Genomewide scan for prostate cancer-aggressiveness loci

Abstract

The aggressiveness of prostate cancer (PCa) varies widely: some tumors progress to invasive, potentially life-threatening disease, whereas others stay latent for the remainder of an individual's lifetime. The mechanisms resulting in this variability are not yet understood, but they are likely to involve both genetic and environmental influences. To investigate genetic factors, we conducted a genomewide linkage analysis of 513 brothers with PCa, using the Gleason score, which reflects tumor histology, as a quantitative measure of PCa aggressiveness. To our knowledge, this is the first time that a measure of PCa aggressiveness has been directly investigated as a quantitative trait in a genomewide scan. We employed a generalized multipoint Haseman-Elston linkage-analysis approach that regresses the mean-corrected cross product between the brothers' Gleason scores on the estimated proportion of alleles shared by brothers identical by descent at each marker location. Our results suggest that candidate regions on chromosomes 5q, 7q, and 19q give evidence for linkage to PCa-aggressiveness genes. In particular, the strongest signals detected in these regions were at the following markers (with corresponding P values): for chromosome 5q31-33, between markers D5S1480 and D5S820 (P=.0002); for chromosome 7q32, between markers D7S3061 and D7S1804 (P=.0007); and, for chromosome 19q12, at D19S433 (P=.0004). This indicates that one or more of these candidate regions may contain genes that influence the progression of PCa from latent to invasive disease. Identification of such genes would be extremely valuable for elucidation of the mechanism underlying PCa progression and for determination of treatment in men in whom this disease has been diagnosed.

Figure 1

Results from a genomewide scan of PCa-aggressiveness genes; Gleason score was used as a quantitative trait. Unbroken lines denote results from the new HE analysis; broken lines denote results from the original HE analysis. Tick marks across horizontal axes indicate marker locations (in cM) (as specified on the Center for Human Genetics, Marshfield Medical Research Foundation Web site). P values are from a t test of the HE regression coefficient, with 324 df (number of affected sib pairs [326] minus the number of parameters [2]). Dotted horizontal lines indicate where P=.001 (−log[P] = 3); thus, for peaks above these lines, P<.001.