CHIP clones in solid tumours: therapeutic targets or bystander phenomena?

Clonal haematopoiesis of indeterminate potential (CHIP) is a premalignant condition that is characterised by the detection of somatic mutations in typical leukaemia-driving genes in individuals without overt haematologic malignancies. An age-dependent condition, CHIP is highly prevalent in older individuals. Unanticipated findings from studies also revealed that CHIP was associated with a non-leukaemia-associated shorter survival compared with individuals without CHIP. These results really fuelled interest in the impact of CHIP on the outcomes of patients with a range of different diseases, including solid tumours.

In 2017, a study reported high incidences of CHIP (approximately 25%) in patients with solid tumours and that this incidence increased with age, reaching around 40% in patients between 70 and 80 years old (Cell Stem Cell 2017;21(3):374-382.e4). The authors also noted differences in the mutation profiles of CHIP in individuals with solid tumours as compared to the general population. CHIP is generally heavily dominated by mutations in epigenetic modifiers, such as DNMT3A and TET2, with only rare observations of mutations in DNA-damage repair pathway genes. However, in patients with solid tumours, there was a much higher representation of mutations in DNA-damage repair pathways such as PPM1D, TP53, ATM and CHEK2. The most likely reason for this is that the exposure of patients with solid tumours to chemotherapy and/or radiotherapy – around 70% in the study – provided selective pressure for DNA-damage repair pathway gene mutations. In common with earlier studies, the findings in patients with solid tumours showed that those with CHIP had worse survival than those without CHIP. Among a number of potential reasons for this finding, there are two compelling suggestions. One, and the most exciting from a treatment point of view, is that there is a mechanistic link through which a mutated blood-cell clone is able to exert a tumour-promoting influence on the concomitant solid tumour cells. This possibility is one that is actively being investigated by a number of research groups. An alternative explanation could be that the expanded CHIP clone is simply a surrogate biomarker that reflects the extent of anticancer pre-treatment with DNA-damaging agents and, by association, the aggressiveness of the solid tumour. Determining which of these scenarios is the correct one is hugely important because it could lead to different clinical management strategies for patients with solid tumours, depending on whether or not they have a concomitant CHIP clone.

In this context, the trial described at the Molecular Analysis for Precision Oncology Virtual Congress 2021 (Abstract 83TiP) – which aims to evaluate the prevalence and type of CHIP mutations in patients with solid tumours, and their influence on survival – could provide invaluable data. Matched tumour tissue, peripheral blood cells and multiple time‐point cell-free DNA (cfDNA) samples for longitudinal monitoring will be collected from patients diagnosed with solid malignant tumours at a single centre in Romania. Probably the most exciting aspect of this trial is that it is prospective. This means that patients will not have received the type of anticancer treatment that can hinder the interpretation of CHIP clones on outcome. And the data it provides could really help to clarify whether CHIP directly influences survival, and so is a potentially useful treatment target, or whether it is merely a bystander phenomenon. However, the utility of CHIP clones to help select treatment may still be some time away. Right now, the most important clinical relevance of CHIP is that it can confound the findings and validity of cfDNA and liquid biopsies and could lead to inappropriate treatment decisions, particularly if some of the CHIP mutations, such as TP53, are shared with the solid tumours. This issue is also being addressed by the trial described at MAP Virtual 2021, which is planning to evaluate the impact of identifying CHIP-related mutations on the interpretation of liquid biopsy in the clinical setting.

Further research will add to the accumulating bank of knowledge that will help us to determine whether CHIP has any future as a potential therapeutic target for patients with solid tumours.