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Genetic variation and prostate cancer: population-based association studies in Sweden
Umeå University, Faculty of Medicine, Radiation Sciences.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prostate cancer constitutes the most common malignancy and the most common cause of cancer‐related death in Swedish men. A large body of evidence suggests that inherited genetic variants contribute to both development and progression of prostate cancer. The aim of this thesis is to identify genetic variants that alter prostate cancer risk and progression. All papers included in this thesis are based on a Swedish population‐based case‐control study (CAPS) comprising 2,965 incident prostate cancer cases and 1,823 controls.

In paper I, we investigated if genetic variants in the E‐cadherin gene altered prostate cancer risk. Seven haplotype tagging SNPs(tagSNPs) were selected and genotyped in CAPS and families with hereditary prostate cancer. We confirmed association of a promoter SNP rs16260 previously reported to increase risk of hereditary prostate cancer (OR: 2.6; 95% CI: 1.6‐4.3) for homozygous ‘A’ carriers.

In paper II, we assessed 46 polymorphisms earlier reported to be associated with prostate cancer risk. Six polymorphisms in five different genes were replicated. Interestingly, three of these genes were involved in the androgen biosynthesis.

In paper III, we followed up on the results from paper II by genotyping 23 tagSNPs located in the hormone regulating genes AR, CYP17 and SRD5A2. Multiple SNPs and haplotypes were associated with

prostate cancer risk, especially in the AR gene. Combining risk alleles from all genes revealed a substantial risk increase for each additional allele carried (OR: 1.12; 95% CI: 1.1‐1.2, P=0.00009).

In paper IV, we collected information about cause of death for all case patients in CAPS. At time of follow‐up 300 study subjects were deceased from prostate cancer. We assessed AR, CYP17 and SRD5A2 variants for association with lethal prostate cancer and found overall no association. However, one AR promoter SNP was associated with an increased risk of dying from prostate cancer amongst men who received palliative hormonal therapy as primary treatment.

In paper V, we assessed common genetic variation at the ERG locus for association between prostate cancer risk and survival. ERG is recognized as a protooncogene frequently overexpressed in prostate cancer. A total of 21 tagSNPs in the 5’ region of ERG were genotyped. There was no correlation between ERG SNPs and prostate cancer risk but common genetic variation located approximately 100,000 basepairs upstream of ERG was significantly associated with prostate cancer specific survival.

In summary, our results suggest that common genetic variation in Ecadherin alters prostate cancer risk in Swedish men with a positive family history of prostate cancer. Moreover, common genetic variation in the androgen‐related genes AR, CYP17 and SRD5A2 affects the risk of developing prostate cancer but is unlikely to alter prostate cancer progression. However, genetic variants in AR may affect hormonal therapy response. Finally, ERG polymorphisms are associated with prostate cancer‐specific death but are not likely to play a role in prostate cancer development.

Place, publisher, year, edition, pages
Umeå: Strålningsvetenskaper , 2007. , 90 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1114
Keyword [en]
Prostate cancer, epidemiology, SRD5A2, ERG, progression, genetics, association studies, polymorphism, haplotype, CDH1, AR, CYP17
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-1329ISBN: 978-91-7264-367-3 (print)OAI: oai:DiVA.org:umu-1329DiVA: diva2:140666
Public defence
2007-09-20, Hörsal Betula, 6M, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2007-09-03 Created: 2007-09-03 Last updated: 2009-06-03Bibliographically approved
List of papers
1. Comprehensive genetic evaluation of common E-cadherin sequence variants and prostate cancer risk: strong confirmation of functional promoter SNP
Open this publication in new window or tab >>Comprehensive genetic evaluation of common E-cadherin sequence variants and prostate cancer risk: strong confirmation of functional promoter SNP
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2005 (English)In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 118, no 3-4, 339-347 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-14471 (URN)doi:10.1007/s00439-005-0060-6 (DOI)16189707 (PubMedID)
Available from: 2007-02-26 Created: 2007-02-26 Last updated: 2017-12-14Bibliographically approved
2. Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway.
Open this publication in new window or tab >>Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway.
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2006 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 16, 1729-1743 p.Article in journal (Refereed) Published
Keyword
Prostate cancer, association, polymorphism, replication, androgen pathway
Identifiers
urn:nbn:se:umu:diva-15701 (URN)doi:10.1002/pros.20489 (DOI)16998812 (PubMedID)
Available from: 2007-02-26 Created: 2007-02-26 Last updated: 2017-12-14Bibliographically approved
3. Germ-line genetic variation in the key androgen-regulating genes androgen receptor, cytochrome P450, and steroid-5-alpha-reductase type 2 is important for prostate cancer development
Open this publication in new window or tab >>Germ-line genetic variation in the key androgen-regulating genes androgen receptor, cytochrome P450, and steroid-5-alpha-reductase type 2 is important for prostate cancer development
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2006 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 22, 11077-11083 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-2504 (URN)10.1158/0008-5472.CAN-06-3024 (DOI)17108148 (PubMedID)
Available from: 2007-09-03 Created: 2007-09-03 Last updated: 2017-12-14Bibliographically approved
4. Inherited genetic variation in hormone regulating genes and prostate cancer survival
Open this publication in new window or tab >>Inherited genetic variation in hormone regulating genes and prostate cancer survival
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2007 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 17, 5156-5161 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-2505 (URN)10.1158/1078-0432.CCR-07-0669 (DOI)17785571 (PubMedID)
Available from: 2007-09-03 Created: 2007-09-03 Last updated: 2017-12-14Bibliographically approved
5. Do polymorphisms in the ERG promoter region affect prostate cancer risk and survival
Open this publication in new window or tab >>Do polymorphisms in the ERG promoter region affect prostate cancer risk and survival
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Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:umu:diva-2506 (URN)
Available from: 2007-09-03 Created: 2007-09-03Bibliographically approved

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