A common coding variant in CASP8 is associated with breast cancer risk

Cox, Angela; Dunning, Alison M.; García-Closas, Montserrat; Balasubramanian, Sabapathy P; Reed, Malcolm; Pooley, Karen A.; Scollen, Serena; Baynes, Caroline; Ponder, Bruce A.J.; Chanock, Stephen J.; Lissowska, Jolanta; Brinton, Louise A.; Pepłońska, Beata; Southey, Melissa C.; Hopper, John L.; McCredie, Margaret; Giles, Graham G.; Fletcher, Olivia; Johnson, Nichola; dos‐Santos‐Silva, Isabel; Gibson, Lorna; Bojesen, Stig E.; Nordestgaard, Børge G.; Axelsson, C. K.; Torres, Diana; Hamann, Ute; Justenhoven, Christina; Brauch, Hiltrud; Chang‐Claude, Jenny; Kropp, Silke; Risch, Angela; Wang-Gohrke, Shan; Schürmann, Peter; Bogdanova, Natalia; Dörk, Thilo; Fagerholm, Rainer; Aaltonen, Kirsimari; Blomqvist, Carl; Nevanlinna, Heli; Seal, Sheila; Renwick, Anthony; Stratton, Michael R.; Rahman, Nazneen; Sangrajrang, Suleeporn; Hughes, David J.; Odefrey, Fabrice; Brennan, Paul; Spurdle, Amanda B.; Chenevix-Trench, Georgia; Beesley, Jonathan; Mannermaa, Arto; Hartikainen, Jaana M.; Kataja, Vesa; Kosma, Veli Matti; Couch, Fergus J.; Olson, Janet E.; Goode, Ellen L.; Broeks, Annegien; Schmidt, Marjanka K.; Hogervorst, Frans B.L.; Veer, Laura J. van ’t; Kang, Daehee; Yoo, Keun Young; Noh, Dong Young; Ahn, Sei Hyun; Wedrén, Sara; Hall, Per; Low, Yen Ling; Li, Jianjun; Milne, Roger L.; Ribas, Gloría; González-Neira, Anna; Benı́tez, Javier; Sigurdson, Alice J.; Stredrick, Denise L.; Alexander, Bruce H.; Struewing, Jeffery P.; Pharoah, Paul D.P.; Easton, Douglas F.

doi:10.1038/ng1981

Cited by 486 publications

(419 citation statements)

References 28 publications

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“…24,25 Even though conflicting evidences have been presented, 26 this particular polymorphism has been associated with decreased risk of multiple cancers. 25,27 Similarly, a large study including 17 109 breast cancer patients (versus 16 423 controls) concluded that the CASP8 D302H polymorphism in some populations was associated with a reduced risk of breast cancer, 28 a correlation that has been confirmed also for other tumor types. 27 A CASP10 V410I substitution was also less frequently observed in patients suffering from breast cancer compared with control groups and the risk of carcinogenesis significantly decreased in individuals harboring a combination of these variant alleles, indicating a mutual protective effect.…”

Section: Casp Polymorphismmentioning

confidence: 95%

Caspases and cancer

2011

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Evasion of apoptosis is considered to be one of the hallmarks of human cancers. This cell death modality is executed by caspases and several upstream regulatory factors, which direct their proteolytic activity, have been defined as either tumor suppressors or oncogenes. Often these regulatory factors, in addition to being potent apoptosis inducers, function in cell survival or repair signaling pathways in response to cellular stress. Thus, loss of function in a distinct regulatory mechanism does not necessarily mean that tumor formation is due to apoptosis malfunction resulting from insufficient caspase activation. Although each caspase has been assigned a distinct role in apoptosis, some redundancy with respect to their regulatory functions and substrate recognition is evident. Jointly, these proteases could be considered to possess solid tumor suppressor function, but what is the evidence that deregulation of specific caspases per se induces inappropriate cell survival, leading to enhanced tumorigenic potential? This question will be addressed in this review, which covers basic molecular mechanisms derived from in vitro analyses and emphasizes new insights that have emerged from in vivo and clinical studies. In organisms, excess cells during development, as well as potentially harmful cells resulting from pathophysiological conditions, are eliminated by various cell death modalities. Among them, apoptosis is the most investigated, and almost 40 years ago, it was described as a major defense strategy that prevents cells from acquiring tumorigenic potential. 1 This suicide mechanism is controlled by multiple and interrelated pathways ensuring that caspases, the proteolytic initiators and executioners of apoptosis, are triggered only in cells requiring termination. There is overwhelming experimental evidence supporting the idea that disturbances in the regulation of caspase activation are central for the avoidance of cancer cell death, both in vitro and in vivo. However, what evidences suggest that caspases per se act as tumor suppressors? It was reported that cells do not necessarily undergo caspaseindependent cell death in the absence of active caspases, but may instead survive insult and even promote clonogenic tumor growth. 2 Yet, it was unclear which individual caspases could fulfill this function. Recently, certain initiator caspases have been suggested as putative tumor suppressor genes. 3,4 This review is focusing on caspases and their role in tumor suppression, and emphasizing new evidences that have emerged from in vivo observations and clinical material, taking into consideration supporting in vitro data that has enlightened basic molecular mechanisms. CaspasesClassification of human caspases is based either on their function, the size of their pro-domain or cleavage specificity.Considering the first criteria, caspase-1, -4 and -5 belong to the group I (inflammatory) caspases that are involved in cytokine maturation. These proteases are primarily associated with the innate immunity against pathogens an...

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Section: Casp Polymorphismmentioning

confidence: 95%

Caspases and cancer

2011

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“…However, with the efforts of the Breast Cancer Association Consortium in conducting candidate gene case -control association studies with enhanced statistical power by combining several breast cancer cohorts, two novel genes were identified, namely, CASP8 and TGFB1. 76 Recently, the success of genetic studies of breast cancer has also been seen in three studies 52 -54 and their findings are starting to shed some new light on the genetic basis of this cancer. With their three-stage study design and a sample size of more than 50 000 cases and controls, Easton et al 52 identified six highly significant SNPs.…”

Section: Breast Cancermentioning

confidence: 99%

The success of the genome-wide association approach: a brief story of a long struggle

Seng

2008

Eur J Hum Genet

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The genome-wide association approach has been the most powerful and efficient study design thus far in identifying genetic variants that are associated with complex human diseases. This approach became feasible as the result of several key advancements in genetic knowledge, genotyping technologies, statistical analysis algorithms and the availability of large collections of cases and controls. With all these necessary tools in hand, many genome-wide association studies were recently completed, and many more studies which will explore the genetic basis of various complex diseases and quantitative traits are soon to come. This approach has started to reap the fruits of its labor over the past several months. Publications of genome-wide association studies in several complex diseases such as inflammatory bowel disease, type-2 diabetes, breast cancer and prostate cancer have been abundant in the first half of this year. The aims of this review are firstly, to provide a timely summary for most of the genome-wide association studies that have been published until June/July 2007 and secondly, to evaluate to what extent these results have been validated in subsequent replication studies.

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“…23,24 Twenty-seven studies investigated the potential functional polymorphisms (19 for IGF1 (CA) n , 16 for IGFBP3 AÀ202C and 6 for IGFBP3 Gly32Ala), including 27 852 cases and 40 354 controls. One multicenter study 14 was included and two duplicated articles were excluded for the association between genotypes and cancer risk. 25,26 Nine studies were available for genotypephenotype correlation analysis.…”

Section: Identification and Eligibility Of Studiesmentioning

confidence: 99%

Phenotypes and genotypes of insulin-like growth factor 1, IGF-binding protein-3 and cancer risk: evidence from 96 studies

et al. 2009

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Insulin-like growth factor 1 (IGF1) and its main binding protein, IGF-binding protein 3 (IGFBP3), play an important role in cancer development. Circulating levels and functional polymorphisms of IGF1 and IGFBP3 may be biomarkers of cancer development. However, the results of published studies remain conflicting rather than conclusive. We searched MEDLINE and EMBASE databases for all published studies related to circulating levels and polymorphisms of IGF1 and IGFBP3 and cancer risk. In all, 96 studies and over 110 000 subjects were available for this meta-analysis. Higher IGF1 circulating levels significantly increased 15% of cancer risk (odds ratio (OR), 1.15, 95% confidence interval (CI), 1.03-1.29), especially among prostate, pre-menopausal breast and colorectal cancer patients, whereas higher concentrations of IGFBP3 significantly decreased the risk of advanced prostate cancer by 56% (OR, 0.44, 95% CI, 0.25 -0.77). Meanwhile, IGFBP3 À202CC genotype was associated with an increased risk of prostate cancer with borderline significance (OR, 1.18, 95% CI, 0.99 -1.41). Genotype-phenotype correlation analyses showed that circulating levels of IGFBP3 could be modified by its promoter polymorphism AÀ202C (P o 0.001). In conclusion, circulating levels of IGF1, IGFBP3 and IGFBP3 AÀ202C play a crucial role in carcinogenesis and could serve as susceptibility biomarkers for cancer development.

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A common coding variant in CASP8 is associated with breast cancer risk

Cited by 486 publications

References 28 publications

Caspases and cancer

Caspases and cancer

The success of the genome-wide association approach: a brief story of a long struggle

Phenotypes and genotypes of insulin-like growth factor 1, IGF-binding protein-3 and cancer risk: evidence from 96 studies

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