Susceptibility to prostate cancer commonly runs in families and has a large hereditary component, but despite numerous linkage studies and whole-genome scans, the genes responsible have eluded us. Now, a consortium of researchers from the United States, Finland and Sweden seem to be closing in on a suceptibility target. They report that mutations in a tumour-suppressor gene can be linked to hereditary prostate cancer (HPC).

In the February issue of Nature Genetics, Carpten et al. examined a region on chromosome 1, known as HPC1 , that had been previously identified as a prostate cancer susceptibility locus. In analysing candidate genes in this region, they found that mutations in a gene encoding ribonuclease L ( RNASEL ) were carried by members of two separate HPC families. In one family, a heterozygous mutation introduced a premature stop codon into the RNASEL gene, whereas in the other family a heterozygous mutation disrupted the initiation codon. Most importantly, all the male family members who carried these mutations eventually developed prostate cancer.

Analysis of tumour DNA from one of these men revealed loss of heterozygosity — cancer cells had managed to delete the remaining wild-type copy of the gene. Accordingly, no RNase L protein could be detected in tumour cells. Low levels of protein were expressed in non-cancerous epithelial cells of these individuals, presumably from the remaining wild-type allele. RNase L therefore seems to function as a tumour suppressor. Previous studies showing that RNase L activity is completely lost in hepatoma cell lines support this conclusion.

So what is the exact role of RNase L in normal prostate function and during tumorigenesis? Mice deficient in this protein have defects in interferon-induced apoptosis and antiviral responses, indicating that it might be involved in regulating cell survival. Prostate cells are known to walk a fine (hormonally regulated) line between cell proliferation and death. The authors speculate that loss of function of one protein in either of these pathways is enough to tip a cell's balance from death towards proliferation — which might be enough to initiate tumorigenesis.

Carpten et al. suggest that this gene might someday be useful in early prostate cancer diagnosis. Other RNASEL mutations, however, must be identified in additional groups of men with prostate cancer to confirm that this is a bona fide susceptibility gene.