Linkage and Association Studies of Prostate Cancer Susceptibility: Evidence for Linkage at 8p22-23

• Published in: American journal of human genetics Vol. 69; no. 2; pp. 341 - 350
• Main Authors: Xu, Jianfeng, Zheng, Siqun L., Hawkins, Gregory A., Faith, Dennis A., Kelly, Brian, Isaacs, Sarah D., Wiley, Kathleen E., Chang, Bao-li, Ewing, Charles M., Bujnovszky, Piroska, Carpten, John D., Bleecker, Eugene R., Walsh, Patrick C., Trent, Jeffrey M., Meyers, Deborah A., Isaacs, William B.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-08-2001; University of Chicago Press; The American Society of Human Genetics
• Subjects: Age of Onset; Alleles; Biological and medical sciences; Chromosome Mapping; Chromosomes, Human, Pair 8 - genetics; DNA Mutational Analysis; Female; Gene Frequency - genetics; Genetic Linkage - genetics; Genetic Markers - genetics; Genetic Predisposition to Disease - genetics; Genetic Testing; Genotype; Humans; Jews - genetics; Lod Score; Male; Medical sciences; Microsatellite Repeats - genetics; Molecular Sequence Data; Mutation - genetics; Nephrology. Urinary tract diseases; Odds Ratio; Pedigree; Polymorphism, Single Nucleotide - genetics; Polymorphism, Single-Stranded Conformational; Prostatic Neoplasms - epidemiology; Prostatic Neoplasms - genetics; Racial Groups - genetics; Tumors of the urinary system; Urinary tract. Prostate gland; Human; Short arm; Urinary system disease; Linkage; Prostate disease; Family study; Pathogenesis; Malignant tumor; Chromosome C8; Genetic determinism; Genetic disease; Allele; Gene; Mutation; Male genital diseases; Haplotype; Prostate
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/321967

Multiple lines of evidence have implicated the short arm of chromosome 8 as harboring genes important in prostate carcinogenesis. Although most of this evidence comes from the identification of frequent somatic alterations of 8p loci in prostate cancer cells (e.g., loss of heterozygosity), studies have also suggested a role for 8p genes in mediation of inherited susceptibility to prostate cancer. To further examine this latter possibility, we performed linkage analyses, in 159 pedigrees affected by hereditary prostate cancer (HPC), using 24 markers on the short arm of chromosome 8. In the complete set of families, evidence for prostate cancer linkage was found at 8p22-23, with a peak HLOD of 1.84 (
P=.004), and an estimate of the proportion of families linked (α) of 0.14, at D8S1130. In the 79 families with average age at diagnosis >65 years, an allele-sharing LOD score of 2.64 (
P=.0005) was observed, and six markers spanning a distance of 10 cM had LOD scores >2.0. Interestingly, the small number of Ashkenazi Jewish pedigrees (
n=11) analyzed in this study contributed disproportionately to this linkage. Mutation screening in HPC probands and association analyses in case subjects (a group that includes HPC probands and unrelated case subjects) and unaffected control subjects were carried out for the putative prostate cancer–susceptibility gene,
PG1, previously localized to the 8p22-23 region. No statistical differences in the allele, genotype, or haplotype frequencies of the SNPs or other sequence variants in the PG1 gene were observed between case and control subjects. However, case subjects demonstrated a trend toward higher homozygous rates of less-frequent alleles in all three
PG1 SNPs, and overtransmission of a
PG1 variant to case subjects was observed. In summary, these results provide evidence for the existence of a prostate cancer–susceptibility gene at 8p22-23. Evaluation of the
PG1 gene and other candidate genes in this area appears warranted.