Monday, December 24, 2012

Deck the halls with boughs of HOXB

Prostate cancer ranks as the most commonly diagnosed non-skin cancer in Caucasian men, and it’s the most heritable common cancer. Genome-wide association studies (GWAS) have yielded perhaps 30 – 40 SNPs each associated with a (rather small) increase in risk, and so most inherited risk remains unexplained. A paper published early this year (PMID 22236224) about rs138213197 may have begun a new chapter in the search for inherited prostate cancer risk, and it’s indicative of how new methods can bring about highly significant discoveries.

For almost a decade since linkage evidence emerged indicating that a predisposition to prostate cancer was due to variants in the ch 17q21-22 region, GWAS studies yielded little from the region. The labs of K. Cooney (U Mich) and W. Isaacs (JHU) turned to exome sequencing – specifically, they looked at over 2000 exomes from 200 genes spanning around 15.5MB of ch 17q21-22, and they did this for almost 100 prostate cancer patients. In these exomes, each patient had around 12 novel variants, along with almost 700 already reported in dbSNP. Due to its occurrence in several patients and the role of HOXB13 as a transcription factor involved in prostate development, HOXB13 variant rs138213197(T) was identified. Based on a subsequent case-control study, where this SNP was seen in 72 of ~5,000 patients but in only 1 person out of 1400 controls, the researchers concluded that although the variant is clearly rare, it is recurrent. A carrier’s odds of developing prostate cancer are much higher - 10 to 20 fold - compared to a non-carrier’s risk. Since the publication of this finding early this year, already at least five other labs have confirmed the rs138213197 association with prostate cancer risk in independent populations, totaling over 20,000 patients. While the odds for increased risk are bit lower (ranging from 3 to 8 fold) in these studies, they remain far higher than for previously known markers.

In addition to its implications for prostate cancer diagnosis and treatment, the finding of a “rare but recurrent” variant with such a strong effect on cancer risk supports the concept that a significant fraction of the heritability of common diseases will indeed be due to quite rare variants. These variants will not have been detectable by GWAS studies (or the meta-analyses based on them, for that matter), but will now come to light thanks to exome and genome sequencing. Whether it is indeed due to our species population growth from a few million to 7 billion in just 400 generations or for other reasons (1), we each carry a different set of quite rare alleles with quite profound effects.

No comments: