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Tumour-Infiltrating Clonal Haematopoiesis Increases the Risk of Recurrence or Death Among Patients with NSCLC and the Risk of Death From Any Cause Among Patients with Solid Tumours

Findings from the analysis of TRACERx and MSK-IMPACT studies
07 May 2025
Translational Research
Non-Small Cell Lung Cancer

Characterisation of clonal haematopoiesis of indeterminate potential (CHIP) and tumour-infiltrating clonal haematopoiesis (TI-CH) in patients with early-stage non–small-cell lung cancer (NSCLC) from the TRACERx study and in patients from the MSK-IMPACT pan-cancer cohort revealed that TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumours.

TI-CH remodelled the tumour immune microenvironment and accelerated tumour organoid growth, findings that support a role for an aging-related haematologic clonal proliferation in cancer evolution according to Dr. Charles Swanton of the Francis Crick Institute and University College London Hospitals in London, UK, Dr. Elsa  Bernard of the Gustave Roussy in Villejuif, France and colleagues, who published the findings on 23 April 2025 in The New England Journal of Medicine.

CHIP is a prevalent age-associated condition involving the expansion of blood cells derived from a somatically mutated haematopoietic stem cell without haematologic disorders. CHIP increases the risk of haematologic malignancies and chronic inflammatory diseases. CHIP is also associated with an increased incidence of lung cancer as well as an increased risk of death among patients with solid tumours. CHIP mutations with high variant-allele frequencies (VAFs) can be detected in tumours, a phenomenon termed TI-CH. The frequency of TI-CH and its effect on tumour evolution are unclear, the authors wrote in the background.

In this analysis, the authors defined the presence of CHIP mutations with high VAFs within tumours as TI-CH. They determined the prevalence of TI-CH in 421 patients with early-stage NSCLC from the TRACERx study and 49,351 patients across 75 cancer types from a real-world MSK-IMPACT cohort, studied its associations with patient outcomes in terms of survival and disease recurrence, and evaluated its functional effect using preclinical models of lung cancer.

Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio (HR) of 1.80 (95% confidence interval [CI] 1.23 to 2.63) as compared with the absence of CHIP and an adjusted HR of 1.62 (95% CI 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumours, 26% of those with CHIP had TI-CH.

TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumour cells, fuelled a myeloid-rich tumour microenvironment in mice, and resulted in the promotion of tumour organoid growth.

The authors commented that the age-associated TI-CH emerges as an important facet influencing cancer progression. The associations between TI-CH and adverse outcomes, the increased odds of TI-CH with TET2-mutated CHIP, and the effect of TET2-mutated immune cells on the tumour microenvironment and cancer cell growth support the role of TI-CH in tumour evolution and its potential usefulness in cancer diagnostics. Future studies should evaluate these findings in larger and more ethnically diverse cohorts of patients with cancer and further interrogate the functional effect of TI-CH on tumour progression.

The ability of age-associated somatic clonal expansions in one tissue, such as the haematopoietic compartment, to regulate malignant progression in another tissue represents a new perspective in cancer biology. Given the pervasiveness of somatic mosaicism in humans, more examples of the interplay among non-malignant somatic clones, aging, and human disease may emerge, opening a role for prevention strategies that attenuate somatic clonal proliferation and tissue inflammation, according to the authors.

In an accompanied editorial article, Drs. Lachelle D. Weeks and Benjamin L. Ebert of the Dana–Farber Cancer Institute in Boston, MA, US wrote that as with other CHIP phenotypes, the observed CHIP-associated solid tumour progression is a genotype-specific phenomenon, but the biologic factors underlying genotype specificity remain to be elucidated. This novel characterisation of the prognostic significance of TI-CH positions TI-CH, rather than circulating CHIP, as a potential target for interventions that regulate tumour progression and metastasis in solid cancers.

This work was supported by the Royal Society grants; the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council grants, and the Wellcome Trust grants; Cancer Research UK grant; the European Union Horizon 2020 research and innovation programme grant; an EMBO Postdoctoral Fellowship; IHU PRISM (National Precision Medicine Center in Oncology), funded by the France 2030 programme and the French National Research Agency grant, the Edward P. Evans Foundation, and the Clarendon Fund Scholarship; the Kay Kendall Leukaemia Fund grant; the European Research Council grant, RASImmune grant, and START, funded by an UKRI Frontier Research grant; a Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship; UK Medical Research Council Studentship Award; a National Institute for Health and Care Research clinical lecturer award; a Cancer Research UK Career Development Fellowship; the Swiss National Science Foundation grant; Leukaemia UK grant; the UK Medical Research Council grant; the European Hematology Association grant; the British Society for Haematology; a National Institutes of Health Outstanding Investigator Award; the National Cancer Institute grant; a Damon Runyon-Rachleff Innovation Award; the Myelodysplastic Syndromes Foundation; and the Starr Cancer Consortium.

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