Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer.

A clearer definition of the molecular determinants that drive the development and progression of prostate cancer (PCa) is urgently needed. Efforts to map recurrent somatic deletions in the tumor genome, especially homozygous deletions (HODs), have provided important positional information in the search for cancer-causing genes. Analyzing HODs in the tumors of 244 patients from two independent cohorts and 22 PCa xenografts using high-resolution single-nucleotide polymorphism arrays, herein we report the identification of CHD1, a chromatin remodeler, as one of the most frequently homozygously deleted genes in PCa, second only to PTEN in this regard. The HODs observed in CHD1, including deletions affecting only internal exons of CHD1, were found to completely extinguish the expression of mRNA of this gene in PCa xenografts. Loss of this chromatin remodeler in clinical specimens is significantly associated with an increased number of additional chromosomal deletions, both hemi- and homozygous, especially on 2q, 5q and 6q. Together with the deletions observed in HEK293 cells stably transfected with CHD1 small hairpin RNA, these data suggest a causal relationship. Downregulation of Chd1 in mouse prostate epithelial cells caused dramatic morphological changes indicative of increased invasiveness, but did not result in transformation. Indicating a new role of CHD1, these findings collectively suggest that distinct CHD1-associated alterations of genomic structure evolve during and are required for the development of PCa.

A quantitative analysis of the costs and benefits of prostate cancer screening.

The present study attempts to quantitate in an economically and clinically meaningful manner the cost and cost-effectiveness of prostate cancer screening and subsequent treatment, including complications from that treatment. Outcome data from large prostate cancer screening trials using prostate specific antigen (PSA) and digital rectal examination (DRE) and PSA alone were used to construct the screening model. The benefit of screening is expressed in years of life saved by screening, which is calculated by comparing the survival rate of men with prostate cancer to the survival rate of men in the general population. The cost of screening, treatment, and complications were estimated using the Medicare data base and published reports on the cost, morbidity and mortality for radical prostatectomy. The cost per year of life saved by prostate cancer screening with PSA and DRE was $2339-3005 for men aged 50-59, $3905-5070 for men aged 60-69, and $3574-4627 overall for men aged 50-69. The cost per year of life saved by prostate cancer screening with PSA alone for men aged 50-70 was $3822-4956. A sensitivity analysis demonstrates that the cost per year of life saved by prostate cancer screening will not change substantially even if the assumptions in this model have been underestimated or overestimated by 100%. This study quantifies only those parameters which can be reliably compared in concrete terms such as dollars, treatment impact on survival, published complication rates and published treatment costs. Using this type of analysis, prostate cancer screening appears to be a cost-effective intervention. However, the issue of whether prostate cancer screening is cost-effective will be decided definitively only when randomized, controlled trials are available to quantify the costs and benefits of prostate cancer screening.Prostate Cancer and Prostatic Diseases (2001) 4, 138-145.