Our pooled analysis of three independent series of aggressive prostate cancer and controls demonstrates that the histidine allele of CASP8 D302H is associated with a decreased risk of aggressive PCa. Our analysis of PLCO cases and controls shows no evidence that this allele is associated with protection from indolent disease, supporting the hypothesis that the protective effect is not important in patients with indolent disease.
Increasing evidence points to an overdiagnosis of indolent PCa defined as cancer unlikely to cause harm. Studies examining surgical specimens have estimated that between 6% and 27% of patients undergoing radical prostatectomy have tumors similar to the tumors identified incidentally at autopsy [22
]. While surgery has clearly altered the natural history of the disease, it is believed that many of these tumors were of no clinical significance. Clinical data from both the United States and Europe support this conclusion. Etzioni et al. [8
] and Draisma et al. [7
] used mathematical models to analyze PSA screening data and estimated the risk of over-detection was 18–66%. As such markers which indicate a patient’s risk of developing aggressive disease would have clear clinical utility by identify patients which might benefit from aggressive screening or treatment.
While upwards of 42% of prostate cancer risk is attributed to heritable factors [24
], the majority of genetic risk factors identified to date have been for general risk [1
], not risk specifically associated with aggressive disease. Zheng et al. [25
] examined 16 previously implicated variants and found a strong association between five SNPs and prostate cancer risk (P=1.29×10−8
); importantly, none were linked to risk of aggressive PCa defined similarly to our study as spread to nearby lymph nodes and metastasis, a Gleason score of 8 or more, or a PSA level of more than 50 ng/ml. A meta-analysis of the 8q24 region recently demonstrated an association with advanced disease, using a somewhat wider definition of aggressive disease (Gleason sum _7, PSA >10 ng/ml, and stage >T2c) [10
Haiman et al. [17
] did not find a statistically significant association between a 6-bp deletion polymorphism (−652 6N del) in the promoter of the CASP8 gene and prostate cancer; however, the per allele OR approached statistical significance in Caucasians (OR=0.83; 95% CI: 0.68–1.01) and results for aggressive cases were not reported. MacPherson et al. demonstrated a reduction in breast cancer risk associated with this polymorphism (OR=0.83, 95% CI: 0.74–0.94 for DH and OR=0.58, 95% CI: 0.39–0.88 for HH). A second confirmatory breast cancer study determined a similar protective effect (OR=0.89, 95% CI: 0.85–0.94 for DH and OR=0.74, 95% CI: 0.62–0.87 for HH) [20
]. In contrast, no association was found in a recent study of colorectal cancer [18
The mechanism by which the D302H variant or another variant in linkage disequilibrium protects against aggressive prostate cancer is unknown. It may alter the ability of CASP8 to activate executioner caspases and therefore increase the likelihood that malignant cells undergo apoptosis. A second possibility is that the decreased risk is mediated through the immune system. The characterization of immunomodulatory genes associated with inherited susceptibility to prostate cancer [26
], epidemiologic links between prostatitis and prostate cancer [27
], and histologic evidence of inflammation in preneoplastic lesions [28
] suggest that inflammation contributes to the development of prostate cancer [29
]. Caspases are responsible for aspects of inflammation and immune cell death [15
] and other genetic variants in CASP8 result in a blunted immune response to tumor cell antigens [16
]. A third hypothesis is that the variants effect may be related to steroid signaling, as CASP8 directly interacts with the androgen receptor (AR) and inhibits AR-dependent gene expression [30
]. Furthermore, the fact that this polymorphism has been implicated in breast and prostate cancer, but not in colorectal carcinoma, lends some credence to hypothesis that CASP8 may affect risk by interacting with the hormonal axis.
In summary, our results in three independent series indicate that the H allele of the CASP8 D302H polymorphism is associated with reduced risk for aggressive prostate cancer and is unassociated with less aggressive forms of the disease.