Cancer genomics of urothelial cancer and fibroepithelial tumors of the breast

Prof Bin Tean Teh - National Singapore Cancer Center, Singapore

Our interest has been Asian-centric cancer for obvious reasons because we are in the centre of Southeast Asia. The cancer that we study is actually the cancer of tumours that have higher incidence in Asia, in the region. The upper urinary tract or urothelial cancer is already known to be highly prevalent or at least has higher incidence in Taiwan and we have been collaborating with our colleagues in Taiwan to look at the genetic background of this particular type of cancer. For the second tumour type, which is the fibroepithelial tumours, again we also realised that for one particular type called phyllodes tumour there is a higher incidence, about sevenfold more common in Asian women as compared with Caucasian women.

Could you give us an overview of your research on urothelial cancer?

We have characterised and identified a mutation signature associated with a carcinogen called aristolochic acid, for short AA. That is found actually, or derived, from a herbal plant, so the plant species called Aristolochia. This plant is frequently used in the preparation of herbal medicine and used for different indications from cough suppression to slimming to gout, inflammation. So it was once widely used. Of course in many countries it’s now banned but still people can have access to some of these herbal medicines, some may be through the internet and some people are simply not aware of it because usually in herbal medicine people don’t know the detailed components that are contained in the herbal medicine.

So we identified this particular, very peculiar and unique mutation signature. So, for example, this carcinogen always causes change of A to T, the nucleotide, and you see a massive… lots of these changes in the tumours that are associated with this carcinogen. So in a way we can use this approach to screen for exposure to this carcinogen in other cancer types because still we don’t know enough how much and how prevalent this problem is.

What is the significance of the discovery of the aristolochic acid (AA) molecular fingerprint?

One thing is that until the study it was not known to be associated with liver cancer, which is a very common and deadly cancer, particularly in Asia. Now we’ve found that probably 10% of liver cancer from southern China and Taiwan are probably associated with AA. Another thing is that it may also be involved in a subset of liver cancer even in the rest because not only Asian or Chinese take herbal medicine, some Caucasian people may also take the herbal medicine.

Could you highlight some of the research that you have undertaken in fibroepithelial tumours of the breast?

Fibroepithelial tumour is considerably under-studied so its genetic background was not known. So we are very lucky to identify a particular gene called MED12 that is frequently mutated in one subtype of fibroepithelial tumours called fibroadenoma. This is a benign tumour but is very common, it occurs in probably 1 in 10 young women. It is benign but still quite a lot of people undergo surgery just to remove them. Obviously from the scientific point of view it is very interesting to find out what actually causes them, what caused it. We know that it is hormone independent and I think very few people think of a genetic alteration. Now we have found this gene that is very frequently mutated, up to 80%.

What is the significance of your findings?

The follow-up study we actually have characterised a set of genes that seem to be able to push this benign tumour into a more aggressive entity and the end of the spectrum is a type of tumour we call malignant phyllodes tumour, it’s actually a cancer. As I said, it’s much less common than the conventional breast cancer but still with this set of genes we always need to identify the patients with breast lumps that may have potential to develop into a malignancy. But I don’t want to scare people, it’s still not a very common problem but at least we now have a genetic tool to be able to tell which benign tumour may have this potential to develop into a tumour.

Could the exon 2 MED12 gene mutation be as significant as the BRCA mutation?

The BRCA, obviously, for breast cancer which is a much more common entity. First of all we found that the genetic alterations of fibroepithelial tumours are very different from the genetic alterations found in breast cancer. So clearly they are a distinct entity, yes.

What’s the take-home message from your presentation?

What I want to say is that there are going to be more and more cancer cases in many regions, especially in Asia. A lot of them still need to be studied because of the difference in ethnicity, environment, diet. There could be a lot of interesting findings that we’re going to obtain from these studies. Our study is not just to… sure, it will help us to understand the biology of these cancers from the scientific point of view but it will also help us to understand the biology of cancer as a whole, including tumours from the West. So I think breast fibroadenoma is probably a very good example because it is a very common problem both in the Asian population and Caucasian population. The difference is the phyllodes tumour that is much more common in Asian women compared with Caucasian women.