The largest map of lung cancer puts the focus on tumor diversity

He cancer Lung is a heterogeneous disease, no two tumors are the same, and understanding this variety is key to fine-tuning the prognosis of patients and treatments. Now, more than 300 scientists have achieved the most comprehensive analysis of the genomic evolution of this cancer.

In seven articles published in the journals Nature and Nature Medicine, the researchers, grouped in the British TRACERx project, publish the details of this map made thanks to the sequence of 1,644 samples from 421 patients, which confirms that cancer progression is mediated by intratumoral heterogeneity.

The program, which began in 2014, today presents the conclusions of half of the patients recruited, which help explain why treatments sometimes stop working or why the tumor metastasizes in some cases.

The final objective of the project is to understand how this tumor diversity is generated and how it affects it at the clinical level, as well as how to exploit this knowledge for prevention or to generate therapies.

Lung cancer is the leading cause of cancer death worldwide, and although knowledge of it has advanced greatly in recent years, a full understanding of the biological mechanisms underlying the disease is still lacking.

In general, it is grouped into two types: small cell or microcytic lung cancer and non-small cell cancer, the most frequent and the subject -in three different stages- of this analysis. In turn, the latter is divided into several types depending on the cells affected.

Thus, of the 421 patients (188 women) included, with a mean age of 69 years and a total of 432 tumors, 248 developed the adenocarcinoma subtype, 138 squamous cell carcinoma, and 46 other subtypes.

Several samples were obtained from all of them after surgery, extracting different genetic material (both DNA and RNA), as well as images by computed tomography or microscopy, and the patients were followed up for years. The researchers obtained information from various regions -fragments- of the tumor.

Tumor heterogeneity versus cancer evolution

The main article is led by Charles Swanton, from the Francis Crick Institute in London, who also authored other works. In it, the authors identify, among other things, the patterns of intratumoral heterogeneity associated with the evolution of the patients.

Lung cancer is an evolving disease, in which tumor cell populations or clones can adapt to the environment and become resistant to drugs; “the fuel” This adaptability is due to the diversity of each tumor, explained to EFE Carlos Martínez-Ruiz, from the Cancer Institute of University College London, and another of the signatories.

And it is that, he details, tumors are made up of several populations of cells that are not homogeneous, that are differentiated by changes in their genetic code: they have seen that diversity at the level of large changes in intratumoral genetic material has a very strong impact on the prognosis (likelihood of metastasis/recurrence) of the patient.

Another lesson learned from this map is that there are small populations of cells that expand as the tumor evolves, cells with a large number of mutations that give the tumor an advantage in that it reproduces faster.

There are patients who present from the beginning of their evolution mutations in all the cells of the tumor, which are relevant to understand the biology and define the clinical treatment. However, there are cases where the mutations are not in all cells.

These works confirm that these can arise later in specific cell populations, leading to their expansion and giving them an advantage. It is these populations that usually generate metastases, points out the Spanish biologist and bioinformatician, who adds that this is relevant at a clinical level. “If we want personalized therapies, these studies say that we must focus on these cell populations,” he underlines.

Although Martínez-Ruiz signs all seven articles, he leads the one that talks about the importance of RNA in the development of this cancer.

Most of the work on the evolution of tumors and personalized medicine, he says, is based on DNA -instructions necessary to produce and maintain cells- and less on RNA -the way the cell reads those instructions to put them into practice-.

“We have seen that there are changes in RNA that are independent of those in DNA and that are maintained from the primary tumor to metastasis”summarizes the scientist: these are important modifications for the evolution of the tumor and, although the finding does not yet have clinical implications, it does represent a first step to know that this nucleic acid must be taken into account in the prognosis of lung cancer and future therapies .

In addition, thanks to machine learning and combining information from DNA and RNA, the researchers were able to predict in which region of the tumor metastasis would be most likely to occur, which would also favor the possibility of achieving more personalized therapies.

liquid biopsy

Another article describes a tool based on liquid biopsy and bioinformatics capable of detecting traces of circulating tumor DNA -present in the blood-, which could help determine the metastatic potential of the cancer and identify factors that can predict which part of the tumor may be responsible. of the recurrence

In addition, early evolution metastasis is also addressed -in some cases there are tumors that metastasize before being diagnosed- and cachexia, the loss of muscle and fat mass.

The seven articles expose novelties, but also develop and corroborate previous results. “What this analysis does very well is take the information already known, put it together and associate it”points out Martínez-Ruiz.

This advanced map of lung cancer, whose data will be available to the scientific community, can be crossed with other databases. “Many times there is molecular, clinical or metastasis information, but now we have everything together and supervised”concludes the Spanish researcher.

Source: EFE