AACR 102nd Annual Meeting, 2—6 April 2011, Orlando, Florida

Cancer causing gene fusion in prostate cancer

Professor Arul Chinnaiyan – University of Michigan Medical School, USA

Dr Chinnaiyan, you’ve been just addressing this august meeting here at the American Association for Cancer Research on a new idea, really, it’s gene rearrangements rather than gene mutations being centre stage, so to speak, in cancer formation. Can you tell me what it was you were presenting here?

Yes, we discovered that a percentage of patients with metastatic prostate cancer harboured this gene fusion or rearrangement in this pretty well-known cancer gene called KRAS which previously was thought to be associated with point mutations but in our particular study it suggests that gene fusions or rearrangements are involved.

What is the difference between a gene fusion or rearrangement as compared with a mutation?

A mutation is essentially where you change the base coding while a gene fusion is where you actually rearrange parts of the genome, so different genes come together which shouldn’t be together.

And what kind of effect would that have, theoretically?

The greatest example of that is a BCR/ABL gene fusion which many people know which is associated with chronic myeloid leukaemia, that’s the driving gene fusion for that particular disease. So in that particular case, that is the cancer-causing or oncogenic gene, so that is what we believe we’ve identified in prostate cancer as well, a cancer-causing gene fusion like BCR/ABL in chronic myeloid leukaemia.

And that’s in the UBE2L3 gene?

It’s the UBE2L3 gene fused to KRAS, so two different genes which are in different parts of the human genome, coming together creating this chimeric gene.

So it’s an alternative mechanism for activating KRAS, making it into a cancer forming gene?

Right, it’s a different mechanism than what’s been classically associated with KRAS base substitution, for example, in pancreatic cancer, lung cancer and colon cancer, but in prostate cancer we basically identify this gene rearrangement event is causing activation of the KRAS oncogene.

What might it tell you that’s new about prostate cancer?

It suggests that prostate cancers have different biological behaviour that might be associated with the different types of molecular lesions that cause them. So the fusions that we identified in this particular study with KRAS suggested that that particular fusion might be a more aggressive form of prostate cancer because we identified them exclusively in metastatic prostate cancer.

So you’ve got a subgroup of patients who might get a different treatment?

Exactly, they might get a different treatment and be associated with a different prognosis. So potentially a more aggressive treatment or, if we can find ways of blocking the KRAS pathway, they might be amenable to KRAS based drug treatments.

Of course, there are dilemmas in treating prostate cancer because it can be very aggressive, it can, on the other hand, be very benign and you could easily do more harm than good. Could this help?

Yes, I think that one of our thoughts is that in the future we will be able to molecularly subtype prostate cancer patients, identify those that have the more aggressive molecular alterations, like these gene fusions of KRAS and those that have more indolent mutations that might not require treatment.

So have you got a handle on prognosis and also prediction of how treatments will work, do you think, a clear one?

I would say that these are early days of sequencing the prostate cancer genome, so we’re still learning about what all of the different players are and the types of mutations that patients get, but we’re just understanding the road map. So in the future I think we’ll be able to link that with therapy.

How big a cause of cancer could rearrangements be, as compared with mutations, do you think?

I would say in prostate cancer it is a major cause of prostate cancer, probably in the order of 60-70%, if not all of prostate cancer, we believe is actually a rearrangement based disease because very few point mutations have really been identified as being driving mutations in prostate cancer. That may be different for other common solid tumours but certainly for prostate cancer, as well as hematologic malignancies and rare soft tissue tumours, they have been defined as rearrangement based diseases.

Does this new understanding help doctors right now, do you think, in any way?

I would say that it does not necessarily help doctors right now today but in the future the prediction is that these patients, if they were typed, would be predicted to have a more aggressive form of prostate cancer, so theoretically being treated differently.

And could that subtyping be done reasonably efficiently in the hospital or clinic?

I believe in the next five to ten years we should have tests that should much more easily detect these mutations.

Well, you’ve just published on this very exciting new discovery, what’s the take home message? What’s the bottom line, how would you summarise this?

I would say that there is a rare subset of prostate cancers that are potentially caused by rearrangements of KRAS and those prostate cancer patients likely have a more aggressive course, but this is again early days.

Dr Arul Chinnaiyan, thank you very much for joining us here on ecancer.tv.

Thank you very much.