Reacción a "Reactions: genomic evolution of lung cancer under scrutiny"

This study was based on prospective samples from patients with NSCLC (non-small cell lung cancer), from localised stages (lineages 1 and 2) and both tissue and blood samples were taken throughout the pathology in those patients who relapsed after surgery (lineage 3) and in those who relapsed after treatment (lineage 4). The study has collected tissue and blood samples, and molecular studies have been done at the genomic, transcriptomic and free tumour DNA circulating in blood level, comparing patients who have not relapsed with those who have relapsed, mainly to platinum-based therapy. In all cases, the clinical variables of response to treatment have focused on the study of patients' overall survival or disease-free survival (until relapse).  

The results are directed towards the genetic characterisation of the initial clones and subclones and those that subsequently prevail in metastases, in relation to tumour heterogeneity. They differentiate between early divergence metastases, which are those that appear before the priority clone has been established in the early tumour. Those that appear later or those that maintain characteristics of many clones are associated with poorer survival. They identify as early or truncal events those related to alterations in the MYC gene and alterations in the genes involved in the tyrosine kinase pathways, well known as activators of cell signalling pathways of survival in cancer, while the also well known alterations such as P53, KRAS are related to subclonal events and, therefore, with worse survival.  

Interestingly, these results seem to indicate that lymph node metastases do not appear to be a causal pathway for future recurrences, but rather a fingerprint to identify patients with a more aggressive tumour prognosis. 

At the transcriptomic study level, they identify alterations in the expression of specific transcripts of the same gene which, in cases where the origin of the alteration is not genetic (i.e. not due to copy number variations or similar alterations), are related to genes related to the epigenetic regulation machinery that affects DNA methylation and preferably histones. 

Regarding the alterations observed in metastases that appear or are maintained after receiving platinum-based treatment, they also confirm data previously reported in the literature, centred on the fact that these treatments produce drastic evolutions in tumours, the appearance of resistance and, therefore, greater heterogeneity.  

One of the strengths of these studies is the large sample size (421 patients) that allows access to tissue samples from second surgeries, which in most studies are so limited that they lack statistical power. In this study, we were able to sequence second surgeries from 48 patients out of the total number of patients recruited. Also the use of software and computer algorithms that allow to see the clonal marks in circulating tumour DNA of patients with localised tumours, in which these alterations are very poorly represented, since less than 1% of the circulating free DNA is of tumour origin in metastatic patients. They also report that in local tumours, early divergence metastases may already exist that can be confused with the initial primary tumour as these would have arisen when the diameter of the primary tumour was smaller (8 mm) than the threshold for CT detection, which could limit their use in the early detection of these metastases. On the other hand, the patterns of clonal alterations they carry could be the axis on which to follow up before a distal metastasis has implanted and, above all, to define treatments in untreated primary tumours.  

One of the weaknesses is that plastic alterations derived from epigenetic processes, especially those that occur after cancer treatments, are not considered. It is well known that chemotherapy treatments produce genome-wide alterations, such as loss of entire chromosome arms, which drastically affect tumour heterogeneity. However, these treatments are also associated with epigenetic alterations that affect DNA methylation and thus the silencing of numerous gene regions, and also affect non-coding RNAs such as miRNAs, which are post-transcriptional regulators of a very large number of messenger RNAs. It would also be of great interest to address in liquid biopsy the content of extracellular vesicles, a compartment that more closely reflects the characteristics of the tumour of origin than ctDNA (circulating tumour DNA).