No evidence that CDKN1B (p27) polymorphisms modify breast cancer risk in BRCA1 and BRCA2 mutation carriers
Queensland Institute of Medical Research, Brisbane, Australia.Breast Cancer Research and Treatment (Impact Factor: 3.94). 07/2008; 115(2):307-13. DOI: 10.1007/s10549-008-0083-5
The p27(kip1) protein functions as an inhibitor of cyclin dependent kinase-2, and shows loss of expression in a large percentage of BRCA1 and BRCA2 breast cancer cases. We investigated the association between CDKN1B gene variants and breast cancer risk in 2359 female BRCA1 and BRCA2 mutation carriers from Australia, the UK, and the USA. Samples were genotyped for five single nucleotide polymorphisms, including coding variant rs2066827 (V109G). Cox regression provided no convincing evidence that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, either alone or as a haplotype. Borderline associations were observed for homozygote carriers of the rs3759216 rare allele, but were opposite in effect for BRCA1 and BRCA2 carriers (adjusted hazard ratio (HR) 0.72 (95% CI = 0.53-0.99; P = 0.04 for BRCA1, HR 1.47 (95% CI = 0.99-2.18; P = 0.06 for BRCA2). The 95% confidence intervals for per allele risk estimates excluded a twofold risk, indicating that common CDKN1B polymorphisms do not markedly modify breast cancer risk among BRCA1 or BRCA2 carriers.
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ABSTRACT: Deleterious mutations in two breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2 have been identified in breast and ovarian cancer families. Women with a BRCA1 or BRCA2 mutation are candidates for additional risk reduction measures such as intensive screening, prophylactic surgery or chemoprevention. Additional susceptibility genes have been identified, including PTEN, ATM, TP53, CHEK2, CASP8, PBRL and BRIP1. Yet, many women with a personal or family history suggestive of a hereditary susceptibility to breast cancer undergo genetic testing and no significant genetic alteration is found. Thus, there are other susceptibility genes that have not been identified, and it is likely that the remaining familial contribution to breast cancer will be explained by the presence of multiple low penetrance alleles that coexist to confer high penetrance risks (a polygenic model). The American Cancer Society has identified cancer prevention as a key component of cancer management and there is interest in developing individualized cancer prevention focused on identifying high risk individuals who are most likely to benefit from more aggressive risk reduction measures. Breast cancer risk assessment and genetic counseling are currently provided by genetic counselors, oncology nurse specialist, geneticists, medical and surgical oncologists, gynecologists and other health care professionals, often working within a multidisciplinary clinical setting. Current methods for risk assessment and predictive genetic testing have limitations and improvements in molecular testing and risk assessment tools is necessary to maximize individual breast cancer risk assessment and to fulfill the promise of cancer prevention.Reviews in Endocrine and Metabolic Disorders 10/2007; 8(3):255-67. DOI:10.1007/s11154-007-9038-0 · 4.89 Impact Factor
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ABSTRACT: The aim of this study is to assess if common genetic variants located in the CDKN1B locus, coding for the cell cycle inhibitor p27(Kip1), are involved in thyroid cancer susceptibility. Based on the literature and functional predictions, we selected three polymorphisms within the CDKN1B gene (rs2066827 (T326G, V109G), rs34330 (-79C>T) and rs36228499 (-838C>A)) to perform the first case-control study in thyroid cancer involving this locus. We had 649 Spanish patients with sporadic thyroid cancer and 385 healthy representative controls available. Luciferase reporter gene assays, real-time quantitative reverse transcription-PCR and immunoblot experiments were carried out to demonstrate the putative effect of the associated variant. The polymorphism rs34330 (-79C>T) was identified as a risk factor for developing the follicular variant of papillary thyroid carcinoma (FVPTC), fitting a recessive model (odds ratio=2.12; 95% confidence interval=1.09-4.15; P value=0.023). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27(Kip1) promoter (P value <0.001). This effect was observed in -79TT genotype control carriers, who showed a tendency towards lower CDKN1B mRNA levels in lymphocytes, as well as at the protein level. This is the first study that identifies CDKN1B as a low-penetrance gene in thyroid cancer, and specifically in FVPTC subtype. We propose a reduced CDKN1B gene transcription depending on the genotype of the -79C>T (rs34330) variant as a novel mechanism underlying p27(Kip1) downregulation.Endocrine Related Cancer 06/2010; 17(2):317-28. DOI:10.1677/ERC-09-0016 · 4.81 Impact Factor
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ABSTRACT: Genetic and lifestyle/environmental factors are implicated in the aetiology of breast cancer. This review summarizes the current state of knowledge on rare high penetrance mutations, as well as moderate and low-penetrance genetic variants implicated in breast cancer aetiology. We summarize recent discoveries from large collaborative efforts to combine data from candidate gene studies, and to conduct genome-wide association studies (GWAS), primarily in breast cancers in the general population. These findings are compared with results from collaborative efforts aiming to identify genetic modifiers in BRCA1 and BRCA2 carriers. Breast cancer is a heterogeneous disease, and tumours from BRCA1 and BRCA2 carriers display distinct pathological characteristics when compared with tumours unselected for family history. The relationship between genetic variants and pathological subtypes of breast cancer, and the implication of discoveries of novel genetic variants to risk prediction in BRCA1/2 mutation carriers and in populations unselected for mutation carrier status, are discussed.Molecular oncology 06/2010; 4(3):174-91. DOI:10.1016/j.molonc.2010.04.011 · 5.33 Impact Factor
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