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Edwards S.M.,Institute of Cancer Research | Evans D.G.R.,St Marys Hospital | Hope Q.,Institute of Cancer Research | Norman A.R.,Royal Marsden NHS Foundation Trust | And 19 more authors.
British Journal of Cancer | Year: 2010

Background:The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours.Methods:Two cohorts were compared: one was a group with young-onset PrCa, tested for germline BRCA2 mutations (6 of 263 cases had a germline BRAC2 mutation), and the second was a validation set consisting of a clinical set from Manchester of known BRCA2 mutuation carriers (15 cases) with PrCa. Survival data were compared with a control series of patients in a single clinic as determined by Kaplan-Meier estimates. Loss of heterozygosity was tested for in the DNA of tumour tissue of the young-onset group by typing four microsatellite markers that flanked the BRCA2 gene, followed by sequencing.Results:Median survival of all PrCa cases with a germline BRCA2 mutation was shorter at 4.8 years than was survival in controls at 8.5 years (P0.002). Loss of heterozygosity was found in the majority of tumours of BRCA2 mutation carriers. Multivariate analysis confirmed that the poorer survival of PrCa in BRCA2 mutation carriers is associated with the germline BRCA2 mutation per se.Conclusion:BRCA2 germline mutation is an independent prognostic factor for survival in PrCa. Such patients should not be managed with active surveillance as they have more aggressive disease. © 2010 Cancer Research UK All rights reserved. Source


Mocellin S.,University of Padua | Verdi D.,University of Padua | Pooley K.A.,Cancer Research UK Genetic Epidemiology Unit | Landi M.T.,U.S. National Institutes of Health | And 7 more authors.
Journal of the National Cancer Institute | Year: 2012

Background Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer.MethodsA systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as "strong," "moderate," and "weak" according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association.ResultsEighty-five studies enrolling 490901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types.ConclusionsTo our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans. © 2012 The Author. Source


Hackett A.,Genetics of Learning Disability Service | Tarpey P.S.,Wellcome Trust Sanger Institute | Licata A.,Jc Self Research Institute | Cox J.,Cambridge Institute of Medical Research | And 19 more authors.
European Journal of Human Genetics | Year: 2010

Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A > T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported. © 2010 Macmillan Publishers Limited All rights reserved. Source


Lose F.,Queensland Institute of Medical Research | Lose F.,Queensland University of Technology | Batra J.,Queensland Institute of Medical Research | Batra J.,Queensland University of Technology | And 25 more authors.
Urologic Oncology: Seminars and Original Investigations | Year: 2013

The human tissue Kallikrein family consists of 15 genes with the majority shown to be differentially expressed in cancers and/or indicators of cancer prognosis. We sought to elucidate the role of common genetic variation in four of the Kallikrein genes, KLK5, KLK6, KLK12, and KLK13, in prostate cancer risk and tumor aggressiveness. Genotyping of all 22 tagging single nucleotide polymorphisms (tagSNPs) in the KLK5, KLK6, KLK12, and KLK13 genes was performed in approximately 1,000 prostate cancer cases and 1,300 male controls from Australia. Data from any positive results were also accessed for 1,844 cases and 1,886 controls from a previously published prostate cancer genome-wide association study set from the United Kingdom. For one SNP in KLK12, rs3865443, there was evidence for association with prostate cancer risk of similar direction and magnitude in the replication set to that seen in the Australian cohort. We conducted genotyping of a further 309 prostate cancer cases, and combined analyses revealed an increased risk of prostate cancer for carriers of the rare homozygous genotype for rs3865443 (OR 1.28, 95% CI 1.04-1.57; P = 0.018). No other tagSNPs in the KLK5, KLK6, and KLK13 genes were consistently associated with prostate cancer risk or tumor aggressiveness. Analysis of a combined sample of 3,153 cases and 3,199 controls revealed the KLK12 tagSNP rs3865443 to be marginally statistically significantly associated with risk of prostate cancer. Considering the total number of SNPs investigated in this study, this finding should be interpreted cautiously and requires additional validation from very large datasets such as those of the Prostate Cancer Association group to investigate cancer associated alterations (PRACTICAL) Consortium. © 2013 Elsevier Inc. Source


Mitra A.V.,Institute of Cancer Research | Bancroft E.K.,Institute of Cancer Research | Barbachano Y.,Institute of Cancer Research | Page E.C.,Institute of Cancer Research | And 74 more authors.
BJU International | Year: 2011

OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA >3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men. © 2010 BJU International. Source

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