Genetic determinants for susceptibility, progression and prognosis of prostate cancer
Author: Szulkin, Robert
Date: 2015-11-13
Location: Hörsal Atrium, Nobels väg 12B, Karolinska Institutet, Solna.
Time: 09.00
Department: Inst för medicinsk epidemiologi och biostatistik / Dept of Medical Epidemiology and Biostatistics
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Thesis (1.716Mb)
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.
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.
List of papers:
I. Szulkin R, Whitington T, Eklund M, Aly M, Eeles RA, Easton D, Kote-Jarai Z, Amin Al Olama A, Benlloch S, Muir K, Giles GG, Southey MC, Fitzgerald LM, Henderson BE, Schumacher F, Haiman CA, Schleutker J, Wahlfors T, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw KT, Stanford JL, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Lubiński J, Kluźniak W, Cannon-Albright L, Brenner H, Butterbach K, Stegmaier C, Park JY, Sellers T, Lim HY, Slavov C, Kaneva R, Mitev V, Batra J, Clements JA, BioResource, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Kierzek A, PRACTICAL Consortium, Gronberg H, Wiklund F. Prediction of individual genetic risk to prostate cancer using a polygenic score. Prostate. 2015 Sep; 75(13):1467-1474.
Fulltext (DOI)
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II. Szulkin R, Clements M, Magnusson P, Wiklund F, Kuja-Halkola R. Estimating heritability of prostate cancer-specific survival using population-based registers. [Manuscript]
III. Szulkin R, Holmberg E, Stattin P, Xu J, Zheng S, Palmgren J, Grönberg H, Wiklund F. Prostate cancer risk variants are not associated with disease progression. Prostate. 2012 Jan;72(1):30-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Szulkin R, Karlsson R, Whitington T, Aly M, Gronberg H, Eeles RA, Easton DF, Kote-Jarai Z, Amin Al Olama A, Benlloch S, Muir K, Giles GG, Southey MC, FitzGerald L, Henderson BE, Schumacher FR, Haiman CA, Sipeky C, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Neal D, Donovan JL, Hamdy FC, Pharoah PD, Pashayan N, Khaw KT, Stanford JL, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Lubinski J, Kluzniak W, Cannon-Albright L, Brenner H, Herrmann V, Holleczek B, Park JY, Sellers TA, Lin HY, Slavov C, Kaneva RP, Mitev VI, Batra J, Clements JA, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha HS, Michael A, Kierzek A, Albanes D, Andriole GL, Berndt SI, Chanock SJ, Gapstur SM, Giovannucci EL, Hunter DJ, Kraft P, Le Marchand L, Ma J, Mondul AM, Penney KL, Stampfer M, Stevens VL, Weinstein SJ, Trichopoulou A, Bueno-de-Mesquita HB, Tjonneland A, Cox DG, Maehle L, Schleutker J, Lindstrom S, Wiklund F. Genome-wide association study of prostate cancer-specific survival. Cancer Epidemiol Biomarkers Prev. 2015 Aug 25 [Epub ahead of print].
Fulltext (DOI)
Pubmed
I. Szulkin R, Whitington T, Eklund M, Aly M, Eeles RA, Easton D, Kote-Jarai Z, Amin Al Olama A, Benlloch S, Muir K, Giles GG, Southey MC, Fitzgerald LM, Henderson BE, Schumacher F, Haiman CA, Schleutker J, Wahlfors T, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw KT, Stanford JL, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Lubiński J, Kluźniak W, Cannon-Albright L, Brenner H, Butterbach K, Stegmaier C, Park JY, Sellers T, Lim HY, Slavov C, Kaneva R, Mitev V, Batra J, Clements JA, BioResource, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Kierzek A, PRACTICAL Consortium, Gronberg H, Wiklund F. Prediction of individual genetic risk to prostate cancer using a polygenic score. Prostate. 2015 Sep; 75(13):1467-1474.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Szulkin R, Clements M, Magnusson P, Wiklund F, Kuja-Halkola R. Estimating heritability of prostate cancer-specific survival using population-based registers. [Manuscript]
III. Szulkin R, Holmberg E, Stattin P, Xu J, Zheng S, Palmgren J, Grönberg H, Wiklund F. Prostate cancer risk variants are not associated with disease progression. Prostate. 2012 Jan;72(1):30-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Szulkin R, Karlsson R, Whitington T, Aly M, Gronberg H, Eeles RA, Easton DF, Kote-Jarai Z, Amin Al Olama A, Benlloch S, Muir K, Giles GG, Southey MC, FitzGerald L, Henderson BE, Schumacher FR, Haiman CA, Sipeky C, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Neal D, Donovan JL, Hamdy FC, Pharoah PD, Pashayan N, Khaw KT, Stanford JL, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Lubinski J, Kluzniak W, Cannon-Albright L, Brenner H, Herrmann V, Holleczek B, Park JY, Sellers TA, Lin HY, Slavov C, Kaneva RP, Mitev VI, Batra J, Clements JA, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha HS, Michael A, Kierzek A, Albanes D, Andriole GL, Berndt SI, Chanock SJ, Gapstur SM, Giovannucci EL, Hunter DJ, Kraft P, Le Marchand L, Ma J, Mondul AM, Penney KL, Stampfer M, Stevens VL, Weinstein SJ, Trichopoulou A, Bueno-de-Mesquita HB, Tjonneland A, Cox DG, Maehle L, Schleutker J, Lindstrom S, Wiklund F. Genome-wide association study of prostate cancer-specific survival. Cancer Epidemiol Biomarkers Prev. 2015 Aug 25 [Epub ahead of print].
Fulltext (DOI)
Pubmed
Institution: Karolinska Institutet
Supervisor: Wiklund, Fredrik
Issue date: 2015-10-23
Rights:
Publication year: 2015
ISBN: 978-91-7676-044-4
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