CASP8 D302H polymorphism delays the age of onset of breast cancer in BRCA1 and BRCA2 carriers

Abstract

The polymorphic genetic differences among individuals may modify the high risk for breast cancer (BC) and/or ovarian cancer (OC) susceptibility conferred by BRCA1 and BRCA2 mutations. In the present study we investigate the relevance of RAD51 -135C > G, TP53 R72P, NQO1*2 and CASP8 D302H polymorphisms as potential modifiers of BC and/or OC susceptibility conferred by these mutations. The study group encompasses 390 BRCA1/BRCA2 mutation carriers (182 affected with BC and/or OC and 208 unaffected) of 131 unrelated families studied in the Program of Genetic Counselling on Cancer of Valencia Community. The polymorphisms were detected in genomic DNA by ASRA method or real time PCR using fluorescently labeled probes. We found similar incidence of RAD51 -135C > G, TP53 R72P and NQO1*2 polymorphisms among affected and unaffected individuals considering BRCA1/BRCA2 mutations together and separately. However, the CASP8 D302H polymorphism was strongly associated with the absence of BC [OR = 3.41 (95% CI 1.33-8.78, P = 0.01)]. In fact, in the females with CASP8 D302H polymorphism the BC appeared at a median age of 58 in opposition to the 47 years observed for the wild type subjects (P = 0.03). Furthermore, the CASP8 D302H positive females showed a 50% probability of being free of BC by the age of 78 versus the 2% of the CASP8 negative ones. Our results support that the presence of the CASP8 D302H polymorphism diminishes the high risk of BC conferred by BRCA1 and BRCA2 mutations, making possible that some of the carriers could escape from suffering BC along their life span.

Single-nucleotide Polymorphisms in the p53 Signaling Pathway

“…This study consisted of an analysis of 14 independent studies with a total of 16,423 cases and 17,109 controls. In line with these observations, in case-control studies of sporadic breast cancer, a significant 11-year delay of breast carcinoma onset has been reported for the H-allele in a Spanish cohort of 390 patients carrying germ-line BRCA1/2 mutations (Palanca Suela et al 2009). Similar associations were seen in a study conducted in chronic lymphocytic leukemia (Enjuanes et al 2008).…”

Association of two CASP8 polymorphisms with breast cancer risk: a meta-analysis

“…Figure 1 graphically illustrates the trial flow chart. Out of the 30 abstracts retrieved through the search criteria, 17 studies were irrelevant, two studies were excluded due to the fact that they did not report the allele frequencies [14,18], and two articles were meta-analyses [4,13]. As a result, nine case-control studies were included in this metaanalysis; five of them pertained to the -652 6N del polymorphism (12,439 breast cancer cases, 13,253 controls), and four of them concerned D302H polymorphism (18,791 breast cancer cases, 20,318 controls).…”

“…Two studies have reported a protective effect of the polymorphism [3,5], which has been confirmed by a recent critical meta-analysis [13]; nevertheless, the majority of data come from the Breast Cancer Association Consortium [5], which seems to have established the protective action. Since then two studies have appeared [6,14]; Palanca Suela et al were in accordance with the protective effect, whereas Sigurdson et al limited the effect of CASP8 D302H on homozygous carriers.…”

Breast cancer susceptibility variants alter risks in familial disease

“…However, the results of these candidate gene studies have often been conflicting, and robust, replicable susceptibility variants have not emerged 4. An exception is the common missense variant, aspartic acid to histidine (Asp302His) in CASP8 , which has been associated with a moderate reduction in breast cancer risk and delayed onset of cancer in BRCA1 and BRCA2 carriers 5 6. Recent advances in genotyping technology and statistical analysis have facilitated the conduct of large-scale and genome-wide association studies (GWASs) 7.…”