Genetic Polymorphisms Linked To Prostate Cancer Susceptibility

NEW YORK (Reuters Health) - Two papers in the August 18th issue of the Journal of the National Cancer Institute describe several genetic polymorphism that appear to influence susceptibility to prostate cancer.

In the first paper, Dr. Henrik Gronberg and colleagues report that a polymorphism in a gene regulating macrophage activity is associated with prostate cancer susceptibility. "Inflammation in the prostate may go unchecked in carriers with this polymorphism, leading to an increased risk for tumor development."

In the second paper, Dr. Jeffrey M. Trent and colleagues report the results of a genome-wide linkage analysis that revealed several chromosomal regions associated with prostate cancer. Their findings suggest that multiple genes acting either independently or simultaneously "will increase the susceptibility to a genetically complex disease such as prostate cancer."

Dr. Gronberg, at Umea University, Sweden, and his team note that previous studies have shown altered levels of expression of the macrophage-inhibitory cytokine-1 (MIC-1) gene in prostate cancer. They therefore performed a systematic genetic analysis of the MIC-1 gene in a population-based case-control study in Sweden that included 1383 prostate cancer patients and 780 control subjects.

Dr. Gronberg's team observed a significant difference in genotype frequency for the nonsynonymous change of histidine to aspartic acid at position 6 of the MIC-1 protein between patients and controls (p = 0.006).

They estimate the population-attributable risk for the H6D variant to be 7.2% for sporadic cancer and 19.2% for familial cancer. They noted an even stronger association of the H6D variant with advanced disease.

MIC-1 is believed to suppress proinflammatory monokines, and Dr. Gronberg's group suggests that the H6D variant alters the function of the protein, reducing or abolishing MIC-1 activity, and increasing the risk of prostate cancer.

Dr. Trent, at the Translational Genomics Research Institute in Phoenix, and his group combined four hereditary prostate cancer (HPC) study populations to perform a genome-wide linkage analysis to systematically search for susceptibility genes.

Included were 426 HPC families, 285 of which had at least four men diagnosed with prostate cancer.

The strongest association was found at chromosome region 17q22, yielding a LOD score of 3.16 (p = 0.00007). Evidence was strongest among the 201 families with early-onset disease and among the 285 with four or more affected men.

Four other chromosomal regions were associated with LOD scores greater than 2. Moreover, a susceptibility gene segregated at the 15q11 region among HPC families with late-onset prostate cancer, and at the 4q35 region among those with four or more affected family members.

"Results of this large genome-wide scan for prostate cancer susceptibility genes provide a basis for renewed interest, excitement, and confidence in genetic linkage studies of prostate cancer," Dr. Trent and associates conclude.

Source: J Natl Cancer Inst 2004;96:1240-1254. [ Google search on this article ]

MeSH Headings: Biological Sciences : Biology : Genetics : Genital Neoplasms, Male : Linkage (Genetics) : Neoplasms : Neoplasms by Site : Prostatic Neoplasms : Urogenital Neoplasms : Biological Sciences : Diseases