester: Lorraine Roberts, Jayne Beesley. RGC teams are as follows, Nottingham RGC: Gareth Cross; Guys Hospital: Adam Shaw; Manchester RGC: Andrew Wallace.Peer reviewedPublisher PD

Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach

Endoxifen is the most important metabolite of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX) is observed under tamoxifen standard dosing breast cancer patients that do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at higher recurrence risk. In this investigation, 10 clinical tamoxifen studies were pooled (nPatients=1388) to investigate influential factors on CSS,min ENDX using nonlinear mixed-effects modelling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared to post-menopausal patients, pre-menopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget CSS,min ENDX compared to elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for pre-menopausal patients, this subpopulation may benefit most from individualised tamoxifen dosing

A Dominantly Inherited 5' UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer

Pathogenic variants in BRCA1 or BRCA2 are identified in ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1 or BRCA2 have not explained the missing heritability. Here, we report a dominantly inherited 5′ UTR variant associated with epigenetic BRCA1 silencing due to promoter hypermethylation in two families affected by breast and ovarian cancer. BRCA1 promoter methylation of ten CpG dinucleotides in families who are affected by breast and/or ovarian cancer but do not have germline BRCA1 or BRCA2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants. BRCA1 promoter hypermethylation was identified in 2 of 49 families in which multiple women are affected by grade 3 breast cancer or high-grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa, and hair follicles. Pyrosequencing showed that DNA was ∼50% methylated, consistent with the silencing of one allele, which was confirmed by clonal bisulfite sequencing. RNA sequencing revealed the allelic loss of BRCA1 expression in both families and that this loss of expression segregated with the heterozygous variant c.−107A>T in the BRCA1 5′ UTR. Our results establish a mechanism whereby familial breast and ovarian cancer is caused by an in cis 5′ UTR variant associated with epigenetic silencing of the BRCA1 promoter in two independent families. We propose that methylation analyses be undertaken to establish the frequency of this mechanism in families affected by early-onset breast and/or ovarian cancer without a BRCA1 or BRCA2 pathogenic variant

Cancer Variant Interpretation Group UK (CanVIG-UK): an exemplar national subspecialty multidisciplinary network.

Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly; the volume of clinical sequencing has increased dramatically; and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic-high risk and benign-no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease-gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that 'national subspecialist multidisciplinary meetings' (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has >100 UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership

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 straightforwar

Development of SNP markers present in expressed genes of the plant-pathogen interaction: Theobroma cacao - Moniliophtora perniciosa

We report the detection, validation and analysis of SNPs in the plant-pathogen interaction between cacao and Moniliophthora perniciosa ESTs using resequencing. This analysis in 73 EST sequences allowed the identification of 185 SNPs, 57% of them corresponding to transversion, 29% to transition and 14% to indels. The ESTs containing SNPs were classified into 14 main functional categories. After validation, 91 SNPs were confirmed, categorized and the parameters of nucleotide diversity and haplotype were calculated. Haplotype-based gene diversity and polymorphic information content (PIC) ranged from 0.559 to 0.56 and 0.115 to 0.12; respectively. Also, it was the advantage when considering haplotypes structure for each locus in place of single SNPs. Most of the gene fragments had a major haplotype combined to a series of low frequency haplotypes. Thus, the re-sequencing approach proved to be a valuable resource to identify useful SNPs for wide genetic applications. Furthermore, the cacao genome sequence availability allow a positional selection of DNA fragments to be re-sequenced enhancing the usefulness of the discovered SNPs. These results indicate the potential use of SNPs markers to identify allelic status of cacao resistance genes through marker-assisted selection to support the development of promising genotypes with high resistance to witch's broom disease. (Résumé d'auteur

Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility

We recently reported that a sequence variant in the cell-cycle-checkpoint kinase CHEK2 (CHEK2 1100delC) is a low-penetrance breast cancer-susceptibility allele in noncarriers of BRCA1 or BRCA2 mutations. To investigate whether other CHEK2 variants confer susceptibility to breast cancer, we screened the full CHEK2 coding sequence in BRCA1/2-negative breast cancer cases from 89 pedigrees with three or more cases of breast cancer. We identified one novel germline variant, R117G, in two separate families. To evaluate the possible association of R117G and two germline variants repo

Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men

Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals

Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.

BACKGROUND: Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer. METHODS: We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing. FINDINGS: Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0-9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5-98·4] vs 96·6% [95·8-97·3]; at 5 years: 83·8% [79·3-87·5] vs 85·0% [83·5-86·4]; at 10 years: 73·4% [67·4-78·5] vs 70·1% [67·7-72·3]; hazard ratio [HR] 0·96 [95% CI 0·76-1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89-97] vs 91% [88-94]; HR 0·59 [95% CI 0·35-0·99]; p=0·047) but not 5 years (81% [73-87] vs 74% [70-78]; HR 1·13 [0·70-1·84]; p=0·62) or 10 years (72% [62-80] vs 69% [63-74]; HR 2·12 [0·82-5·49]; p= 0·12). INTERPRETATION: Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences. FUNDING: Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis