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Carla Daniela Robles-Espinoza is an associate professor of the International laboratory for Human Genome Research, National Autonomous University of Mexico and an International Fellow at the Wellcome Sanger Institute UK. She studied a BSc in Genome Sciences at the National Autonomous University of Mexico, followed by a PhD in cancer genetics at the University of Cambridge, UK. Her research focuses on using large scale sequencing data for investigating the driver alterations, risk factors, and potential therapeutic targets of types of cancer important in Mexico and Latin America, such as acral lentiginous melanoma, and hepatocellular carcinoma. She is a Newton Advanced Fellow, Academy of Medical Sciences UK, and has received the Christopher Marshall award at the Society for Melanoma Research USA, and Scholar Award at the Fullbeck Research Foundation, USA.

For world cancer day 2023 we interviewed Carla Daniela Robles-Espinoza to explore her research into acral melanoma and learn how studies like this can help to close the care gap for lesser researched diseases.

Your career path has definitely involved a lot of passion, tenacity and networking. Could you tell us a bit more about your journey to date and what led you into cancer genetics?

Since I was young, I’d always liked biology, maths, computer programming, all of those things in high school.Then I had very good luck when I was in second year of my high school education and this new degree opened here at the National University of Mexico, which was genomics, one of the first programmes in the world just focused on genomics. While I was there, I had the opportunity of doing several internships in different labs, and one of the last ones I did was in a cancer lab. So I started emailing people in other places that were doing interesting research in cancer genomics.

Can you tell us a bit more about this and why you're specifically interested in melanoma?

A clinician from the University of Leeds approached us with a problem and she said, ‘I have all these patients and their families with melanoma, and we don't know why they have melanoma. We know they're at an increased risk, because they have a higher prevalence of the disease in these families than you find overall in the general population, but we don't know why. Because they don't have any of the barriers to genetic variants that we know are high risk for melanoma. We want to solve this problem, and you guys are genomic scientists, can you help us?’
I took on this project which had just over 100 exome sequences from different family members with unknown causes, and basically tried to identify why they had increased risk for melanoma, the characteristics of the cell of origin the melanocyte, its functions, how it produces melanin to protect all their cells against UV damage, how it's very resistant to UV damage itself because of its biological function, its embryonic origin etc. All of these became really interesting to me.

Within this field, you've been involved in some high profile research papers, including being the first author of a major publication that led to changes in gene panels for melanoma through your PhD. Could you tell us a bit more about that work and the impact of it?

We studied the exomes of more than 100 families that had melanoma with unknown cause, and because of the amount of families and the amount of sequences that we had, we were able to find new genetic variants that correlated with the segregation of the disease in these families. Very strikingly to us, these variants were all in a single gene called POT1 (Protection Of Telomeres One), and this gene is part of a complex called the sheltering complex that functions to safeguard the ends of chromosomes.

Since humans, other mammals, nonbacterial beings etc have linear chromosomes, we need a mechanism to protect them from being recognised as sites of DNA damage because chromosomes can be caught in the middle and they have to be repaired. The POT1 gene produces a protein that is part of a complex that tells the cell, ‘this is where the chromosome ends.’.
Now, the variants in these families basically stopped this protein from binding the DNA, and that led to these people having much longer telomeres compared to the normal population levels. Another group at the same time as us also studied other different families with these variants, and they also found that they not only had longer telomeres, but also they were damaged. This means that those cells may be dividing more, because if you have longer telomeres, then you have a longer cell life. So that could be a chance to accumulate more mutations. Also, because the chromosomes are unprotected and they may be recognised as the site of DNA damage in the cell, the repair machinery may try to repair those ends, possibly by putting another chromosome there, for example. This would then affect the segregation of chromosomes when the cell divides. All of those mechanisms can lead to cancer. That was striking, because it was a single gene, but all these families had different variants and all those variants basically had the same consequence, which meant the protein couldn't bind DNA, they had longer and protected telomeres and therefore an increased risk of cancer.
We found these in melanoma because we were studying melanoma patients, but then subsequently, it was also described for other types of cancer: leukemias, lymphomas, cardiac angiosarcomas and since then it's been recognised as a multi cancer syndrome. So due to all of this other subsequent research it's now included in some gene panels for families that are cancer prone.

I’m quite intrigued about the gene panels, what does that mean? Is there anything that can be done if that shows up on a gene panel? Is it risk prediction and what is the consequence of this showing up on the panel?

So far, it can only be for genetic counselling, for example, and for giving peace of mind to the patients that have these cancers running in their families, and they want to know the cause. So far, at least as far as I know, there's not much that can be done when you have a germline factor like this one, because it’s in all cells. What the patient can do if they are found to have these variants, at least in the context of melanoma, is regularly visit their dermatologist and have all moles, for example, checked to see if they have changed shape or colour, and thorough scans very frequently, just in case there's something that has changed and needs to be extracted. Of course, that melanoma needs to be visible, for the most part, but in other types of cancer which these genes also increase the risk for, it is more complicated than that.

Can you tell us a bit more about your transition from research into the UK to your current research in Mexico?

I came to Mexico about 10 years ago now. I started talking to medical doctors and oncologists here to ask them, ‘What are the problems that you see here?’, because it's very different doing research here than, for example, in the UK. There's actually not a lot of literature here about the problems here, each hospital, each state will have their own cancer registries. It's a bit more complicated to research exactly what the problems may be. Talking to medical doctors and oncologists, they said, ‘In Mexico, the most common type of melanoma seems to be a different subtype known as Acral Melanoma.’

Melanoma, as with many other types of cancer, can be subdivided into subtypes. For example, in countries such as the UK, the US and Australia that have a high proportion of light skinned individuals, and where there is economic power, because that's important too, they develop mostly melanomas induced by UV light. This is due to light skin (not a lot of melanin) and also, because of the economic advantage, which allows them to travel to places where they can get a lot of sunlight exposure, like a beach holiday. These people may have a very outdoor lifestyle like in Australia, therefore melanoma incidence in this country is actually high.

On the other hand, in countries like Mexico, the situation is very different. People are darker skinned generally and also it’s not that common for people to travel for holidays and just spend money to go to the beach. Within the country you can see that because the high income populations tend to be lighter skinned, and they tend to go to the beach they tend to get these types of melanoma as well. Although that mirrors what happens in other countries, Mexico actually has a higher incidence of a melanoma that is not UV related, Acral melanoma.

Acral melanoma arises in the palms of the hands, the soles of the feet and under the nails. The causes are unknown at the moment, and this is one of the reasons we study it. We know it’s not related to UV light. We know that because of mutational signatures and also because those parts of the body are not exposed to the sun. In most hospitals Acral melanoma constitutes a higher proportion of cases than any other subtype of melanoma, not only in Mexico but in other countries in Latin America, plus in Africa and Asia as well.

Acral melanoma is not very common in the UK or Australia, where the great majority of cases are UV light related, and due to this, it’s not actually being that studied. Not only do we not know the causes of this disease, but also, we don't know what's the best treatment for these patients. At the genomic level, the genomes of these two types of melanoma look very, very different. They look almost like two completely different diseases. Sometimes, the treatments don't work as well for acral melanoma patients as they work for the cutaneous melanoma patients. I've started talking to other collaborators across Latin America, and we're trying to build a collection of samples for people to hear from patients here to try and characterise this.

Is it quite an aggressive form? And how urgently do we need solutions to this type of melanoma?

Many of the patients that arrive with this type of melanoma actually have gone through several other diagnoses before. This type of cancer is rare, and it can look like other, more common diseases, for example, diabetic feet, ulcers, or fungal infections. So because those things are much more common, they tend to be diagnosed with one or more of these, rather than cancer. When patients actually get diagnosed with acral melanoma, they are usually at a later stage. My collaborators in Europe ask sometimes ‘How has this happened?’ and these patients have actually sought help, but they got diagnosed with something else and they were treated as something else before actually arriving to the correct diagnosis. This makes this question harder to answer. Is it more aggressive? It's harder to compare something that is already advanced.

Cutaneous melanomas are usually diagnosed super early because they have these new instruments like a dermascope and it's very visible on the skin and people tend to check their moles. Some speculate that it actually is more aggressive, even if you control for the stage of diagnosis, but I still think the data may not be conclusive yet. What is real is that because of all these other factors, it can be social factors, education factors, there is a need to find treatments and effective therapies.

The first time I saw you speak was at a mutational signatures virtual conference, in December 2021. I was really struck by a particular slide where you were showing the inequity and inequality in datasets that had a real bias towards European ancestry. I'd been aware of it in the background, but when I saw that slide, it's the first time I’d seen an example of that where the data is really clearly biassed towards certain populations. I'd love to know more about your take on this problem and the scope of it?

I think now people are paying more attention to it. I think it’s a real problem, because different people in different parts of the world will have different frequencies of variants that may be disease predisposing, and they may have higher incidence of certain diseases, just because of their genomes.

It's not only ancestry, it's also the environment, and if we only sample people from certain specific parts of the world, you're missing out on not only analysing these genetic diversity, but also the interaction with certain specific environments. It's been seen that cancer patients in different parts of the world have different genomic profiles, for example in lung cancer where the rate of mutation of EGFR is actually higher in Asian populations than in other populations. That doesn't necessarily mean it's related to ancestry per se, but it's related to the specific environment and genetic profile of these people. In many cases, we're not including these people, for many reasons. For example I can see here in Mexico that it's actually very hard to obtain samples, people have their own priorities. Understandably, medical doctors are trying to find new treatments but even very basic research just on samples becomes very complicated. We need to make an effort to include other patients that are not currently benefiting as much.

As you were saying, it will take a while for us to even out representation within these datasets. What is your opinion on the impact transparency from databases regarding their representation could have in the short term?

At the beginning this would only help us to know more about, for example, why there could be certain rates of mutations in certain places. I think it's going to be a lot more effort to actually do something. We can think about solutions maybe, but the socio-economic factor is very important to think of. We need to understand how other populations are behaving. That's just the first step I think and to be honest, I'm not sure exactly how to continue this work, because of the many other factors that come into play.

What role do you think should COSMIC be playing in trying to do this, and what sort of ownership should we have? Should there be one centralised resource, or should it be split up into different resources in different countries, for example?

I think COSMIC is great. In my work as a bioinformatician I use several of the resources within COSMIC, mostly the gene sets, because when we are studying these new exomes from this cancer, for example, we have a lot of genes, so we want to know which ones we focus on. So the ranking of genes in COSMIC as tier one, tier two etc is a great resource, for the discovery phase, for us. Mutational signatures is the thing that I've been using the most recently. I have gone into, for example, the cell lines part of COSMIC, and this does have the ethnicity of the cell line marked, which I think is a great first step. I think it's a good start that that has been catalogued, and I think that as long as we can ensure that everyone has access to it and can use the data in their publications, maybe just a little bit more information about a patient’s exposures or where they’re may help find these patterns. I know it's hard to include all of this, but so far, I think it’s a great resource.

I'm very interested to know about how the research ecosystem differs between Mexico and the UK. Where do you currently face different challenges? Are there new opportunities that you wouldn't have had here in the UK?

I have had the opportunity to collect a big set of samples, and I think a big reason is because I'm here, and people want to study together in Mexico and Latin America. So that's an opportunity that I don't think I would have had, or it would be much harder if I was abroad. Also, one of the most important things, at least for me, is that I have the opportunity to train people here. Having the opportunity to come back with what I learned after six years in the UK, and just, you know, teach a course here in the undergrad programme and have students come to do their PhDs and postdocs, and be able to share that with them here, to me, that's the best thing that could happen here. I can also see that many other people that have come back to Mexico recently to start groups and brought more knowledge from abroad, and people now want to stay. Being able to study our own population, with our own people collaborating, of course, with scientists abroad is very important and very enriching. Of course, currently, at least in my case, the funds still come from outside. The ideal thing to me would be to do everything nationally, but the situation is complicated at the moment. The research agenda and the people that are involved, the medical doctors are mostly locals, and that's important for us because at least we can agree on what the most important problems are.

If there's anyone else listening who wants to do something similar for where they're based, is there any advice you give or any kind of pitfalls to look out for?

Things run slowly. So to give some sense of what I mean, I've been here seven years now, and we still haven't got any papers out of this research yet. We hope to very soon, because now we have the data but it's taking all this time to just build the resource. In many cases, when you arrive in these countries or these research environments, it's not already set up like in other countries. Collaborations between clinicians and researchers may in many cases not be there yet, you have to set it up. You can look for funding opportunities abroad. Mexico and many middle income countries are eligible for funding, for example, from Wellcome and several other funding agencies in Europe, in the UK, in the US etc. That can also help to just get your project started. Obviously, building the research team is also very time consuming, but hopefully that also stays for life. The collaborators you find, they’re interested, and hopefully they stay there for a long time and help you with your research. If you have collaborators abroad, ask them for advice. I asked a lot of advice from a lot of people that had already done this in the UK. Some people say, ‘Nothing that is worth doing is easy.’

I think that's great advice! I was wondering, if you'd be able to give us a little bit of a sneak peek into what kind of results you're finding or maybe how you hope to use the data in the future?

We have finally been able to get a lot of data from these tumours, in the end we collected nearly 200. Of course, we lost some in the quality control, but we were able to have a big collection of tumours of this specific and rare subtype.

So far, it does look similar to other genomic profiles from this type of melanoma, but we now have something that looks like a new driver. We're still not sure if it’s a new driver yet, because there are many things that we need to take into account like contamination rates in the sample, or why these samples have certain characteristics like more mutations. We have to ask is this real? Or is this an artefact? So we're still trying to solve that. But if this is confirmed, we would have found a new driver that has not been seen in other cohorts.

We're also finding certain correlations of genomic alterations with clinical characteristics of patients. For example, we have seen that patients that have a somatic mutation in the NRAS driver tend to be younger at diagnosis, which is interesting to us because in cutaneous melanoma, it's actually the BRAF mutated patients that are younger. We are finding new gene fusions as well at the transcriptome level for these. I don't have a lot of very specific information yet, but at least so far, it looks similar overall, but we may have some interesting differences to study between the cohorts that are already published.

We’re working together with the group of Dr. Patricia Possik, in Brazil, in Rio de Janeiro. Her and her team have collected many samples from the same type of melanoma from Brazilian patients, so I'm optimistic that next year, all of this information can finally come out.

So when you have results from something like this, is that something that you hope or you feel would be appropriate to be hosted in somewhere like COSMIC? How could we be collaborating with you more effectively to make sure your data ends up in our database?

I think so. We will try to deposit this data in the biggest repositories where it can be compared with other samples.We're also going to try and characterise some cell lines from this type of cancer. Getting the cell lines is hard as they require very special conditions, but that could also be useful for COSMIC. I don't think there are many cell lines of this type of cancer or of these ancestries, but we will definitely be interested in including the data in large databases. That can only maximise the usefulness of this data for the community.

What are you hoping to achieve in the long term with this research?

My goal really, is to try and make a difference in treatment of patients here and to advance the knowledge internationally of the possibilities of treatment for patients here. That means I'm not only trying to study melanoma, but as part of this bigger goal, I recognise that there are other more important/ pressing health issues in Mexico. For example chronic liver disease and obesity, these diseases are very prevalent here, so we’re also trying to start studying them. With tools and resources such as big databases, and being able to establish relationships with clinicians and medical doctors, we can hopefully also make a difference in those important health issues that we have here in Mexico. I'm really interested in helping train the next generation of scientists here to show them that they can do good research here. There may be challenges, but also a lot of rewards that maybe they wouldn't get somewhere else. I want young students to know that if they want to, they can stay here and make a difference here, which I think it's very needed at the moment.

I think that is a very inspiring point to end on, thank you so much for joining us!