The ICPCG is a working group of investigators, consisting of 16 independent groups from 21 institutions from North America, Europe and Australia, that share a common interest in genetic susceptibility for prostate cancer and all of whom have major ongoing, individual research efforts in this area, and extensive collections of prostate cancer families. The ICPCG was formed in 1996 to explore collaborative studies in the area of prostate cancer and, in particular, to provide a mechanism by which large-scale pooled analyses could be performed.
More than 17,000 DNA samples, including 7014 from affected individuals, have been collected from 2558 multiplex prostate cancer families. Each of the ICPCG sites employed varying designs and sampling schemes to recruit families. This diversity is a primary strength, as it has provided an opportunity to acquire data on subgroups of affected individuals and families with characteristics that represent a continuum of genetic and environmental risk. This collection is the largest family resource in the world available to address the genetic mechanisms underlying inherited susceptibility for PC.
To combine resources to carry out collaborative studies in prostate cancer genetics.
Current Research Aims
Prostate cancer (PC) diagnoses in the U.S. in 2012 are estimated to account for 29% (241,740) of all newly diagnosed cancers in men and 9% (28,170) of male cancer deaths. The heterogeneity of PC aggressiveness and the inability to accurately identify men destined to suffer and die from the disease cause a significant public health problem of possible over-diagnosis and over-treatment of patients with indolent PC. Several studies have implicated a genetic etiology for PC, and multiple genome-wide association studies have identified several risk alleles for PC that account for a small proportion of genetic risk. However, less than 30% of the heritability of PC has been defined, and it is likely that a proportion of the undefined risk is due to rare susceptibility alleles. The genetic causes of PC represent one of the most important questions in PC research today. With the new generation of DNA sequencing technology, the potential application of applying sequencing information to patient care is emerging for screening decisions and identification of molecular pathways involved in the development and progression of PC. Better markers to identify PC could have a substantial effect on patient care. We hypothesize that rare risk alleles can be identified by utilizing next-generation sequencing technologies to perform whole-exome sequencing in highly enriched familial cases of PC. The ICPCG is in the unique position of having identified and sampled the most informative high-risk PC pedigrees known throughout the world. To define these rare risk alleles, we have several objectives for our current work.
- First, we will identify candidate PC susceptibility genes from whole-exome sequencing data derived from ~800 familial cases (from ~475 independent families) and prioritize those genes with variants that are most damaging, co-segregate with PC within the tested families, and are rare in the general population (Aim 1).
- Second, we will further analyze the top 1000 candidate genes identified in Aim 1 by re-sequencing the coding regions in an independent set of 500 hereditary PC cases and 500 controls, looking specifically for genes with multiple damaging variants and variants that are found to be significantly more frequent among our cases compared to control data (Aim 2).
- Third, we will identify the most likely PC susceptibility loci by end-to-end re-sequencing of the top 100 genes identified in Aim 2 in an independent set of 1000 hereditary PC cases and 1000 controls (Aim 3).
ICPCG currently receives funding from the National Cancer Institute (U01CA08960).