Hereditary Prostate Cancer Appears More Aggressive

NEW ORLEANS--The inheritance pattern for prostate cancer is becomingbetter understood by linkage analysis, and it appears that the inheritedform may be more aggressive than sporadic cancer, according to reportsat the American Urological Association meeting.

Patrick Walsh, MD, presented the work of 22 investigators at three institutionswho have identified linkage to the first hereditary prostate cancer gene(HPC1), located on the short arm of chromosome 1.

The study used 341 dinucleotide repeat markers to complete a densitymap involving 91 families who had at least three first-degree relativeswith prostate cancer. The gene appears to be responsible for one thirdto one half of all inherited cases of prostate cancer.

The results showed that men who have an HPC1 mutation are more likelyto be diagnosed with prostate cancer at an earlier age, in a more advancedstate, and with a more poorly differentiated tumor, suggesting that thegene is responsible for an aggressive form of prostate cancer, said Dr.Walsh, McConnell Professor and director of urology at Johns Hopkins.

"The characterization of the first hereditary gene is a major findingin the field," he commented in an interview. "It's the equivalentof the discovery of the BRCA1 gene for breast cancer."

The NIH-sponsored study included Johns Hopkins, the National Centerfor Human Genome Research, and Umeå University in Sweden.

Mayo Clinic Study

More evidence for a gene that conveys a high life-time risk for prostatecancer was offered by Mayo Clinic investigators. Information about familyhistory of prostate cancer was obtained from 4,288 prostate cancer patientsand their 17,684 first-degree male relatives.

Daniel J. Schaid, PhD, who presented the data at the AUA meeting, saidthat, based on their results, the best-fitting genetic model is autosomaldominant, with an estimated susceptibility allele frequency of 0.006. Theirmodel predicts that the cumulative risk of prostate cancer by age 85 is89% among carriers of the risk allele, and 3% among noncarriers.

For first-degree relatives of the proband, the risk varies accordingto the proband's age at diagnosis. If the proband is diagnosed with prostatecancer before age 60, the risk to first-degree relatives is 34%; betweenages 60 and 70, the risk is 31%; and over age 70, the risk is 17%.

Cleveland Clinic researchers added to the interest in genetics at themeeting by reporting that men with a family history of the disease hadworse outcome after treatment.

"Men with a family history were significantly more likely to experiencea relapse within five years after undergoing a radical prostatectomy,"Patrick Kupelian, MD, a radiation oncologist, reported.

The study included 529 men who underwent surgery between 1987 and 1996.About 12% of the men had a brother or father who had also been diagnosedwith prostate cancer.

Only 46% of the men with family histories remained relapse-free forfive years after prostatectomy, compared with 66% of those without a familyhistory, Dr. Kupelian said.

"This study suggests that familial prostate cancer is more aggressivethan sporadic prostate cancer," said Eric A. Klein, chief of urologiconcology at the Cleveland Clinic. "This observation has importantimplications for screening men with a family history."