Our laboratory uses computational approaches to study the interaction between genetic variants in cancer genomes and multiple aspects of cancer, ranging from the immune response against tumors to the susceptibility of cancer cells to different treatments. In recent years we have developed several computational tools to identify which mutations are driving the transformation of healthy cells into malignant ones. To that end, we combined data from protein structures with the mutations of over 10.000 cancer genomes. We have also shown that there is a relationship between which mutations drive oncogenesis in a tumor and how the patient’s immune system responds against it. More recently, we have focused our efforts into deciphering the role of inherited genetic variations into cancer predisposition and immuno-oncology. In the near future, our main goal is to understand how these three things, inherited variants, acquired mutations and the immune system, interact with each other in cancer.
Over the last two decades there has been an explosion of, essentially, three types of big data in cancer research. We started by collecting germline genotypes from cancer patients and matching controls during the Genome Wide Association Studies era that started around 2005. Nowadays, public databases such as dbGaP store hundreds of thousands of germline genotypes of cancer patients, and we have identified over 2000 germline variants linked to some form of cancer. Similarly, since around 2010, there has been an exponential growth in the amount of publicly available somatic tumor genomes, which have provided exceptional insights into tumor evolution and oncogenic mechanisms driving cancer growth. Finally, over the last five years, thanks to the development of single cell sequencing technologies and medical breakthroughs such as immune checkpoint inhibitors, there is a growing appreciation for the role of the amount and composition of the cells in the tumor microenvironment.
So far, most of us have been studying these three different aspects of tumor immunobiology separately. For example, in my case I dedicated the majority of my career into studying the somatic cancer genome, whereas others did the same for germline variants or the tumor microenvironment. However, it is now evident that these three different aspects of cancer are inextricably interwoven and need to be studied together. We know, among others, that the immune system and the somatic genome interact with each other. For example, as explained above, I described how tumors with some somatic driver mutations tend to have certain types of immune cells in their tumor microenvironment. The germline and somatic genomes also interact with each other, as evidenced by the higher prevalence of specific driver mutations depending on the germline genetic background of the cancer patient. Finally, we have just submitted a manuscript describing how the immune response against cancer cells can be predicted using germline data, showing a connection between these two elements. In summary, it is time to move beyond the study of these elements on their own and start to understand this “Cancer Trialogue”.
La Caixa Junior Leader (2018)
Beatriu de Pinos fellowship (2017)