Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics

Xu J (2000) Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics. Am J Hum Genet 66:945-957

A previous linkage study provided evidence for a prostate cancer-susceptibility locus at 1q24-25. Subsequent reports in additional collections of families have yielded conflicting results. In addition, evidence for locus heterogeneity has been provided by the identification of other putative hereditary prostate cancer loci on Xq27-28, 1q42-43, and 1p36. The present study describes a combined analysis for six markers in the 1q24-25 region in 772 families affected by hereditary prostate cancer and ascertained by the members of the International Consortium for Prostate Cancer Genetics (ICPCG) from North America, Australia, Finland, Norway, Sweden, and the United Kingdom. Overall, there was some evidence for linkage, with a peak parametric multipoint LOD score assuming heterogeneity (HLOD) of 1.40 (P=.01) at D1S212. The estimated proportion of families (alpha) linked to the locus was.06 (1-LOD support interval.01-.12). This evidence was not observed by a nonparametric approach, presumably because of the extensive heterogeneity. Further parametric analysis revealed a significant effect of the presence of male-to-male disease transmission within the families. In the subset of 491 such families, the peak HLOD was 2.56 (P=.0006) and alpha =.11 (1-LOD support interval.04-.19), compared with HLODs of 0 in the remaining 281 families. Within the families with male-to-male disease transmission, alpha increased with the early mean age at diagnosis (<65 years,="" alpha=".19," with="" 1-lod="" support="" interval.06-.34)="" and="" the="" number="" of="" affected="" family="" members="" (five="" or="" more="" family="" members,="" alpha=".15," with="" 1-lod="" support="" interval.04-.28).="" the="" highest="" value="" of="" alpha="" was="" observed="" for="" the="" 48="" families="" that="" met="" all="" three="" criteria="" (peak="" hlod="2.25," p=".001," alpha=".29," with="" 1-lod="" support="" interval.08-.53).="" these="" results="" support="" the="" finding="" of="" a="" prostate="" cancer-susceptibility="" gene="" linked="" to="" 1q24-25,="" albeit="" in="" a="" defined="" subset="" of="" prostate="" cancer="" families.="" although="" hpc1="" accounts="" for="" only="" a="" small="" proportion="" of="" all="" families="" affected="" by="" hereditary="" prostate="" cancer,="" it="" appears="" to="" play="" a="" more="" prominent="" role="" in="" the="" subset="" of="" families="" with="" several="" members="" affected="" at="" an="" early="" age="" and="" with="" male-to-male="" disease="">