Tumor-Infiltrating Clonal Hematopoiesis Emerges as a Pan-Cancer Prognostic Signal in Solid Tumors

Highlights

In a retrospective whole-genome sequencing analysis of 10,571 patients with solid tumors from the Genomics England 100,000 Genomes Project, tumor-infiltrating clonal hematopoiesis (TI-CH) was identified in 18.38% of cases.

TI-CH was associated with older age and prior cytotoxic chemotherapy, supporting the idea that both aging hematopoiesis and treatment-related selective pressure may shape the tumor microenvironment.

Across cancers, TI-CH was associated with inferior overall survival, with a particularly strong signal in breast cancer. At the gene level, GATA2 variants were linked to worse pan-cancer survival, and TET2 variants were linked to worse survival in breast cancer.

The findings position TI-CH as a potentially useful prognostic biomarker and raise important biological questions about how mutated hematopoietic clones influence antitumor immunity, stromal interactions, and treatment response.

Background and Clinical Context

Clonal hematopoiesis describes the expansion of blood cell clones carrying acquired somatic mutations, usually in genes involved in epigenetic regulation, DNA damage response, or hematopoietic differentiation. The prevalence of clonal hematopoiesis increases with age and after exposure to cytotoxic therapy. Over the last decade, it has become clear that clonal hematopoiesis is not merely a preleukemic state. It is also associated with broader clinical consequences, including cardiovascular disease, inflammatory phenotypes, and adverse outcomes in some malignant settings.

Most clinical discussions of clonal hematopoiesis focus on peripheral blood or bone marrow. By contrast, tumor-infiltrating clonal hematopoiesis refers to somatically mutated hematopoietic cells detected within tumor tissue. This concept is clinically important because the tumor microenvironment is partly composed of immune and stromal cells, not only malignant epithelial or mesenchymal cells. If infiltrating myeloid or lymphoid populations carry clonal hematopoiesis-associated mutations, they may alter inflammatory signaling, immune surveillance, antigen presentation, tissue remodeling, or therapeutic sensitivity.

Despite the biological plausibility, the epidemiology and prognostic significance of TI-CH in solid tumors have remained poorly defined. The study by Yun and colleagues addresses this gap using a large pan-cancer whole-genome sequencing resource, asking three clinically relevant questions: how common TI-CH is in solid tumors, what factors are associated with its presence, and whether it carries prognostic information for overall survival.

Study Design

Design and Data Source

This was a retrospective cohort study using whole-genome sequencing data from the Genomics England 100,000 Genomes Project. Patients with solid tumors diagnosed between 2015 and 2019 were included. Data analysis was performed from June to November 2025.

Population

The cohort included 10,571 patients with solid tumors. The mean age was 64.68 years, with a standard deviation of 12.18 years, and 6,430 patients, or 60.83%, were female.

Definition of TI-CH

TI-CH was defined by the presence in tumor tissue of somatic variants in 74 driver genes known to be relevant to clonal hematopoiesis, with variant allele frequencies ranging from 2% to 30%. This definition was intended to capture infiltrating hematopoietic clones while reducing the likelihood of including low-confidence sequencing noise or dominant tumor-derived alterations.

Outcomes

The primary outcome was TI-CH prevalence. Secondary outcomes included associations of TI-CH with clinical variables, especially age and cytotoxic chemotherapy exposure, and with overall survival using Cox proportional hazards models.

Key Results

Prevalence Across the Cohort

TI-CH was detected in 1,943 of 10,571 patients, corresponding to a prevalence of 18.38%. This is a clinically meaningful proportion. In practical terms, nearly 1 in 5 sequenced solid tumors contained evidence of infiltrating hematopoietic clones bearing clonal hematopoiesis-associated mutations.

Among individual genes, TET2 variants were the most frequently observed, present in 212 patients with TI-CH, representing 10.91% of TI-CH-positive cases. This finding is biologically plausible given the central role of TET2 in age-related clonal hematopoiesis and immune cell programming.

Across tumor types, endometrial cancer showed the highest TI-CH frequency, with 251 patients, or 32%, testing positive. This tumor-specific enrichment is intriguing and suggests that local immune composition, hormonal milieu, tissue-specific inflammation, or treatment patterns may influence TI-CH detection or biological relevance.

Clinical Factors Associated With TI-CH

Older age was significantly associated with TI-CH, with an odds ratio of 1.15 and a 95% confidence interval of 1.10 to 1.19. This aligns closely with the established age dependence of clonal hematopoiesis in blood. Aging hematopoietic stem cells accumulate mutations over time, and certain clones gain a competitive advantage, especially under inflammatory or treatment-related stress.

Cytotoxic chemotherapy was also associated with increased odds of TI-CH, with an odds ratio of 1.24 and a 95% confidence interval of 1.06 to 1.44. This is another important finding. Cytotoxic agents are known to create selective pressure favoring DNA damage-tolerant or stress-adapted hematopoietic clones. The result supports a model in which prior therapy can influence not only circulating clonal hematopoiesis but also the composition of the tumor-infiltrating immune compartment.

Overall Survival

At the pan-cancer level, TI-CH was associated with worse overall survival, with a hazard ratio of 1.13 and a 95% confidence interval of 1.02 to 1.25. The effect size is modest, but statistically significant and clinically notable given the heterogeneity of solid tumors and the broad population studied. A biomarker that retains prognostic value across a pan-cancer cohort is worth attention, even if the average effect is not large.

The survival association was particularly pronounced in breast cancer, where TI-CH was associated with a hazard ratio for death of 1.95 and a 95% confidence interval of 1.54 to 2.48. This nearly twofold increase suggests that TI-CH may identify a biologically distinct subgroup of breast tumors or host immune states with materially worse outcomes.

Gene-Level Prognostic Signals

Gene-specific analyses yielded two especially notable findings. First, GATA2 variants were associated with worse pan-cancer overall survival, with a hazard ratio of 3.00 and a 95% confidence interval of 1.61 to 5.59. Although likely based on a smaller subset and therefore requiring cautious interpretation, this is a large effect estimate and raises the possibility that specific hematopoietic clones may have disproportionate biological impact.

Second, in breast cancer, TET2 variants were associated with worse overall survival, with a hazard ratio of 2.92 and a 95% confidence interval of 1.59 to 5.37. This is especially interesting because TET2-mutant myeloid cells have been implicated in altered inflammatory signaling, macrophage polarization, and immune dysfunction in preclinical and translational studies.

Clinical Interpretation

The most immediate clinical implication is that TI-CH appears common enough to matter and prognostic enough to merit validation. If these observations are reproduced, TI-CH could become part of a broader molecular risk framework in solid tumors, particularly for patients already undergoing tumor sequencing.

Several potential use cases can be imagined. First, TI-CH might serve as a prognostic biomarker, helping refine survival estimates beyond tumor-intrinsic genomic features. Second, it may act as a treatment-context biomarker, especially in patients exposed to cytotoxic chemotherapy, where therapy-related clonal selection could shape later outcomes. Third, TI-CH may provide mechanistic clues relevant to immunotherapy, inflammation-targeted approaches, and microenvironment-focused drug development.

The breast cancer signal deserves particular attention. A hazard ratio of 1.95 for TI-CH overall, and 2.92 for TET2-specific TI-CH, suggests more than incidental contamination by blood-derived cells. It suggests that mutated infiltrating hematopoietic cells may actively participate in a tumor-promoting ecosystem in at least some breast cancers. Whether this reflects altered macrophage behavior, cytokine secretion, impaired antitumor T-cell priming, or other immune-regulatory effects remains uncertain, but the signal is strong enough to justify focused follow-up studies.

Biological Plausibility and Mechanistic Insights

The study’s conclusions are biologically credible. Clonal hematopoiesis-associated mutations, especially in genes such as TET2, DNMT3A, ASXL1, TP53, PPM1D, and splicing factors, can reshape the behavior of differentiated immune cells. In experimental systems, TET2-deficient myeloid cells can exhibit heightened inflammatory responses, altered cytokine production, and changes in tissue infiltration. Such effects could plausibly influence tumor growth, angiogenesis, extracellular matrix remodeling, and response to therapy.

GATA2 is a particularly interesting signal because it is a critical regulator of hematopoietic stem and progenitor cell function, as well as innate and adaptive immune development. If GATA2-mutated infiltrating clones are present within tumors, they may represent a qualitatively distinct immune infiltrate with impaired surveillance or abnormal inflammatory behavior. The large hazard ratio seen in this study suggests this possibility, although replication is essential before overinterpreting the magnitude.

The association with cytotoxic chemotherapy also fits current understanding. Therapy-related clonal hematopoiesis is increasingly recognized after exposure to platinum agents, topoisomerase inhibitors, alkylators, radiation, and other genotoxic stressors. The current study extends that concept into the tumor microenvironment, implying that treatment history may leave a durable imprint not only on circulating blood compartments but also on immune cells trafficking into tumors.

Strengths of the Study

This analysis has several strengths. The cohort size is large for a sequencing-based pan-cancer study, increasing precision for prevalence estimates and permitting subgroup analyses. Whole-genome sequencing offers broad mutation detection beyond targeted assays. The use of a defined 74-gene driver set and prespecified variant allele frequency thresholds provides a workable operational framework for TI-CH classification. The study also links molecular observations to clinically meaningful endpoints, especially overall survival.

Another strength is the integration of epidemiologic and prognostic perspectives. By showing that older age and chemotherapy exposure track with TI-CH, the investigators support the internal consistency of their findings. These associations make the observed TI-CH signal more believable because they mirror what is already known about clonal hematopoiesis biology.

Limitations and Cautions

As with any retrospective sequencing analysis, several limitations should temper immediate clinical translation. First, TI-CH is inferred from tumor sequencing rather than directly functionally validated in sorted infiltrating immune subsets. Therefore, the exact cellular source of each mutation within the tumor specimen cannot be fully established from the abstract alone.

Second, variant allele frequency thresholds help operationalize detection but cannot perfectly distinguish infiltrating hematopoietic clones from technical artifacts, occult hematologic involvement, or rare tumor-derived events in some contexts. Paired blood analysis, single-cell approaches, and orthogonal validation would strengthen confidence.

Third, residual confounding is likely. Older age and chemotherapy exposure are themselves associated with poorer outcomes, and although multivariable Cox models can adjust for measured factors, unmeasured confounders may remain. The modest pan-cancer hazard ratio of 1.13 should therefore be viewed as hypothesis-generating rather than practice-changing.

Fourth, pan-cancer analyses inherently average across biologically diverse diseases. The stronger signal in breast cancer and the high prevalence in endometrial cancer suggest that TI-CH is unlikely to have uniform importance across tumor types. Disease-specific validation will be essential.

Finally, the abstract does not provide details on race and ethnicity distributions, tumor stage balance, treatment classes beyond cytotoxic chemotherapy, immunotherapy exposure, or cause-specific mortality. These details matter for generalizability and for interpreting how TI-CH interacts with modern cancer care.

Implications for Practice and Research

For clinicians, the study does not yet mandate routine TI-CH reporting in pathology workflows or tumor board practice. However, it does suggest that incidental detection of clonal hematopoiesis-associated variants in tumor sequencing should not automatically be dismissed as irrelevant noise, especially when variant allele frequencies and gene identities are compatible with infiltrating hematopoietic clones.

For translational researchers, the next steps are clear. Prospective validation cohorts are needed. Single-cell and spatial transcriptomic studies should define which immune subsets carry these mutations and how they are distributed within the tumor microenvironment. Mechanistic work should test whether TI-CH alters immune checkpoint responsiveness, metastatic potential, endocrine therapy outcomes, or chemotherapy resistance. It will also be important to distinguish the prognostic value of TI-CH from that of peripheral blood clonal hematopoiesis and determine whether the combination adds information.

For health systems and molecular tumor boards, a practical future question is whether sequencing pipelines should annotate likely TI-CH events when analyzing solid-tumor specimens. If validated, this could improve interpretation of tumor-only next-generation sequencing and reduce misattribution of hematopoietic mutations to the cancer genome itself.

Conclusion

This study positions tumor-infiltrating clonal hematopoiesis as a clinically relevant feature of the solid-tumor microenvironment. In a large pan-cancer cohort, TI-CH was common, associated with older age and cytotoxic chemotherapy, and linked to inferior overall survival. The strongest prognostic signals were seen for GATA2 variants across cancers and TET2 variants in breast cancer.

The work is important because it shifts clonal hematopoiesis from a blood-centered phenomenon to a tumor microenvironment variable with possible prognostic and biological consequences. The results are not yet sufficient for routine clinical implementation, but they are compelling enough to justify validation, mechanistic investigation, and more careful interpretation of clonal hematopoiesis-associated variants encountered in tumor sequencing.

Funding and Trial Registration

The provided abstract does not report a ClinicalTrials.gov registration number. Specific funding information is not included in the supplied citation summary and should be confirmed from the full JAMA Oncology publication.

References

1. Yun D, Chen C, Qin N, Wang Z, Song N. Tumor-Infiltrating Clonal Hematopoiesis and Pan-Cancer Prognosis in Patients With Solid Tumors. JAMA Oncology. Published online May 7, 2026. PMID: 42096237. https://pubmed.ncbi.nlm.nih.gov/42096237/

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4. Bolton KL, Ptashkin RN, Gao T, et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nature Genetics. 2020;52(11):1219-1226.

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