Prostate Cancer, Hereditary, 1

A number sign (#) is used with this entry because of evidence that hereditary prostate cancer-1 (HPC1) is caused by heterozygous germline mutation in the gene encoding ribonuclease L (RNASEL; 180435) on chromosome 1q25.

For a general discussion of hereditary prostate cancer, see 176807.

Smith et al. (1996) noted that segregation analysis of familial prostate cancer suggests the existence of at least 1 dominant susceptibility locus and predicts that high-risk alleles at such loci account in the aggregate for 9% of all prostate cancers and for more than 40% of early-onset disease. They stated further that prostate cancer presents a number of serious obstacles to linkage analysis, including occurrence of phenocopies, late age of onset, and absence of clinical features that might allow subgrouping to reflect potential genetic heterogeneity. Smith et al. (1996) undertook linkage analysis in 79 North American and 12 Swedish pedigrees, each having at least 3 first-degree relatives with prostate cancer. In these families there was also evidence of bilineal inheritance. Affected individuals had an average age at diagnosis of 65 years, with a total of 34 men diagnosed before the age of 55. The investigators analyzed a total of 341 dinucleotide repeat markers in a subgroup of 66 North American families. For the parametric analysis of the data they used a model of dominant inheritance that included a fixed phenocopy rate of 15% and the assumption that unaffected men over 75 were not likely to be gene carriers. The highest lod score observed was 2.75 with the marker D1S218, which maps to the distal long arm of chromosome 1 at 1q24-q25. The investigators then typed additional markers in this region in all 79 North American families and the 12 Swedish families. This analysis provided additional evidence for linkage with a maximum 2-point lod score of 3.65 at theta = 0.18 with marker D1S2883. Significant evidence for locus heterogeneity was obtained by an admixture test, which estimated that 34% of families were linked to the 1q24-q25 region. The maximum multipoint lod score with markers D1S2883, D1S158, and D1S422 under the assumption of heterogeneity was 5.43, with the postulated susceptibility locus mapping close to D1S422. Smith et al. (1996) found no clinical features that appeared to distinguish families showing linkage to chromosome 1 from unlinked families. They noted that Cher et al. (1996) reported that a large portion of chromosome 1, including 1q24-q25, is frequently increased in copy number in advanced prostate cancer specimens examined by comparative genomic hybridization. Smith et al. (1996) proposed the designation of HPC1 (hereditary prostate cancer 1) for the locus. They emphasized that early diagnosis can be life-saving in prostate cancer and that the potential ability to identify individuals at high genetic risk, when combined with physical exam, transrectal ultrasound, and prostate-specific antigen (176820) analysis, could ultimately be of significant medical benefit.

McIndoe et al. (1997) reported results of linkage analysis in the region of the putative HPC1 locus on 1q24-q25. The study was part of the Prostate Cancer Genetic Research Study (PROGRESS) at the Fred Hutchinson Cancer Research Center in Seattle. Analysis by 2 parametric methods and 1 nonparametric method failed to confirm linkage to this region. Additionally, they were unable to demonstrate heterogeneity within the dataset.

Cooney et al. (1997) confirmed 1q24-q25 as a likely location of a prostate cancer susceptibility gene. Nonparametric multipoint linkage analysis of data on 6 polymorphic marker sequences covering the candidate chromosomal region were performed in 59 unrelated families selected for analysis on the sole criterion that more than 1 living family member was affected by prostate cancer. In the entire set of 59 families, tight linkage to D1S466 was found; maximum lod = 1.58. In 20 families fulfilling more rigorous criteria, i.e., 3 or more affected individuals within one nuclear family, affected individuals in 3 successive generations, and/or clustering of 2 or more individuals affected before the age of 55 years a maximum lod score of 1.72 was observed with the same marker. The 6 African American families in this study contributed disproportionately to the observation of linkage, with a maximum nonparametric linkage (NPL) Z score at marker D1S158 of 1.39.

Using both parametric and nonparametric methods, Eeles et al. (1998) attempted to confirm the assignment of a locus (HPC1) to 1q in a study of 60 affected related pairs and 76 families with 3 or more cases of prostate cancer, but could find no significant evidence of linkage. The estimated proportion of linked families, under a standard autosomal dominant model, was 4%, with an upper 95% confidence limit of 31%. They concluded that the HPC1 locus is responsible for only a minority of familial prostate cancer cases and that it is likely to be most important in families with at least 4 cases of the disease.

The original study of Smith et al. (1996) mapping the HPC1 gene to 1q24-q25 involved 91 North American and Swedish families, each with multiple cases of prostate cancer. Gronberg et al. (1999) analyzed 40 (12 original and 28 newly identified) Swedish families with hereditary prostate cancer that, on the basis of 40 markers spanning a 25-cM interval within 1q24-q25, showed evidence of linkage. In the complete set of families, a maximum 2-point lod score of 1.10 was observed at D1S413 (at a recombination fraction of 0.1), with a maximum NPL Z score of 1.64 at D1S202 (P = 0.5). The evidence for linkage to this region originated almost exclusively from a subset of 12 early-onset (age less than 65 years) families, which yielded a maximum lod score of 2.38 at D1S413 (theta = 0.0) and an NPL Z score of 1.95 at D1S422 (P = 0.3). Estimates from heterogeneity tests suggested that, within Sweden, as many as 50% of early-onset families have linkage to the HPC1 region.

Neuhausen et al. (1999) examined evidence for linkage to the 1q24-q25 region in a set of 41 extended multicase prostate cancer pedigrees from Utah containing 440 members with prostate cancer. In comparison with the families reported in the initial localization by Smith et al. (1996), the Utah pedigrees were generally much larger (average of 10.7 vs 5.1 cases) and had an older average age at diagnosis (69 vs 65 years). The authors found that the youngest quartile (by median age at diagnosis) yielded a maximum lod of 2.82, P = 0.0003 (at D1S215 to D1S222), compared with a maximum lod of 0.73, P = 0.07 for the oldest quartile pedigrees at the same locus.

In a combined analysis for 6 markers in the 1q24-q25 region in 772 families segregating hereditary prostate cancer, Xu and the International Consortium for Prostate Cancer Genetics (2000) found some evidence for linkage with a peak parametric multipoint lod score assuming heterogeneity (hlod) of 1.4 (p = 0.01) at D1S212. In a subset of 491 families with male-to-male disease transmission, the hlod score was 2.56 (p = 0.0006) whereas the score was zero in the remaining 281 families. The authors stated that the results supported the finding of a prostate cancer susceptibility gene linked to 1q24-q25 in a defined subset of families in which several members are affected at an early age and in which there is male-to-male transmission.

Cancel-Tassin et al. (2001) examined evidence for linkage to the HPC1 locus in 64 (37 previously reported and 27 newly identified) families from southern and western Europe with at least 3 affected individuals with prostate cancer and an average age at diagnosis of 66.4 years. Using both parametric and nonparametric linkage methods, no significant evidence of linkage was observed. A subset of 25 families with earlier age of diagnosis (under 66 years) also showed negative lod scores. Under the assumption of heterogeneity, low positive lod scores were obtained in a small proportion of families.

By a positional cloning/candidate gene method, Carpten et al. (2002) identified the ribonuclease L gene (180435) as the site of germline mutations in 2 HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway, and it had been a suggested tumor suppressor gene. In that connection, Carpten et al. (2002) found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozygous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway may provide opportunities for developing therapies for those with prostate cancer.