Molecular Genetic Studies on Prostate and Penile Cancer

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…


The process of cancer
Prostate cancer, the most common cancer in men
Penile cancer, a rare but psychologically devastating tumour form
Androgen receptor gene
Vitamin D receptor gene
Insulin gene
Two central signalling pathways relaying growth signals
PI3K/AKT pathway
RAS/MAPK pathway
IRS1 gene
PIK3CA gene
PTEN gene
RAS genes
RAF genes
Prostate cancer patients (I, II)
Penile cancer patients (III, IV)
Normal control subjects (I, II)
DNA isolation (I, II, III, IV)
Whole genome amplification (III)
Single nucleotide polymorphism (I, II)
Single stranded conformation analysis (III)
Sanger chain termination DNA sequencing (III)
Analysis of AR CAG microsatellite (I)
Microarray (IV)
Statistics (I, II)
Short CAG repeat length in the AR gene increases risk of prostate cancer
The TaqI polymorphism in the VDR gene does not modify risk of prostate cancer
The +1127 PstI polymorphism in the insulin gene does not modify risk of prostate cancer
The G972R polymorphism in the IRS1 gene increases risk of prostate cancer
Mutational status of the PIK3CA gene in prostate cancer
The PIK3CA gene is frequently mutated in penile cancer
RAS mutations in penile cancer
Frequent copy number changes in penile cancer
Candidate genes for penile cancer
Relation of mutations in the PIK3CA and RAS genes and amplification of the
PIK3CA gene

Author: Andersson, Patiyan

Source: Linkoping University

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