Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes.

We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.

Pathological features after radical prostatectomy in potential candidates for active monitoring.

PURPOSE: There are numerous reports on the results of watchful waiting or active monitoring protocols for men with low volume, biopsy Gleason grade 6 or less prostate cancer. When counseling patients with low grade prostate cancer about treatment options, it is useful to know the results of surgical treatment in this population. MATERIALS AND METHODS: In a contemporary radical prostatectomy series there were 455 patients with biopsy Gleason grade 3 + 3 prostate cancer and information on the number of positive biopsy cores. Of these men 292 had low volume disease on the basis of 2 or fewer positive cores. RESULTS: Overall 245 of 292 men (84%) with low volume Gleason 3 + 3 prostate cancer on biopsy had organ confined disease. The Gleason score in the prostatectomy specimen was 7 or greater in 78 men (27%), 25 (8%) had extracapsular tumor extension and 29 (10%) had positive surgical margins. In these patients preoperative variables were not reliable predictors of adverse pathological features. CONCLUSIONS: More than a third of Gleason 3 + 3 tumors on biopsy were upgraded in the radical prostatectomy specimen or had other adverse pathological features. Our results suggest that low volume Gleason 3 + 3 prostate cancer is frequently under staged, and that immediate therapy with radical prostatectomy is associated with favorable outcomes.

Under diagnosis and over diagnosis of prostate cancer.

PURPOSE: We quantified the rates of over and under diagnosis of prostate cancer in 2 large patient cohorts during the last 15 years. MATERIALS AND METHODS: A total of 2,126 men with clinical stage T1c prostate cancer were treated with radical prostatectomy during 1 of the 3 periods 1989 to 1995, 1995 to 2001 and 2001 to 2005. The respective proportions of men with a tumor that met our criteria for over diagnosis (0.5 cm3 or less, confined to the prostate with clear surgical margins and no Gleason pattern 4 or 5) and under diagnosis (nonorgan confined, pathological stage T3 or greater, or positive surgical margins) were examined. RESULTS: The proportion of men with an over diagnosed tumor was 1.3% to 7.1%. The proportion with prostate cancer that was under diagnosed was 25% to 30%. An ancillary finding was that decreasing the prostate specific antigen threshold for biopsy from 4.0 to 2.5 ng/ml in the screened population resulted in a lower rate of under diagnosis from 30% to 26%, a higher rate of over diagnosis from 1.3% to 7.1% and an increase in the 5-year progression-free survival rate from 85% to 92%. Men who were 55 years or younger were significantly more likely to meet our criteria for over diagnosed cancer. CONCLUSIONS: Under diagnosis of prostate cancer continues to occur more frequently than over diagnosis. Lowering the prostate specific antigen threshold for recommending biopsy to 2.5 ng/ml resulted in a lower rate of under diagnosis and a higher progression-free survival rate.

Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24.

Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.