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Molecular Genetic Studies on Prostate and Penile Cancer
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
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 [en]
Prostate cancer, IRS1, penile cancer, hTERT, FHIT, PIK3CA, HRAS, KRAS, NRAS, BRAF
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-15102ISBN: 978-91-7393-984-3 (print)OAI: oai:DiVA.org:liu-15102DiVA: diva2:37897
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
List of papers
1. Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk
Open this publication in new window or tab >>Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk
2006 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 42, no 16, 2833-2837 p.Article in journal (Refereed) Published
Abstract [en]

We study the CAG repeat region in exon 1 of the androgen receptor (AR) and the TaqI polymorphism in exon 9 of the vitamin D receptor (VDR) and the association with prostate cancer. 137 incidentally discovered, histologically verified prostate cancers were analysed for CAG repeat length in AR and genotype at the TaqI site of the VDR. 124 control subjects were analysed to determine the CAG repeat length and TaqI genotype determined for 176 control subjects. An unpaired t-test shows that the mean CAG repeat length was significantly (p < 0.001) shorter among cases (20.1 repeats) compared with controls (22.5 repeats). Dividing the prostate cohort and controls into tertiles (19, 20–22, 23 repeats) shows that short repeats are significantly more common among cases (odds ratio (OR) 4.45, p = 0.00003). Genotype frequencies for the TaqI polymorphism reveals no significant differences between cases and controls. We conclude that men with a short CAG repeat in the androgen receptor gene have an increased risk of developing prostate cancer.

Place, publisher, year, edition, pages
Elsevier, 2006
Keyword
Androgen receptor; Vitamin D receptor; Prostate cancer; CAG repeat
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-15097 (URN)10.1016/j.ejca.2006.06.030 (DOI)
Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2017-12-11Bibliographically approved
2. Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk
Open this publication in new window or tab >>Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk
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.

Keyword
IRS1, G972R, INS, Insulin, prostate cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-15098 (URN)
Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2017-12-11
3. PIK3CA, HRAS and KRAS gene mutations in human penile cancer
Open this publication in new window or tab >>PIK3CA, HRAS and KRAS gene mutations in human penile cancer
Show others...
2008 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 179, no 5, 2030-2034 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: The knowledge of somatic mutations that arise in penile cancer is limited. We examined the dysregulation of components in the phosphatidylinositol 3-kinase and Ras pathways.

Materials and Methods: Using single stranded conformational analysis and direct sequencing we performed mutational analysis of the PIK3CA, PTEN, HRAS, KRAS, NRAS and BRAF genes in 28 penile tumors.

Results: We identified somatic missense mutations in 11 of the 28 penile cancer samples (39%). In the PIK3CA gene 8 mutations (29%) were identified that were E542K or E545K. In the HRAS gene a G12S and a Q61L mutation were found (7%). The KRAS gene contained 1 mutation (3%), that is a G12S change. PIK3CA mutations were found in all grades and stages, whereas HRAS and KRAS mutations were found in larger and more advanced tumors. The mutations were mutually exclusive, suggesting that dysregulation of either pathway is sufficient for the development and progression of penile carcinoma.

Conclusions: The high frequency of mutations in the PIK3CA, HRAS and KRAS genes leads us to believe that dysregulation of the phosphatidylinositol 3-kinase or Ras pathway is significant for the development and progression of penile carcinoma.

Keyword
Penis, penile neoplasms, mutation, 1-phosphatidylinositol 3-kinase, carcinoma, squamous cell
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-15099 (URN)10.1016/j.juro.2007.12.040 (DOI)
Note
On the day of the defence date the status of article III was: In Press.Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2017-12-11Bibliographically approved
4. Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arrays
Open this publication in new window or tab >>Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arrays
Show others...
(English)Manuscript (Other academic)
Abstract [en]

The availability of genome-wide high-density single nucleotide polymorphism (SNP) arrays makes it possible to in a structured manner study chromosome aberrations in penile cancer where little is known of disruptive genetic events. In this study 19 penile squamous cell carcinomas were analyzed using the 250k NspI SNP array from Affymetrix. 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 were 3p, 4q, 11p and 13q. We identified four candidate genes residing in the major chromosomal regions of aberration. Eight tumours showed copy number gain of the PIK3CA gene located to 3q26.3. Five of the remaining tumours carried an activating mutation of the PIK3CA gene and these tumours showed very few chromosomal aberrations. Collectively, disruption of the PIK3CA gene was found in 13/19 samples, and presence of active phosphorylated AKT was confirmed immunohistochemically in these tumours indicating an active signalling pathway. We found copy number gain of the hTERT gene (5p15.33) in 7 samples and of the Myc gene (8q24.21) in 7 samples. Copy number loss of the tumoursuppressor gene FHIT (3p14.2) was observed in 8 samples, the same 8 samples that showed copy number gain of the PIK3CA gene. 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.

Keyword
SNP array, penile cancer, PIK3CA, Myc, TERT, FHIT
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-15100 (URN)
Available from: 2008-10-15 Created: 2008-10-15 Last updated: 2010-01-14Bibliographically approved

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