We have been interested for many years in DNA damage repair defects in prostate cancer and we know that we can find some form of DNA damage repair defects in about 30% of patients with metastatic prostate cancer and a certain subset of those have germline defects in DNA damage repair genes. Now, there’s a gene called CDK12 which, when mutated in prostate cancer, leads to a really distinctive genotype...
We have been interested for many years in DNA damage repair defects in prostate cancer and we know that we can find some form of DNA damage repair defects in about 30% of patients with metastatic prostate cancer and a certain subset of those have germline defects in DNA damage repair genes. Now, there’s a gene called CDK12 which, when mutated in prostate cancer, leads to a really distinctive genotype. So, you see these duplications of pieces of chromosomes all across the genome. It looks like, on a copy number profile, like stalagmites growing up from a cave floor. And we used to think these were only somatic in origin, so they only arose in the cancer cells, but we’ve been interested in whether a component of them could actually be germline. So, we took a very large cohort of about four and a half thousand men with mostly metastatic prostate cancer; we teamed up with Colin Pritchard at the University of Washington to create this really large cohort. And we searched for germline CDK12 mutations. And, amazingly, we found five. So, five cases with truncating CDK12 germline mutations. And then, when we profiled their cancer, we can see that their cancers have a second CDK12 mutation in the cancer only. And then that distinctive copy number profile that indicates their disease is driven by CDK12. So, we’re seeing germline mutations and clearly CDK12-driven cancer. Now, it’s probably quite a rare predisposition syndrome overall, maybe 0.1% of all cases. But, at a global level, that’s still several hundred families a year potentially affected. And so, we think that we should be adding CDK12 to germline testing panels. We already screen a lot of other rare genes. We think that this should be now tested clinically in our patients because all of these patients had young-onset prostate cancer, metastatic at first diagnosis, and very aggressive disease. So, this is a really important cancer that we should be screening for as early as possible.
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