Background

Prostate Cancer

Prostate cancer (PC) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in males in the Western world.

PC is a fast growing health and economical problem in Denmark, with an increase of 7.9% new cases per year for the last 10 years, reaching more than 3500 men being diagnosed in 2010.
It is the most treated cancer in Denmark with 63.000 out-patient visits (>63% increase from 2005 to 2007).

A major cause is the increased use of the serum marker PSA (43-fold in 10 years). PSA is a biomarker with low specificity identifying many men with indolent and non-aggressive PC (>90%) - cases that should not have undergone treatment.

On the contrary, PC is the second most frequent cause of cancer death among men. Based on these facts, two major problems still need to be addressed:

1) to limit PSA testing to men with high PC risk and

2) to distinguish aggressive from non-aggressive PC, and only treat the former.

 

Genetic Risk of Prostate Cancer

Prostate cancer is one of the most heritable cancers, yet useful genetic tests for prostate cancer predisposition are missing. 

The genetic basis for prostate cancer is currently believed to derive from multiple low risk genetic variants.

So far, genome wide association (GWAS) studies have identified more than 30 SNPs (single nucleotide polymorphism) associated with PC risk. Each allele confers slightly increased risk of PC, but effects can be cumulative.

A nearly 5-fold increased PC risk has been reported in Swedish and US populations by combination of 4-5 risk SNPs and/or family history.

Moreover, absolute risk estimates based on 14 SNPs and family history makes it possible to distinguish the absolute risk in a 55-year old male from 6-8% (low risk) to 41-52% (high risk) for developing PC in the next 20 years. 

In a case-control study, we have found that these risk SNPs are equally represented in Danish PC patients (unpublished).

Based on this, we aim to develop a SNP-based genetic test for individual PC risk prediction that can form the basis for better decision making in the clinic: high risk individuals can be included in PC surveillance programs, while low risk individuals can be excluded from repeated PSA testing. With one exception, the PC risk alleles found to date are equally associated with low and high grade tumors.

As members of the international UK lead consortium PRACTICAL, we will have early access to newly discovered risk SNPs and SNPs associated with aggressive PC from GWAS studies of over 28.000 cases and 28.000 controls. These SNPs will also be included in our study, which additionally will generate important new biological information.

 

PC biomarkers discovery

Upon diagnosis of PC, the prognostic indicators available today (e.g. Gleason score) often have limited value for the individual patient, since many are mid-range.

The marked genetic heterogeneity characteristic for PC is likely a main reason why useful biomarkers for PC prognosis are still missing.

Our hypothesis is that high-resolution profiling of PC at several different molecular levels, using microarrays and NGS technologies, combined with novel bioinformatics approaches for integrative data analysis, will help unveil the complex genetic/epigenetic basis of PC biology. This can facilitate the identification of new useful biomarkers for PC, a task for which no satisfying solutions have been reached so far with older technologies.

A prerequisite is that the included tumor tissues are microdissected to ensure the validity of the conclusions. This time consuming aspect has been generally ignored in previous studies, also typically lacking sufficient sample numbers.