A bit of progress in understanding prostate cancer genetics

The genetics of prostate cancer has proven surprisingly difficult to unravel. Family history has long been known as a prostate cancer risk, and, through GWAS more than 30 SNPs have been identified that are linked to prostate cancer risk. However, the magnitude of risk elevation attributed to each individual SNP is low, and these SNPs in aggregate account for only an estimated one-quarter of familial risk. Thus, our genetic understanding of prostate cancer has not translated into clinically useful information. This situation stands in stark contrast to that for breast and ovarian cancer, where a minority of cases result from the inheritance of highly penetrant mutations in BRCA1/2 and testing for such mutations has become the standard of care for a significant minority of breast cancer patients.

However, some progress has been made, as recently reported by Ewing et al. in the New England Journal of Medicine (2012;366:141–149). In a large multicenter study, the authors examined a region on chromosome 17q21–22 that had previously been identified as a possible location of a prostate cancer–susceptibility gene. The authors screened more than 200 genes in this region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families with linkage to the candidate region. Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13, a homeobox transcription factor gene known to play a role in prostate development.

The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5,083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1,401 control subjects (0.1%), a highly statistically significant result. The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) and appears to increase risk by 10- to 20-fold.

The recurrent nature of the G84E change and a reported lack of any truncating mutations in HOXB13 in patients with prostate cancer suggest a carcinogenic mechanism that is more consistent with a gain of function (oncogene) than with a loss of function (tumor-suppressor gene).

Thus, although this mutation appears to be relatively rare, a long-sought highly penetrant prostate cancer mutation appears to have finally been identified. Although the variant accounts for a small fraction of all prostate cancers, this finding may have clinical utility in the analysis and counseling of families with early-onset prostate cancer and may provide new mechanistic insights into this common cancer.

Richard King Trainee Award winner for 2011

In our field’s well-justified excitement over advances in genomic sequencing, it’s easy to forget that other fundamental aspects of genomic structure remain critical to understand. One such basic—and often overlooked—issue is determining the cis-trans relationships of alleles.

It is in this context that we are delighted to announce that the winner of our annual trainee award is Neng Chen, PhD, Stanford University School of Medicine, Stanford, California, who coauthored “Allelic Discrimination of cis-trans Relationships by Digital Polymerase Chain Reaction: GJB2 (p.V27I/p.E114G) and CFTR (p.R117H/5T),” published in the December 2011 issue of GIM. In this article, the authors detail a novel method for determining the cis-trans status of alleles in two important clinical contexts: cystic fibrosis and deafness. Importantly, the approach that they describe holds promise for more general application as it does not fully depend on the specific nucleotide changes, enabling efficient assay design and practical implementation of allelic discrimination.

Through a gift from the ACMG Foundation, Dr Chen was awarded $1,000 as well as travel, hotel, and registration costs to attend the Annual ACMG Meeting in 2012.

A Call to Trainees!

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The Annual Richard King Trainee Award for Best Publication

In order to encourage genetics trainees in their professional development, Genetics in Medicine and The American College of Medical Genetics Foundation have an annual award recognizing an outstanding research publication by an ABMG trainee. The award consists of $1,000 cash prize to the recipient as well as travel, hotel and registration costs for the annual ACMG meeting that year. Eligible individuals are ABMG trainees who have been first author or corresponding author on a paper published the preceding calendar year in Genetics in Medicine.

Eligible trainees include those in the following programs: Medical Genetics (MDs) Combined Internal Medicine/Genetics Combined Pediatrics/Genetics Combined OBGYN/Genetics Clinical Biochemical Genetics Clinical Cytogenetics Clinical Molecular Genetics Subspecialty-Medical Biochemical Genetics Subspecialty-Molecular Genetic Pathology

Eligible trainees should identify themselves upon submission of manuscripts to Genetics in Medicine. Original research, brief reports and educational reports are eligible categories, but other categories, such as review articles, are not. The editorial board of Genetics in Medicine will determine the winning trainee and presentation of the award will be made each year at the American College of Medical Genetics Annual Meeting.