Re: Prostate Cancer Susceptibility Locus on Chromosome 1q: a Confirmatory Study

Extract

The recent article in the Journal by Cooney et al. ( 1 ) presented results of nonparametric multipoint linkage (NPL) analysis of the 1q24-25 region reported by Smith et al. ( 2 ) . On the basis of analysis of six markers in 59 families containing more than one living family member with prostate cancer, Cooney et al. reported linkage to marker D1S466 (NPL Z score = 1.58; P = .0574). They found stronger evidence (NPL Z score = 1.72; P = .0451) when analyzing the 20 families fulfilling one of more of the proposed criteria for hereditary prostate cancer (i.e., three or more affected individuals within one nuclear family, affected individuals in three successive generations, and/or clustering of two or more individuals affected before the age of 55 years), hereafter called “hereditary families.”

We report further evidence to support a hereditary prostate cancer susceptibility gene in the 1q24-25 region. This evidence is based on analysis of four markers (D1S452, D1S2883, D1S158, and D1S422) in 92 unrelated families having three or more medically verified diagnoses of prostate cancer within their first- or second-degree relatives. Seventy- eight of these families were hereditary families. Ethnically, 79 families were Caucasian, six were African- American, four were Japanese- American, and three were Chinese- American. The families were identified from a multiethnic, case-control study conducted in Hawaii, Los Angeles, San Francisco, and Vancouver, British Columbia ( 3 ) , from screens of the British Columbia Cancer Registry and the San- Francisco-Oakland Cancer Registry, and from publicity in the San Jose Mercury News . The mean number per family of affected and genotyped individuals was 2.6 (range, 2-6), and the mean age at diagnosis of all affected individuals was 67.2 years (67.2 years in Caucasian families, 64.3 years in African- American families, and 69.8 years in Asian-American families). A total of 295 typed samples was used in this analysis. The primer sequences and polymerase chain reaction (PCR) conditions were obtained from the Genome Data Base. In each reaction, a portion of the forward primers (1/5) was radiolabeled. The final PCR products were resolved on 6% sequencing gels with size standards and control samples on each gel. Allele sizes were determined by use of a molecular imager (Bio-Rad Laboratories, Richmond, CA) and were standardized with control samples. All samples were typed without knowledge of disease status. Estimates of marker allele frequencies obtained from the data were similar to those found by Smith et al. ( 2 ) . NPL Z scores and one-tailed P values were obtained with the software GENEHUNTER ( 4 ) . For the multipoint analyses, the four markers were assumed to be in the order listed above, with inter-marker distances of 9.0, 7.2, and 3.8 centimorgans, respectively, based on estimates from GENETHON and Smith et al. ( 2 ) . Two of the markers (D1S2883 and D1S158) were also used by Cooney et al. ( 1 ) .