Familial Breast Cancer- Risk populations and their surveillance

Women carrying mutations in either BRCA 1 or BRCA2 have a lifetime risk of breast cancer of 80%. As little is known about the risk of other malignancies, apart from ovarian/tubal cancer in mutation carriers, the importance of other malignancies in a family with several cases of breast cancer is hard to evaluate. Women at high risk of breast cancer due to family history are offered genetic counselling and surveillance. Whether women looking for oncogenetic counselling are, in terms of socioeconomic status and health-related quality of life, comparable with women in general is not known. Mammography is a widely used screening method to detect breast cancer and has proven to reduce breast cancer mortality in women older than 50 years. The sensitivity of the method is much lower in women with dense breast and in general young women tend to have denser breast than older women. Most women under surveillance in virtue of family history of breast cancer are younger than 50, thus in a group where mammography alone has not been proved to be effective as a single screening method there is a need for other surveillance methods in women at risk of hereditary breast cancer. We identified 803 BRCA 1/2-negative families with two or more cases of breast cancer and at least one additional malignancy. The observed proportion of different non-breast cancer in the study families was compared with the percentage distribution of non-breast cancer tumours in Sweden. Tumours in endometrium were seen in a significantly larger proportion in the study group than in the general population and could not be explained by previously known syndromes or other explanations for being overrepresented. Thus we suggest that endometrial carcinoma and breast cancer constitute a new breast cancer syndrome. In a cross-sectional study aiming to characterize health-related quality of life and socioeconomic status among all healthy women who had ever visited the Oncogenetic Clinic, Department of Oncology, Södersjukhuset in 1998 – 2004, 306 women consented to participate (82.5%). Significantly more women in the study group were cohabiting (74.2 vs. 43.8%), had the highest education level, (56.7 vs. 39.6%) and had the highest household income (36.9 vs. 12.9 %) as compared to the reference population in the same catchment area. Study subjects reported significantly lower levels of health-related quality of life for subscales related to mental health and for general health compared to normative data, but similar levels on subscales related to physical health. Six-hundred-and-thirty-two women (94%) from one counselling clinic consented to participate in a study aiming to find the most sensitive method to detect breast cancer in women with a familiar risk of the disease. Every woman underwent yearly, and blinded to the other methods, mammography, ultrasound and clinical breast exam. This first report describes the study design and the procedure, and the study cohort regarding hereditary pattern and sociodemographics. Further, the associations between breast density, BMI and other breast-cancer risk factors are elucidated. High breast density was associated with low BMI and young age. However, high density was not associated with increasing risk of breast cancer. Ultrasound and clinical breast examination caused substantially more work-up than MG. The number of detected cancers did not differ from the expected numbers. However, it is too early to draw any conclusion about the sensitivity of the three different modalities.

«VI ER SOM EN POSE TWIST – VELDIG GODE, MEN FORSKJELLIGE!» En narrativ analyse av fellesskapets betydning for karriereutvikling

Hensikten med denne oppgaven har vært å utforske fellesskapets betydning i gruppeveiledning, og studere hvordan unge arbeidssøkere opplever å komme sammen med andre i lignende situasjon og i fellesskap utforske egen karrierekompetanse. Denne oppgavens problemstilling er derfor: Hvilken betydning kan fellesskapet i gruppeveiledning ha for unge arbeidssøkeres karriereutvikling? Med forskningsspørsmålene: hvordan opplever unge arbeidssøkere å komme sammen med andre unge i lignende situasjon for å utforske egen karrierekompetanse? Hvordan kommer gruppeprosessen og fellesskapet til syne i gruppen? Teori. Oppgaven baserer seg på en tverrfaglig tilnærming med hovedteorier innen kollektiv karrierveiledning, gruppearbeid innen sosialt arbeid og systemteori, med perspektiver fra sosial rettferdighet og filosofisk- etiske perspektiver. Metode, utvalg og analyse. Studien har tatt utgangspunkt i et narrativt forskningsdesign på denne oppgaven for å løfte frem de unges stemme og fortellinger om hvordan karriereveiledning i gruppe kan bidra i deres karriereprosesser. Fokusgruppen har bestått av fem unge kvinnelige arbeidssøkere mellom 17-26 år som deltar på et arbeidstiltak i regi av NAV. I denne studien vil leseren ta del i deres fortellinger og opplevelser gjennom en narrativ analyse, laget på bakgrunn av karriereveiledningssamlinger og semistrukturerte fokusgruppeintervjuer. Alle intervjuer har blitt tatt opp på lydopptak og har blitt transkribert. Deretter er de analysert ved hjelp av tematisk narrativ analyse hvor jeg har kategorisert temaene. Resultat og konklusjon. Studien viser at gruppeprosessen til stor grad kommer til syne gjennom gruppen som en ressurs og treningsarena for deltagernes karriereutvikling. Felleskapet kommer til syne blant annet gjennom sosial samhørighet, felles situasjon, deltagelse og medvirkning. Form og struktur i gruppeveiledning viser seg også å ha betydning for hvordan deltagerne opplever å delta i gruppen og hvordan fellesskapet utvikler seg

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.352

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Diet-Induced Abdominal Obesity, Metabolic Changes, and Atherosclerosis in Hypercholesterolemic Minipigs

Background. Obesity and metabolic syndrome (MetS) are major risk factors for atherosclerotic diseases; however, a causal link remains elusive. Animal models resembling human MetS and its complications, while important, are scarce. We aimed at developing a porcine model of human MetS. Methods. Forty pigs with familial hypercholesterolemia were fed a high fat + fructose diet for 30 weeks. Metabolic assessments and subcutaneous fat biopsies were obtained at 18 and 30 weeks, and fat distribution was assessed by CT-scans. Postmortem, macrophage density, and phenotype in fat tissues were quantified along with atherosclerotic burden. Results. During the experiment, we observed a >4-fold in body weight, a significant but small increase in fasting glucose (4.1 mmol/L), insulin (3.1 mU/L), triglycerides (0.5 mmol/L), and HDL cholesterol (2.6 mmol/L). Subcutaneous fat correlated with insulin resistance, but intra-abdominal fat correlated inversely with insulin resistance and LDL cholesterol. More inflammatory macrophages were found in visceral versus subcutaneous fat, and inflammation decreased in subcutaneous fat over time. Conclusions. MetS based on human criteria was not achieved. Surprisingly, visceral fat seemed part of a healthier metabolic and inflammatory profile. These results differ from human findings, and further research is needed to understand the relationship between obesity and MetS in porcine models

A search for modifying genetic factors in CHEK2 : c.1100delC breast cancer patients

The risk of breast cancer associated with CHEK2:c.1100delC is 2-threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.Peer reviewe

Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer

Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio (<inf