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Saleheen D.,Center for Non Communicable Diseases | Saleheen D.,University of Cambridge | Soranzo N.,Wellcome Trust Sanger Institute | Rasheed A.,Center for Non Communicable Diseases | And 75 more authors.
Circulation: Cardiovascular Genetics | Year: 2010

Background-Evidence is sparse about the genetic determinants of major lipids in Pakistanis. Methods and Results-Variants (n=45 000) across 2000 genes were assessed in 3200 Pakistanis and compared with 2450 Germans using the same gene array and similar lipid assays. We also did a meta-analysis of selected lipid-related variants in Europeans. Pakistani genetic architecture was distinct from that of several ethnic groups represented in international reference samples. Forty-one variants at 14 loci were significantly associated with levels of HDL-C, triglyceride, or LDL-C. The most significant lipid-related variants identified among Pakistanis corresponded to genes previously shown to be relevant to Europeans, such as CETP associated with HDL-C levels (rs711752; P<10-13), APOA5/ZNF259 (rs651821; P<10-13) and GCKR (rs1260326; P<10-13) with triglyceride levels; and CELSR2 variants with LDL-C levels (rs646776; P<10-9). For Pakistanis, these 41 variants explained 6.2%, 7.1%, and 0.9% of the variation in HDL-C, triglyceride, and LDL-C, respectively. Compared with Europeans, the allele frequency of rs662799 in APOA5 among Pakistanis was higher and its impact on triglyceride concentration was greater (P-value for difference <10-4). Conclusions-Several lipid-related genetic variants are common to Pakistanis and Europeans, though they explain only a modest proportion of population variation in lipid concentration. Allelic frequencies and effect sizes of lipid-related variants can differ between Pakistanis and Europeans. © 2010 American Heart Association, Inc.

Barnett G.C.,University of Cambridge | Barnett G.C.,Strangeways Research Laboratories | De Meerleer G.,Ghent University | Gulliford S.L.,Institute of Cancer Research and Royal Marsden NHS Foundation Trust | And 3 more authors.
Clinical Oncology | Year: 2011

Aims: A variety of dosimetric parameters have been shown to influence the incidence of late radiation toxicity. The effect of other treatment- and patient-related factors is less well established. The aim of this study was to elucidate the influence of such factors in the development of late symptoms after radical radiotherapy to the prostate. Materials and methods: Patient- and treatment-related factors that are thought to influence the development of late toxicity were analysed in 788 patients who had received radical radiotherapy to the prostate in the Medical Research Council RT01 trial. Late toxicity data were recorded using the Radiation Therapy Oncology Group, Late Effects of Normal Tissues/Subjective, Objective, Management, Analytic, Royal Marsden Hospital and the University of California, Los Angeles, Prostate Cancer Index. Acute toxicity was measured using the Radiation Therapy Oncology Group grading system. Results: On multivariate analysis, acute bowel toxicity was statistically significantly associated with increased proctitis (hazard ratio = 1.63, 95% confidence interval 1.18, 2.24; P= 0.003) and increased stool frequency (hazard ratio = 1.77, 95% confidence interval 1.27, 2.46; P= 0.001). Hypertension was strongly associated with a decreased risk of poor urinary stream (hazard ratio = 0.25, 95% confidence interval 0.09, 0.71; P= 0.009). There was an increased risk of rectal bleeding with increased age (hazard ratio = 1.04 per year of age, 95% confidence interval 1.01, 1.08; P= 0.009). As expected, a higher prescribed dose increased the risk of several late toxicity end points. Although acute bladder toxicity was associated with the presence of bladder symptoms at 5 years, the effect disappeared for all symptoms except increased urinary frequency and haematuria when a change in bladder function from baseline was calculated. Patients with any pretreatment bladder symptoms were more likely to report increased urinary frequency (hazard ratio = 2.09, 95% confidence interval 1.48, 2.95; P<. 0.0005), increased urinary incontinence (hazard ratio = 4.22, 95% confidence interval 2.13, 8.35; P<. 0.0005) and decreased stream (hazard ratio = 2.64, 95% confidence interval 1.62, 4.31; P<. 0.0005), after treatment and before the most recent follow-up assessment. Conclusions: In this study, increased acute gastrointestinal and bladder symptoms and prescribed dose were associated with increased late radiation toxicity. The presence of hypertension seemed to be protective for the development of late effects. Baseline symptoms should be taken into account when radiation toxicity is analysed. © 2011 The Royal College of Radiologists.

Crook A.,University of Melbourne | Plunkett L.,University of Melbourne | Forrest L.E.,Peter MacCallum Cancer Center | Hallowell N.,University of Melbourne | And 10 more authors.
European Journal of Human Genetics | Year: 2015

Population-based genetic research may produce information that has clinical implications for participants and their family. Researchers notify participants or their next of kin (NoK) about the availability of genetic information via a notification letter; however, many subsequently do not contact a family cancer centre (FCC) to clarify their genetic status. Therefore, the purpose of this study was to examine research participants' experience of receiving a notification letter and the factors that influenced contact with an FCC. Twenty-five semi-structured interviews were conducted with research participants (n = 10) or their NoK (n = 15) who had received a notification letter following participation in the Australian Ovarian Cancer Study. There were a number of factors which impacted participants' access to genetic counselling at an FCC. Some participants had unmet information and support needs, which were addressed by their participation in this psychosocial interview study. Recruitment and participation in this study therefore inadvertently increased a number of participants' intention to contact an FCC. For others, participation in this study facilitated access to an FCC. Recommendations are proposed regarding future notification as well as implications for clinical practice. An approach that also provides opportunity to address research participants' support and informational needs before contacting a clinical genetics service as well as practical guidance for accessing genetic services would facilitate timely and smooth access for research participants who are interested in following up clinically relevant genetic test results. © 2015 Macmillan Publishers Limited All rights reserved.

Talbot C.J.,University of Leicester | Tanteles G.A.,University of Leicester | Barnett G.C.,University of Cambridge | Barnett G.C.,Strangeways Research Laboratories | And 12 more authors.
British Journal of Cancer | Year: 2012

Background: Response to radiotherapy varies between individuals both in terms of efficacy and adverse reactions. Finding genetic determinants of radiation response would allow the tailoring of the treatment, either by altering the radiation dose or by surgery. Despite a growing number of studies in radiogenomics, there are no well-replicated genetic association results.Methods:We carried out a candidate gene association study and replicated the result using three additional large cohorts, a total of 2036 women scored for adverse reactions to radiotherapy for breast cancer.Results:Genetic variation near the tumour necrosis factor alpha gene is shown to affect several clinical endpoints including breast induration, telangiectasia and overall toxicity. In the combined analysis homozygosity for the rare allele increases overall toxicity (P=0.001) and chance of being in the upper quartile of risk with odds ratio of 2.46 (95% confidence interval 1.52-3.98).Conclusion:We have identified that alleles of the class III major histocompatibility complex region associate with overall radiotherapy toxicity in breast cancer patients by using internal replication through a staged design. This is the first well-replicated report of a genetic predictor for radiotherapy reactions. © 2012 Cancer Research UK All rights reserved.

Mitra A.V.,Institute of Cancer Research | Jameson C.,Royal Marsden | Barbachano Y.,Royal Marsden | Sodha N.,Institute of Cancer Research | And 9 more authors.
Oncology Reports | Year: 2010

Prostate cancers in men with germline BRCA1 and BRCA2 mutations are more aggressive than morphologically similar cancers in men without these mutations. This study was performed to test the hypothesis that enhanced expression of Ki-67, as a surrogate of cell proliferation, is a characteristic feature of prostate cancers occurring in BRCA1 or BRCA2 mutation carriers. The study cohort comprised 20 cases of prostate cancer in mutation carriers and 126 control sporadic prostate cancers. Of the combined sample cohort, 65.7% stained only within malignant tissues while 0.7% stained in both malignant and benign tissues (p<0.001). Significantly increased expression of Ki-67 occurred in prostate cancers with higher Gleason score (p<0.001). Elevated Ki-67 expression was identified in 71% of prostate cancers in BRCA1 or BRCA2 mutation carriers and in 67% of the sporadic controls (p>0.5). Similar results were obtained when the data were analysed using a threshold set at 3.5 and 7.1%. This study shows that elevated expression of Ki-67 is associated both with aggressive prostate cancers and with high Gleason score irrespective of whether their occurrence is against a background of BRCA1 or BRCA2 mutations or as sporadic disease. The data suggest that, since elevated Ki-67 does not distinguish prostate cancers occurring in BRCA1 or BRCA2 mutation carriers from sporadic prostatic malignancies, the effects of these genetic mutations are probably independent. While all prostate cancers occurring in the presence of BRCA germline mutations are clinically aggressive, their potentially different phenotypes consistently involve maximal rates of cell proliferation.

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