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Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Urology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2008 (English)In: Prostate Cancer and Prostatic Diseases, ISSN 1365-7852, E-ISSN 1476-5608Article in journal (Refereed) Submitted
Abstract [en]

We study the G972R polymorphism in the Insulin receptor substrate 1 gene (IRS1) and the +1127 PstI polymorphism of the Insulin gene (INS), in 120 and 151, respectively, incidentally discovered, histologically verified prostate cancers, and in 185 healthy control subjects. The number of IRS1 R allele was found to be significantly associated with increased risk of prostate cancer. Analysis of the INS +1127 PstI polymorphism shows no significant differences between cases and controls. We conclude that subjects carrying one or two R-alleles at the IRS1 G972R polymorphic site are at an elevated risk of developing prostate cancer.

Place, publisher, year, edition, pages
2008.
Keyword [en]
IRS1, G972R, INS, Insulin, prostate cancer
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-15098OAI: oai:DiVA.org:liu-15098DiVA: diva2:37893
Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2017-12-11
In thesis
1. Molecular Genetic Studies on Prostate and Penile Cancer
Open this publication in new window or tab >>Molecular Genetic Studies on Prostate and Penile Cancer
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is comprised of two parts. In the first part we study the influence of four frequently disputed genes on the susceptibility for developing prostate cancer, and in the second part we attempt to establish a basic understanding of the molecular genetic events in penile cancer.

In a prostate cancer cohort we have investigated the relation of prostate cancer risk and single nucleotide polymorphisms (SNPs) in four different genes coding for the androgen receptor (AR), the vitamin D receptor (VDR), insulin (INS) and insulin receptor substrate 1 (IRS1). Despite strong biological indications of an involvement of these genes in prostate carcinogenesis, the results from different studies are contradictory and inconclusive.

The action of the AR varies between individuals in part owing to a repetitive CAG sequence (polyglutamine) in the first exon of the AR gene. The results presented in this thesis show that in our cohort of prostate cancer patients the average number of repeats is 20.1, which is significantly (p<0.001) fewer repeats compared to healthy control individuals, where the average is 22.5 repeats. We find a 4.94 fold (p=0.00003) increased risk of developing prostate cancer associated with having short repeat lengths (≤19 repeats), compared with long repeats (≥23 repeats). In paper I we also study the TaqI polymorphism in the VDR gene, and find that it does not modify the risk of prostate cancer.

In the INS gene we study the +1127 PstI polymorphism and find no overall effect on the risk of prostate cancer. However, we do find that the CC genotype is associated with low grade disease defined as having a Gleason score ≤6 (OR=1.46; p=0.018). In the IRS1 gene we study the G972R polymorphism and observe that the R allele is significantly associated with a 2.44 fold increased prostate cancer risk (p=0.010).

The knowledge of molecular genetic events in penile cancer is very scarce and to date very few genes have been identified to be involved in penile carcinogenesis. We chose therefore to analyse the penile cancer samples using genome-wide high-density SNP arrays. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses are 3p, 4q, 11p and 13q. We suggest four candidate genes residing in these areas, the PIK3CA gene (3q26.32), the hTERT gene (5p15.33), the MYC gene (8q24.21) and the FHIT gene (3p14.2).

The mutational status of the PIK3CA and PTEN genes in the PI3K/AKT pathway and the HRAS, KRAS, NRAS and BRAF genes in the RAS/MAPK pathway was assessed in the penile cancer samples. We find the PIK3CA, HRAS and KRAS genes to be mutated in 29%, 7% and 3% of the cases, respectively. All mutations are mutually exclusive. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2008. 61 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1041
Keyword
Prostate cancer, IRS1, penile cancer, hTERT, FHIT, PIK3CA, HRAS, KRAS, NRAS, BRAF
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-15102 (URN)978-91-7393-984-3 (ISBN)
Public defence
2008-02-29, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2009-04-22Bibliographically approved

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Andersson, PatiyanVarenhorst, Eberhard Söderkvist, Peter

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