Prostate cancer is the most commonly diagnosed male malignancy in the US with an estimated 33% of all
new male cancer diagnoses and 9% of all cancer deaths in 2006. Progress in finding reproducible prostate
cancer risk variants has been slow even though family and twin studies show that there is a significant
genetic component to the disease.
Using a combination of linkage and association analysis, we identified a common genetic variant on
chromosome 8q24 that is significantly associated with an increased risk of prostate cancer. Importantly, we
have replicated our findings in two populations of European origin and one African American. The variant
explains about 8% of prostate cancer risk in populations of European ancestry but up to 16% of the risk in
African Americans and may partly explain the higher incidence of prostate cancer in this group. Our findings
have now been replicated in Japanese American, Native Hawaiian, Latino American and European
American prostate cancer case-control series lending additional support to the presence of risk variants in
this region that are important in a wide spectrum of populations.
The association signal is located within a linkage disequilibrium block on Chr8q24. This genomic region
contains no known genes but is frequently gained or amplified in prostate cancer as well as other cancer
types. To delineate the functional consequences of carrying the at risk variant(s) we propose to thoroughly
analyze a 2 Mb region on Chr8q24 centered on the genomic region containing the markers that associate
significantly to prostate cancer. We will use several complementary high-resolution array based technologies
to uncover transcripts, copy number variants and methylated sites in the Chr8q24 region and relate these to
the prostate cancer risk variant(s). We thus propose to take the first steps towards identifying the underlying
functional prostate cancer risk factor on Chr8q24 and begin to explain why carriers are at an increased risk
of developing prostate cancer.
A better understanding of the prostate cancer risk factor on Chr8q24 is important for several reasons.
First, it will increase our knowledge of how possibly minor differences in normal cellular physiology can over
time lead to prostate cancer. Second, this information may unveil new cellular mechanisms that affect
predisposition to prostate cancer and possibly other cancer types. Last, but not least, increased knowledge
about the functional aspects of predisposition to prostate cancer may lead to the development of new
methods for diagnosing and treating the disease.
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