1,720,973 research outputs found
An investigation of DNA sequence variants of unknown significance in hereditary breast cancer
No full textInheritance of a protein truncating mutation of the tumour suppressor gene BRCA1 causes approximately 5% of breast tumours. Over 450 distinct BRCA1 missense mutations have also been found in patients with a family history of breast cancer and the functional significance of most of these is unclear. Increasing evidence suggests that DNA missense mutations can affect RNA stability or sequence by disrupting splicing regulators. I have used a variety of techniques to investigate the effect of genomic BRCA1 missense mutations on transcript expression. BRCA1 monoallelic expression has previously been reported in association with missense mutations. I therefore initially used the technique of Pyrosequencing™ to identify imbalances in BRCA1 cDNA allele expression. Analysis of patients with known BRCA1 truncating mutations, missense mutations and controls identified no examples of monoallelic expression and indicated that a previous report of monoallelic BRCA1 expression was erroneous. I subsequently developed a series of multiplex RT-PCR reactions using overlapping primer pairs to identify alternative BRCA1 transcripts in the same groups of subjects. This technique effectively demonstrated the common BRCA1 isoforms and confirmed that the c4185A>G silent mutation is associated with deletion of exon 12. To provide a systematic analysis of the effect of BRCA1 mutations on splicing regulation I designed minigenes centred on 4 different BRCA1 exons; 5,6,10 and 18. All mutations within these exons reported to the Breast Cancer Information Core database were introduced into the appropriate minigenes, and wildtype and mu'tant miriigel1es were transfected into HEK 293 cells. The resulting transcripts were examined to identify aberrant splicing. Only one of twenty-one missense mutations investigated resulted in alternative transcripts, suggesting that only a small proportion of BRCA1 missense mutations do affect splicing. Additional work was also performed to investigate whether the MDM2 SNP 309 acts as a disease modifying gene in BRCA1 associated hereditary cancer.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Early breast cancer: why does obesity affect prognosis?
No full textHigh body mass index (BMI) is associated with an increased risk of breast cancer in post-menopausal women but poorer outcomes in all age groups. The underlying mechanism is likely to be multi-factorial. Patients with a high BMI may present later due to body habitus. Some studies have also indicated an increased incidence of biologically adverse features, including a higher frequency of oestrogen receptor (ER negative) tumours, in obese patients. Obese patients have a higher frequency of surgical complications, potentially delaying systemic therapies, and reports suggest that chemotherapy and endocrine therapy are less effective in patients with BMIs of ≥30 kg/m2 High BMI is generally interpreted as excess adiposity and a World Cancer Research Fund report judged that the associations between BMI and incidence of breast cancer were due to body fatness. However, BMI cannot distinguish lean mass from fat mass, or characterise body fat distribution. Most chemotherapy drugs are dosed according to calculated body surface area (BSA). Patients with a similar BSA or BMI may have wide variations in their distribution of adipose tissue and skeletal muscle (body composition); however few studies have looked at the effect of this on chemotherapy tolerance or effectiveness. Finally, adjuvant treatments for breast cancer can themselves result in body composition changes. Research is required to fully understand the biological mechanisms by which obesity influences cancer behaviour, and the impact of obesity on treatment effectiveness and tolerance so that specific management strategies can be developed to improve the prognosis of this patient group
A Review of Modifiable Risk Factors in Young Women for the Prevention of Breast Cancer
No full textBreast cancer is the most common cancer diagnosis in women aged less than 40 years and the second most common cause of cancer death in this age group. Global rates of young onset breast cancer have risen steadily over the last twenty years. Although young women with breast cancer have a higher frequency of underlying pathogenic mutations in high penetrance breast cancer susceptibility genes (CSG) than older women, the vast majority of young breast cancer patients are not found to have a germline CSG mutation. There is therefore a need to inform young women regarding non-genetic breast cancer risk factors which have the potential to be influenced by changes in individual behaviour. A Pubmed search was performed using the search terms "young" or "early onset", and "breast cancer" and "modifiable risk". Titles and abstracts from peer-reviewed publications were screened for relevance. This review presents evidence for potentially modifiable risk factors of breast cancer risk in young women, including lifestyle factors (physical activity, body habitus, alcohol use, smoking, shift work and socioeconomic factors), reproductive and hormonal factors and iatrogenic risks. The extent to which these factors are truly modifiable is discussed and interactions between genetic and non-genetic risk factors are also addressed. Health care professionals have an opportunity to inform young women about breast health and risk when presenting at a "teachable moment", including the benefits of physical activity and alcohol habits as risk factor. More focussed discussions regarding individual personal risk and benefit should accompany conversations regarding reproductive health and take into consideration both non-modifiable and iatrogenic BC risk factors.</p
Impact of obesity, lifestyle factors and health interventions on breast cancer survivors
No full textThe incidences of both breast cancer and obesity are rising in the United Kingdom. Obesity increases the risk of developing breast cancer in the postmenopausal population and leads to worse outcomes in those of all ages treated for early stage breast cancer. In this review we explore the multifactorial reasons behind this association and the clinical trial evidence for the benefits of physical activity and dietary interventions in the early and metastatic patient groups. As more people with breast cancer are cured, and those with metastatic disease are living longer, cancer survivorship is becoming increasingly important. Therefore, ensuring the long-term implications of cancer and cancer treatment are addressed is vital. Although there remains a lack of definitive evidence that deliberate weight loss after a diagnosis of breast cancer reduces disease recurrence, a number of studies have reported benefits of weight loss and of physical activity. However, the limited data currently available mean that clinicians remain unclear on the optimal lifestyle advice to give their patients. Further high quality research is needed to provide this evidence base, which will be required to optimise clinical care and for the commissioning of lifestyle interventions in the United Kingdom in breast cancer survivors.</p
Mindfulness for the self-management of fatigue, anxiety, and depression in women with metastatic breast cancer: a mixed methods feasibility study
No full textThe impact of living with metastatic breast cancer (MBC) is considerable and psychosocial support can be beneficial. Mindfulness-based stress reduction (MBSR) can help self-management of anxiety, depression, quality of life (QoL), and fatigue and has been evaluated in early-stage breast cancer but not MBC. This study investigated the acceptability and feasibility of providing MBSR for women with MBC and of introducing MBSR into a National Health Service (NHS) setting. A mixed methods convergent design was used. Eligible women with MBC, an Eastern Cooperative Oncology Group (ECOG) score of 0 to 2, stable disease, and life expectancy of at least 6 months were invited to attend (by their oncologist) an 8-week MBSR course. Qualitative interviews with patients, a focus group, and interview with NHS staff were held to explore acceptability and feasibility of MBSR. Questionnaires at baseline, during (weeks 4, 8), and after (weeks 16, 24) the course measured fatigue, anxiety and depression, mindfulness, disease-specific QoL, and generic preference based QoL. Of 100 women approached, 20 joined the study. One woman dropped out prior to the intervention due to illness progression. Nineteen women took part in 3 MBSR courses. Recruitment to 2 of the 3 courses was slow. Commitment to 8 weeks was a reason for non-participation, and proved challenging to participants during the course. Participants found the course acceptable and reported many cumulative and ongoing benefits. These included feeling less reactive to emotional distress and more accepting of the disruption to life that occurs with living with MBC. There was high attendance, completion of course sessions, adherence to home practice, excellent follow-up rates, and high questionnaire return rates. MBSR was acceptable to MBC patients, who perceived benefits such as improved anxiety and QoL; but the MBSR course requires a considerable time commitment. There is scope to tailor the intervention so that it is less intensive. <br/
Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers
Full text linkBackgroundThe MDM2 gene encodes a negative regulator of the p53 tumour suppressor protein. A single nucleotide polymorphism (SNP) in the MDM2 promoter (a T to G exchange at nucleotide 309) has been reported to produce accelerated tumour formation in individuals with inherited p53 mutations. We have investigated the effect of the MDM2 SNP309 on clinical outcome in a cohort of patients with germline mutations of BRCA1.MethodsGenomic DNA was obtained for 102 healthy controls and 116 patients with established pathogenic mutations of BRCA1 and Pyrosequencing technology™ was used to determine the genotype at the MDM2 SNP309 locus.ResultsThe polymorphism was present in 52.9% of the controls (G/T in 37.3% and G/G in 15.6%) and 58.6% of the BRCA1 mutation carriers (47.4% G/T and 11.2% G/G). Incidence of malignancy in female BRCA1 carriers was not significantly higher in SNP309 carriers than in wildtype (T/T) individuals (72.7% vs. 75.6%, p = 1.00). Mean age of diagnosis of first breast cancer was 41.2 years in the SNP309 G/G genotype carriers, 38.6 years in those with the SNP309 G/T genotype and 39.0 years in wildtype subjects (p = 0.80).ConclusionWe found no evidence that the MDM2 SNP309 accelerates tumour development in carriers of known pathogenic germline mutations of BRCA1
Assessment of body composition in breast cancer patients: concordance between transverse computed tomography analysis at the fourth thoracic and third lumbar vertebrae
No full textIntroduction: Specific body composition markers derived from L3 axial computed tomography (CT) images predict clinical cancer outcomes, including chemotherapy toxicity and survival. However, this method is only applicable to those undergoing lumbar (L3) CT scanning, which is not universally conducted in early breast cancer cases. This study aimed to evaluate CT analysis at T4 as a feasible alternative marker of body composition in breast cancer. Method: All patients participated in the Investigating Outcomes from Breast Cancer: Correlating Genetic, Immunological, and Nutritional (BeGIN) Predictors observational cohort study (REC reference number: 14/EE/1297). Staging chest-abdomen-pelvic CT scan images from 24 women diagnosed with early breast cancer at University Hospital Southampton were analysed. Adipose tissue, skeletal muscle, and muscle attenuation were measured from the transverse CT slices’ cross-sectional area (CSA) at T4 and L3. Adipose tissue and skeletal muscle area measurements were adjusted for height. Spearman’s rank correlation coefficient analysis was used to determine concordance between body composition measurements using CT analysis at L3 and T4 regions. Results: Derived estimates for total adipose tissue, subcutaneous adipose tissue, and intramuscular adipose tissue mass following adjustment for height were highly concordant when determined from CSAs of CT slices at T4 and L3 (R
s = 0.821, p < 0.001; R
s = 0.816, p < 0.001; and R
s = 0.830, p < 0.001). In this cohort, visceral adipose tissue (VAT) and skeletal muscle estimates following height adjustment were less concordant when measured by CT at T4 and L3 (R
s = 0.477, p = 0.039 and R
s = 0.578, p = 0.003). The assessment of muscle attenuation was also highly concordant when measured by CT at T4 and L3 (R
s = 0.840, p < 0.001). Discussion: These results suggest that the CT analysis at T4 and L3 provides highly concordant markers for total adipose, subcutaneous adipose, and intramuscular adipose estimation, but not VAT, in this breast cancer population. High concordance between T4 and L3 was also found when assessing skeletal muscle attenuation. Lower concordance was observed for the estimates of skeletal muscle area, potentially explained by differences in the quantity and proportions of axial and appendicular muscle between the thorax and abdomen. Future studies will determine the value of T4 metrics as predictive tools for clinical outcomes in breast cancer.</p
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