| 11. |
- Szulkin, Robert
(författare)
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Genetic determinants for susceptibility, progression and prognosis of prostate cancer
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer is the most commonly diagnosed form of non-skin cancer among men in developed countries. Although a large proportion of patients eventually die from the disease, many indolent tumors are found via prostate specific antigen (PSA) testing. However, todays diagnostic tools are unable to distinguish small localized tumors that will have a benign development from early stage aggressive disease. Thus, over-diagnosis and over-treatment are two major concerns in prostate cancer management. Genetics have been shown to play an important role for prostate cancer initiation with an estimated heritability of 58% and over 100 identified single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, much less is known about the involvement of genes in the progression and prognosis of the disease. The overall objective of this thesis is to enhance the understanding of genetic determinants for initiation, progression and prognosis of prostate cancer. The purpose of Study I was to develop a prediction model for prostate cancer susceptibility, based on the current knowledge of genetic risk variants. Furthermore, we aimed to study the potential role of established prostate cancer risk variants in disease progression among men with a localized disease (Study III). In Study II, the heritability of prostate cancer-specific survival among diagnosed men was estimated and a genome-wide search for genetic determinants of the same outcome was performed in Study IV. We found that a polygenic risk score model with 65 established prostate cancer risk SNPs and 68 novel variants optimally separates prostate cancer cases from healthy controls, with a prediction accuracy measured using the area under the curve (AUC) of 0.68. Furthermore, we observed that these 133 SNPs could be used for risk stratification; compared with an intermediate genetic risk score category (40%-60%), men with a low genetic risk score (lowest 5% percentile) had 84% decreased relative risk of prostate cancer and men with 5% highest risk scores had a four-fold increased relative risk. Using a novel conditional likelihood approach for time-to-event data in brother pairs and father-son pairs, the heritability of prostate cancer survival was estimated to be 10%. We could also observe that common family environment had no effect (estimated to 0%) on prostate cancer survival. However, data simulations suggest that this may be underestimated. Furthermore, we could not find any association between SNPs and prostate cancer prognosis. None of 23 established prostate cancer risk SNPs investigated were found to be associated with disease progression in a cohort of men with localized disease. Moreover, in a genome-wide association study (GWAS) we did not find any association with prostate cancer survival at a genome-wide significant level. In conclusion, with the current knowledge of prostate cancer genetics it is possible to identify men with high and low prostate cancer susceptibility risk. However, the predictive performance of established SNPs is not yet sufficient to be used alone in a screening program of prostate cancer. Furthermore, the findings in this thesis regarding prostate cancer progression and survival suggest that development of prostate cancer and progression to lethal disease may be two separate biological mechanisms that involve different genes. In order to identify genetic risk variants associated with prostate cancer progression, future studies should be designed to find common variants with very low penetrance or rare variants with moderate to large effect.
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| 12. |
- Szulkin, Robert, et al.
(författare)
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Prediction of individual genetic risk to prostate cancer using a polygenic score.
- 2015
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 75:13, s. 1467-74
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction.METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls.RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk.CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
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| 13. |
- Szulkin, Robert, et al.
(författare)
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Prostate cancer risk variants are not associated with disease progression
- 2012
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 72:1, s. 30-39
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Currently used prognostic markers are limited in their ability to accurately predict disease progression among patients with localized prostate cancer. We examined 23 reported prostate cancer susceptibility variants for association with disease progression. METHODS: Disease progression was explored among 4,673 Swedish patients treated for clinically localized prostate cancer between 1997 and 2002. Prostate cancer progression was defined according to primary treatment as a composed event reflecting termination of deferred treatment, biochemical recurrence, local progression, or presence of distant metastasis. Association between single variants, and all variants combined, were performed in Cox regression analysis assuming both log-additive and co-dominant genetic models. RESULTS: Three of the 23 genetic variants explored were nominally associated with prostate cancer progression; rs9364554 (P = 0.041) on chromosome 6q25 and rs10896449 (P = 0.029) on chromosome 11q13 among patients treated with curative intent; and rs4054823 (P = 0.008) on chromosome 17p12 among patients on surveillance. However, none of these associations remained statistically significant after correction for multiple testing. The combined effect of all susceptibility variants was not associated with prostate cancer progression neither among patients receiving treatment with curative intent (P = 0.14) nor among patients on surveillance (P = 0.92). CONCLUSIONS: We observed no evidence for an association between any of 23 established prostate cancer genetic risk variants and disease progression. Accumulating evidence suggests separate genetic components for initiation and progression of prostate cancer. Future studies systematically searching for genetic risk variants associated with prostate cancer progression and prognosis are warranted. Prostate © 2011 Wiley-Liss, Inc.
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