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Inherited risk of breast and prostate cancer

Final Report Summary - POLYGENE (Inherited risk of breast and prostate cancer)

The overall objective of POLYGENE was to identify inherited risk factors of two important cancers that have been shown to have a substantial genetic component, prostate cancer in men and breast cancer in women. The specific objectives of the project were:

1. Genome-wide association study of breast and prostate cancer.
Associations between SNP polymorphisms and the risk of breast and prostate cancer were to be examined in unselected samples from breast and prostate cancer patients in Iceland and the Netherlands, two populations with different structure and history.

2. Development of efficient statistical and computational methods for the analysis of genetic and association data.
Two areas of research were proposed: multipoint and multi-locus methods. The long-term objective of POLYGENE was to gain an increased understanding of the genetic underpinnings of breast and prostate cancer which may, in turn, lead to more effective risk assessment, increase the efficiency of screening programs and lead to improved diagnosis and treatment. The improved analysis methods will also aid genomic research for other diseases.

Both prostate and breast cancer are diseases with a considerable genetic factor that cannot be easily modified with environmental changes, high prevalence in the population and high impact on public health. It has been estimated that genetic factors contribute over 40 % of the variation in prostate cancer risk and 27 % of breast cancer risk. Thus, they represent diseases with great potential for use of genetic information. Once all genetic risk factors for the two diseases have been characterised, it will be possible to produce genetic risk models that can be used to identify those individuals with the highest genetic risk. Both breast and prostate cancer have a high cure rate when detected early. Therefore, frequent screening of individuals with high genetic risk can facilitate early detection, improve prognosis and eventually result in lower mortality due to these diseases.

At the outset of the project, only a minor fraction of genetic risk for breast cancer had been characterised and most of this risk could be attributed to mutations in the breast cancer genes, BRCA1 and BRCA2. The high genetic fraction of prostate cancer remained almost entirely unexplained. Accumulating evidence suggested that most of genetic cancer risk was due to multiple common risk alleles, where the risk associated with each individual allele was small to moderate. Importantly, as the variants may interact in a multiplicative or super-multiplicative (epistatic) way, an individual with several susceptibility alleles might be at significant risk. It had been realised that if the polygenic model of cancer risk was correct, linkage analysis of families with multiple cases of breast or prostate cancer would not suffice because it lacks power to detect the low-penetrance risk variants. The association approach was suggested as the method of choice for identifying low-penetrance genes (risk ratio 1.1-2.0). However, until about 2006, genome-wide genetic association studies had been prohibitively expensive.

In the beginning of 2006, genotyping technologies became available that allowed the scanning of the human genome with hundreds of thousands of genetic markers in order to detect small but possibly relevant differences in allelic frequencies of all genes. POLYGENE was perfectly poised to take advantage of this revolution, having already assembled the three most important ingredients; i.e. biological samples, clinical data and a dedicated team of researchers. To summarise the success of the project, POLYGENE has discovered a considerable fraction of the variants identified to affect risk of breast and prostate cancer. Specifically, six variants that affect prostate cancer risk were identified and four variants that affect risk of breast cancer.

These variants, along with additional variants identified by us and others, have been incorporated into genetic risk models for both cancer types. Although much of the genetic risk elements for breast and prostate cancer still remain to be found, our results indicate that a model including low risk variants can be useful in predicting risk for prostate cancer. A genetic diagnostic test incorporating 22 common low-risk variants for prostate cancer demonstrates that the average relative risk of prostate cancer in the top 10 % of men having the highest risk is > 2.3-fold the risk of the general population. Currently, cancer risk models which incorporate genetic and non-genetic risk factors are being developed for prostate and breast cancer by several groups in the United Kingdom and the United States.

The utility of the genetic tests for prostate and breast cancer will grow rapidly as more variants are uncovered and included. At the same time, we will gain knowledge about the biological pathways that play a role in prostate and breast cancer initiation and which may subsequently be used to develop more effective prevention and treatment strategies.

The major exploitable result from POLYGENE is the discovery of six genetic variants that associate with prostate cancer risk and four genetic variants that associate with risk of breast cancer. Knowledge about genetic factors that increase risk of cancer can be used to develop DNA-based test that evaluate a person's genetic risk of developing the disease. This information can in turn help to guide measures that aim to prevent the disease in those at high risk or increase their chance of early diagnosis through screening programs.

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