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hereditary prostate cancer

Tuesday 7 February 2012

familial prostate cancer

Inherited susceptibility

- BRCAs : BRCA2 (high risk) / BRCA1 (moderate risk)
- HOXB13
- 8q24 locus
- MSH2 and HNPCC

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. Currently the evidence for a strong genetic component is compelling.

Strengthening the genetic evidence is a high frequency for prostate cancer in monozygotic as compared to dizygotic twins in a study of twins from Sweden, Denmark, and Finland.

Work over the past decade using genome wide scans in prostate cancer families has identified high risk alleles, displaying either an autosomal dominant or X-linked mode of inheritance for a hereditary prostate cancer gene, from at least 7 candidate genetic loci.

Of these loci, three candidate genes have been identified:
- HPC2/ELAC2 on 17p,
- RNASEL on 1q25,
- MSR1 on 8p22-23.

These 3 genes do not account for the majority of hereditary prostate cancer cases.

In addition, more than 10 other loci have been implicated by at least some groups. The discovery of highly penetrant prostate cancer genes has been particularly difficult for at least 2 main reasons.

First, due to the advanced age of onset (median 60 years), identification of more than two generations to perform molecular studies on is difficult.

Second, given the high frequency of prostate cancer, it is likely that cases considered to be hereditary during segregation studies actually represent phenocopies; currently it is not possible to distinguish sporadic (phenocopies) from hereditary cases in families with high rates of prostate cancer.

In addition, hereditary prostate cancer does not occur in any of the known cancer syndromes and does not have any clinical (other than a somewhat early age of onset at times) or pathologic characteristics to allow researchers to distinguish it from sporadic cases.

Perhaps even more important in terms of inherited susceptibility for prostate cancer are common polymorphisms in a number of low penetrance alleles of other genes - the so-called genetic modifier alleles.

The list of these variants is long, but the major pathways currently under examination include those involved in androgen action, DNA repair, carcinogen metabolism, and inflammation pathways.

It is widely assumed that the specific combinations of these variants, in the proper environmental setting, can profoundly affect the risk of developing prostate cancer.

Prostate cancer susceptibility loci

Twenty-three new prostate cancer susceptibility loci have been identified at genome-wide significance (P @<@ 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. (23535732)

On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. (23535732)

See also

- prostate cancer


- Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array.Eeles RA, Olama AA, Benlloch S et al. Nat Genet. 2013 Apr;45(4):385-91, 391e1-2. doi : 10.1038/ng.2560 PMID: 23535732