Clonal Hematopoiesis and Solid Cancers

ABSTRACT

Clonal hematopoiesis refers to the expansion of hematopoietic stem cells harboring somatic mutations, a phenomenon increasingly recognized in aging populations. This review highlights the emerging relationship between clonal hematopoiesis and solid cancers, focusing on the prevalence and impact of clonal hematopoiesis–associated mutations such as DNMT3A, TET2, ASXL1, and TP53 in tumorigenesis. Key risk factors for the co‐occurrence of clonal hematopoiesis and solid cancers, including germline genetic factors, aging, and environmental factors, are also discussed. We explore how clonal hematopoiesis mutations shape the tumor microenvironments in solid cancers by modulating immunoregulation, inflammation, and angiogenesis, thereby contributing to tumor progression. These findings underscore the dual role of clonal hematopoiesis as both a marker of cancer risk and a potential driver of solid cancer progression. The clinical implications of clonal hematopoiesis are also considered, including the prognostic value, impact on treatment response, and potential as a therapeutic target. Future directions are outlined to advance our understanding of clonal hematopoiesis and to exploit its clinical potential for cancer management.

This review explores the relationship between clonal hematopoiesis and solid cancers. Clonal hematopoiesis mutations influence the tumor microenvironment by altering immune regulation, inflammation, and angiogenesis. Understanding these mutations has important clinical implications, including their role in prognosis, treatment response, and potential as therapeutic targets.

Abbreviations

CH

clonal hematopoiesis

CHIP

clonal hematopoiesis of indeterminate potential

CVD

cardiovascular disease

HSC

hematopoietic stem cell

VAF

variant allele frequencies

1. Introduction

Clonal hematopoiesis (CH) is a process in which a single hematopoietic stem cell (HSC) acquires genetic mutations that enable it to expand and dominate the blood and immune cell populations (Figure 1) [1, 2]. CH was first proposed after the observation of skewed X‐chromosome inactivation patterns in the peripheral blood leukocytes of older women, identifying HSCs as primary targets of CH‐related mutations [3]. The subsequent discovery of somatic mutations in TET2, linked to hematologic malignancies, demonstrated that epigenetic changes in HSCs could drive disease development [4]. A more specific term, “clonal hematopoiesis of indeterminate potential” (CHIP), was introduced to describe a subset of CH characterized by gene mutations associated with hematologic malignancy with normal hematogram and no evidence of hematologic malignancies [5].

FIGURE 1.

Evolution and migration of CH in the human body. CH, clonal hematopoiesis.

Advancements in genomic research have expanded our understanding of CH. Large‐scale genome‐wide studies in healthy individuals revealed that these somatic mutations, particularly in genes associated with epigenetic regulation, are widespread in the general population [1, 2, 6]. These studies established that CH is not only a hallmark of aging but is also linked to an increased risk of hematologic malignancies such as acute leukemia, as well as nonhematologic diseases, including cardiovascular disease (CVD) and various solid cancers [7, 8, 9]. Recent research has further highlighted the potential relevance of CH in the context of solid cancers. Indeed, CH‐related mutations have been identified in patients with solid tumors, including lung, breast, prostate, and colon cancers, suggesting a potential role in cancer predisposition [7, 10, 11, 12, 13].

The most frequent CH mutations in either healthy individuals or patients with solid cancers occur in genes associated with epigenetic regulation, including DNMT3A, TET2, and ASXL1 (Table 1) [7, 12, 13, 14, 15]. Additional mutations are found in genes associated with RNA splicing factors (SF3B1, SRSF2, and U2AF1), DNA damage response (PPM1D and TP53), and signaling pathways (e.g., JAK2 V617F) [7]. Although typically asymptomatic, mutations in critical pathways—such as self‐renewal, differentiation, DNA repair, and inflammatory signaling—reportedly influence both hematopoietic and solid tumor biology, potentially driving tumor progression [1, 2, 8, 16, 17]. While our understanding of the clinical significance of CH is growing, the precise characterization of mutations and their impact on patient outcomes, particularly in relation to solid cancer risk, is ongoing [7, 12, 13, 18, 19]. In this review, we aimed to clarify the terms defining the origin of CH mutation, the impact of CH in various solid cancers, and the potential clinical applications.

TABLE 1.

Top frequent CH mutations from genome‐wide association studies.

CH mutation	Groups a
	UKB [13]	TOPMed [14]	UKB [15]	GHS [15]
DNMT3A	50	53.1	63.1	50.6
TET2	21.1	18.2	17.9	19.8
ASXL1	7.9	7.1	8.3	9.6
PPMID	2.7	3.5	2.7	6.3
TP53	2.6	1.8	1.7	3
SRSF2	1.3	1.9	1.1	2.4
SF3B1	1.1	2.2	0.8	2.9
JAK2	1.1	2.9	0.9	1.2
Others	12.2	9.4	3.4	4.2

^a Individual groups: UK Biobank (UKB); Trans‐omics for Precision Medicine (TOPMed); Geisinger MyCode Community Health Initiative (GHS); CH, clonal hematopoiesis; Distribution of CH Mutations Across Groups (Total = 100%).

2. The Interplay of Genetic Factors, Aging, and Environmental Stressors in Cancer and CHIP

Cancer develops when a single cell accumulates genetic and epigenetic alterations, leading to the clonal expansion of aberrant cells [20, 21, 22]. This clonal evolution is driven by various risk factors, including environmental factors (radiation, ultraviolet light, and carcinogenic chemicals), viral infections (Epstein–Barr virus, human papillomavirus, and hepatitis C virus, etc.), chronic inflammation ( Helicobacter pylori infection, autoimmune diseases), lifestyle factors (smoking, excessive alcohol consumption, unhealthy diet), aging, and genetic predisposition (germline mutations, family history) [22, 23]. Interestingly, these risk factors significantly overlap with the predispositions for CHIP, such as aging, smoking, chronic inflammation, radiation exposure, and chemotherapy [7, 12, 15, 24, 25]. This overlap arises because both conditions fundamentally involve the accumulation of genetic mutations at the stem cell level with age [26, 27]. Additionally, DNA damage induced by lifestyle factors (smoking, alcohol consumption), chronic inflammation, and environmental exposures (radiation, chemicals) serves as a common underlying cause [28]. The following sections describe these contributing factors in detail, explore their broader implications, and take a closer look at their role as key risk factors in CHIP.

2.1. Germline Mutations

Germline genetic factors have emerged as critical contributors to the development and progression of CH [29]. Genome‐wide studies have identified germline variants significantly associated with CH at key loci, including TERT, PARP1, SMC4, CD164, ATM, and TP53 [13, 14, 15]. Notably, several genetic variants at the TERT locus are strongly related to increased CH, highlighting the essential role of telomere maintenance in promoting the clonal expansion of mutant HSCs [14]. Overall, these studies identified target genes that play key roles in DNA damage repair [30, 31], stem cell migration [27, 32], and oncogenic signaling pathways [32, 33].

Consequently, these germline mutations influence the occurrence of distinct CH mutations, including DNMT3A‐CH, TET2‐CH, and ASXL1‐CH. Among these, DNMT3A‐CH, the most common subtype, is associated with loci such as TCL1A, RABIF, ABCC5, FLT3, and MYB [24]. TET2‐CH shares several genetic variants, including those in the TERT, ATM, and TP53 loci with other CH subtypes [29]. However, it also exhibits unique associations with genes such as GATA2 and TMEM209 [15]. In contrast, ASXL1‐CH is linked to fewer loci, with CD164 and TCL1A being the most notable [34]. The association with CH susceptibility varies depending on the variant. For instance, variants in PARP1 and LY75 are thought to reduce the risk of DNMT3A‐CH, as they are associated with multiple blood characteristics [13, 15, 35, 36, 37]. Interestingly, TCL1A demonstrates opposing associations with different CH subtypes, increasing the risk of DNMT3A‐CH while decreasing the risk of TET2‐CH and ASXL1‐CH [15, 29, 38, 39]. This dual role reflects the distinct biological behaviors and growth kinetics of these CH subtypes, emphasizing the complexity of CH pathogenesis. The CD164 locus is associated with an increased risk of both DNMT3A‐ and ASXL1‐CH via HSC adhesion and migration [13, 15, 40]. GATA2 and TMEM209 variants are involved in DNA damage repair, transcriptional regulation [41, 42], and HSC function [43, 44], reflecting the diverse mechanisms driving TET2‐CH [29].

2.2. Aging

Aging increases the risk of CH by promoting the accumulation and expansion of somatic mutations in hematopoietic stem and progenitor cells [1, 2, 5, 8]. Studies have demonstrated that age‐related changes in the bone marrow microenvironment promote the occurrence of CH mutations [26, 45]. Investigations into the behavior of CH mutant clones suggest that aging interacts with specific mutations, potentially through cell‐intrinsic factors or cell‐extrinsic alterations in the aging hematopoietic niche [46]. These changes may preferentially favor mutations in splicing factors [47, 48].

The prevalence of CH increases significantly with age, as evidenced by large‐scale genome sequencing studies [1, 2, 6]. While CH mutations are rare in individuals < 40 years, they are present in approximately 10%–20% of individuals > 70 years [1, 2]. These studies also revealed that CH clones with variant allele frequencies (VAFs) < 2% are common in individuals aged 50–70 years and become almost universally prevalent in individuals > 70 years. Interestingly, the timing of CH mutation emergence exhibits an inverse trend [37, 48]. DNMT3A, TET2, and ASXL1 mutations are more common in younger individuals, while SRSF2 and SF3B1 mutations typically appear in those over 70 [2, 8, 49].

2.3. Environmental Factors

Environmental stressors act synergistically with CH mutations, enhancing clonal fitness and expansion [50]. Tobacco use and radiation exposure are strongly linked to CH development [12, 25, 51]. Large‐scale studies have shown that former smokers and individuals with smoking‐related diseases, including lung cancer and chronic obstructive pulmonary disease (COPD), exhibit higher rates of CH [12, 15]. Cancer treatments like chemotherapy, radiation, and radionucleotide therapy are strongly associated with CH expansion [7, 12, 52, 53]. Among chemotherapeutic agents, topoisomerase II inhibitors and platinum compounds pose the highest risk, and these treatments have also been strongly associated with therapy‐related myeloid neoplasms [12]. Interestingly, cytotoxic therapies primarily select for pre‐existing somatic mutations in DNA damage genes such as TP53, PPM1D, ATM, and CHEK2, which provide a clonal fitness advantage under stress [7, 52, 53, 54].

Elevated levels of pro‐inflammatory cytokines, including interleukin (IL)‐6, IL1B, and tumor necrosis factor, act as driving forces for CH progression, particularly in older individuals [8, 55]. CH mutations further exacerbate the hyperinflammatory environment, creating a positive feedback loop that promotes further growth and expansion of CH clones in a cyclic manner [56].

3. Relationship Between CH and Solid Cancers

3.1. Prevalence of CH Mutations in Solid Cancers

CH mutations have been identified in patients with solid cancers through multiple cohort studies, with detection rates and associations varying by cancer type [7, 12, 13, 15]. One of the earliest studies, conducted at Memorial Sloan Kettering Cancer Center (MSK), analyzed data from 8810 patients and found that CH was present in > 25% of patients with solid cancer [7]. Among cancer types, thyroid and ovarian cancers exhibited the highest rates of CH, while melanoma, prostate cancer, colon cancer, and renal cell carcinoma showed the lowest rates of CH [7]. These findings highlight the complexity of carcinogenic mechanisms, which are influenced by distinct biological contexts and require further in‐depth studies.

The frequently observed genetic mutations include those associated with epigenomic alterations such as DNMT3A, TET2, and ASXL1 in healthy individuals, whereas in patients with cancer, in addition to these abnormalities, TP53 and PPM1D mutations are highly prevalent [7, 13, 15]. Furthermore, among patients with cancer, when comparing newly diagnosed groups with those with a treatment history, TP53, PPM1D, and CHEK2 mutations are more frequently observed in the treatment group [12].

Larger longitudinal studies, such as those using the UK Biobank (UKB), have provided additional insights into the relationship between CH and solid cancers [13]. In a cohort of 200,453 individuals, CH with VAF higher than 10% was associated with an increased risk of lung and kidney cancers, as well as lymphoma and sarcoma [13]. Specific mutations have also been linked to particular cancer types: for instance, DNMT3A mutations are associated with an increased risk of stomach and bladder cancer, while splicing factor mutations (SF3B1 and SRSF2) are linked to an increased risk of colon and head/neck cancers (Table 2). A larger analysis of the UKB involving 628,388 individuals confirmed associations between CH and increased risks of lymphoma, lung cancer, and breast cancer, although no significant association was observed with prostate cancer [15]. The presence of CH mutations is particularly notable in lung cancer [51]. The study reported that CH mutations were associated with a higher risk of lung cancer, with the highest frequency of CH (22.5%) observed among 2279 patients in the MSK‐IMPACT cohort. This association remained significant even after excluding individuals with COPD. Similar findings were reported in the MGBB and MSK cohorts, which observed higher VAF of the CH mutation in patients with lung cancer before treatment [12]. Additionally, the INTEGRAL‐ILCCO project identified a strong correlation between high‐VAF CH mutations and an elevated risk of lung cancer [10]. Preoperative CH mutations have also been associated with poorer overall survival in patients with non–small cell lung cancer [64]. These studies suggest that CH, especially with higher VAF, not only increases the risk of lung cancer but also correlates with poorer survival outcomes.

TABLE 2.

Incidence and clinical implications of CH mutations in various solid cancers.

Tumor type	Top mutations	% Frequency
		Blood samples	cfDNA from plasma
Bladder cancer	DNMT3A, TET2, PPM1D [12]	38 [12]	25.8 [57]
Breast cancer	DMNT3A (HR: 1.25) [15]; DNMT3A, TET2, PPM1D [12]	26 [12], 21 [7]	11.7 [57]
Colorectal cancer	DNMT3A, TET2, PPM1D [12]; DNMT3A, TET2, ROS [58]	25 [12], 27.6 [58]	13.5 [57]
Endometrial cancer	DNMT3A, TET2, PPM1D [12]	39 [12]	21.1 [57]
Esophagogastric cancer	DNMT3A, TET2, PPM1D [58]	30 [12], 34.6 [58]
Head and neck cancer	DNMT3A, TET2, ASXL1 [59]	31 [12]	13.3 [57], 43.5 [59]
Kidney cancer	TET2 (HR: 1.47), DNMT3A (HR: 1.43), ASXL1 (HR: 1.20) [13]	22 [12]	9.0 [57]
Lung cancer	DNMT3A (HR: 1.64), TET2 (HR: 1.6), ASXL1 (HR: 1.55) [15]; DNMT3A, TET2, PPM1D, ASXL1 [12] DNMT3A, ASXL1, TET2 [51], DNMT3A, TET2, ATM, and TP53 [10]	27 [7]; NSCLC 37, SCLC 40 [12]; 52.6 [10]	NSCLC 13.2, SCLC 16.2 [57]
Melanoma	DNMT3A, TET2, PPM1D, ASXL1 [12]	31 [12]	26.8 [57]
Ovarian cancer	DNMT3A, PPM1D, TP53, CHEK2 [12]; DNMT3A, PPM1D, TET2, ASXL [60]	38 [12]; 17.6 [60]	17.1 [57]
Pancreatic cancer	DNMT3A, TET2, PPM1D [12]	32 [12]	12.8 [57]
Prostate cancer	DMNT3A (HR: 1.27) [15]	35 [12]	20.7 [57]
Thyroid cancer	DNMT3A, SHOC2, SH2B3 [61]; DNMT3A, TET2 [62]	30 [12]; 37 [63]	7.5 [57]

Abbreviations: CH, clonal hematopoiesis; HR, hazard ratio.

3.2. CH Modulates the Tumor Microenvironment in Solid Cancers

Mutations linked to CH were originally investigated within the framework of hematological malignancies [65, 66, 67]. However, recent studies have expanded our understanding of CH, revealing its critical role in the progression of solid cancers [18, 19, 68, 69, 70]. Emerging evidence suggests that CH influences tumorigenesis, immunoregulation, and tumor microenvironment dynamics [18, 19, 68, 69, 70].

Mouse models of DNMT3A loss of function have long demonstrated its important role in tumor development and progression [11, 68]. Recently, in a colitis‐associated colon cancer model, CH induced by heterozygous Dnmt3a‐deficiency in blood cells has led to increased tumor burden and invasiveness compared to controls, along with increased epithelial damage, dysplasia, and adenocarcinoma formation [68]. Analysis of tumors from this model revealed enrichment of gene signatures implicated in carcinogenesis, including angiogenesis pathways. Interestingly, treatment with the angiogenesis inhibitor axitinib significantly reduced tumor growth in Dnmt3a‐deficient mice.

The effect of TET2‐mutated CH immune cells in the development of solid tumors is context‐dependent. In a melanoma model using the YUMM1.7 murine cell line, Tet2 expression in tumor‐associated macrophages (TAMs) and myeloid‐derived suppressor cells (MDSCs) is activated via the IL‐1R/MyD88 axis, promoting immunosuppressive gene expression [18]. Consequently, Tet2‐deficient TAMs/MDSCs lead to the shutdown of this signaling pathway and reverse to antitumor activity by enhancing CD4+/CD8+ T cells to the tumor site [18]. However, in a syngeneic mice model injected with hepatoma cells, Tet2 deficiency showed the tumor‐enhanced effect through the IL‐6/MDSC/T‐cell axis [19]. Tet2 ^−/− mice exhibit IL‐6 overexpression upon tumor challenge, which increases the number of immunosuppressive granulocytic MDSCs, thereby reducing CD8+ T cell infiltration and impairing immune surveillance. Similarly, in lung cancer models, Tet2 loss of function exacerbates tumor progression through the Il1b/S100a8/S100a9/Granulocytic Myeloid Derived Cells (GMDs)/Emmprin/Vegfa axis [69]. Signaling through the S100a8/S100a9/Emmprin/Vegfa axis is crucial for lung cancer progression in the context of the Tet2‐deficient immune cell microenvironment. Specifically, S100a8/S100a9 secreted by Tet2‐deficient myeloid subclusters, particularly GMDs, activates the Emmprin receptor on lung cancer cells, resulting in increased Vegfa secretion and enhanced tumor angiogenesis (Figure 2).

FIGURE 2.

A mechanism of loss‐of‐function Tet2 on lung cancer progression.

ASXL1 mutations are implicated in tumorigenesis by impairing T‐cell growth and function in various cancer models [70]. Using conditional knock‐in mice expressing CH‐associated Asxl1 mutations, researchers demonstrated that T‐cell–specific expression of Asxl1‐MT accelerated the growth of melanoma, lung, and colon cancer cells in allogeneic xenograft models [70]. Intratumoral analysis revealed reduced T‐cell infiltration and increased PD‐1 expression at tumor sites, indicating impaired antitumor immunity [70].

4. Clinical Implications

CH is a promising biomarker for cancer predisposition and progression, as well as a potential therapeutic target [18, 19, 53, 65, 69, 71]. The risk of CH progressing to hematological malignancies increases significantly when VAF of CHIP mutations reaches at least 10% in patients with solid cancers [2, 5, 72]. This underscores the importance of monitoring CH dynamics, particularly in individuals at higher risk, such as those undergoing cancer therapy or with a family history of malignancy. Identifying and quantifying these genetic alterations can provide critical insights into disease progression and inform personalized management.

Emerging evidence highlights the broader clinical implications of CH, including secondary complications such as therapy‐related myeloid neoplasms (tMN) and CVD [7]. Recent studies have shown that CHIP in patients with solid tumors is strongly therapy‐related, particularly following chemotherapy or radiotherapy [15]. Among CHIP mutations, TP53 mutations confer the highest risk of developing tMN [12, 15, 73]. A pivotal study involving 1000 patients with ovarian cancer treated with PARP inhibitors found that pre‐existing TP53 CHIP significantly increased the risk of posttreatment tMN, while no such association was observed with other CHIP mutations [74]. Additionally, patients with prostate cancer harboring CHIP mutations are at an elevated risk of CVD [75].

CHIP has also been linked to poorer outcomes in patients with solid tumors [10, 58, 64, 71]. For example, some studies have observed reduced overall survival (OS) in CHIP‐positive patients, even after adjusting for confounding factors such as age, sex, and smoking history [7, 12, 76]. In these cases, the mortality factor appears to be primarily due to the progression of the primary cancer. The impact of CHIP mutations on treatment outcomes has also been evaluated in clinical trials, particularly in the context of immune checkpoint inhibitors (ICIs) [7, 10, 71, 77]. For most cancers, CHIP has been found to negatively predict the efficacy of ICIs, with the notable exception of colorectal cancer [77]. The FIRE‐3 trial demonstrated that DNMT3A mutations were associated with improved outcomes, although no significant differences were observed in progression‐free survival (PFS) [78]. Similarly, the PREMIS trial found that patients with CHIP mutations, including DNMT3A, TET2, or ASXL1, had a median PFS of 7.7 months compared with 5.7 months in patients without CHIP, though the difference in OS was not significant [79]. The PA.7 trial reported improved PFS in CHIP‐positive patients with pancreatic cancer treated with ICIs, whereas the PREDiCT‐1 study demonstrated worse outcomes for CHIP‐positive patients receiving chemotherapy [51, 71]. These findings underscore the complexity of CH and its interaction with solid cancers, highlighting the need for further research to tailor treatment strategies based on CHIP mutation profiles and cancer types (Table 3).

TABLE 3.

The impact of CH mutations on treatment outcomes in solid cancers.

Therapy/Study	CH Status	Outcomes	Reference
Chemotherapy, radiation therapy	CH+ CH‐PD+	Increased risk of subsequent hematologic malignancies; reduced OS.	Comb CC, et al., 2017 [7].
ICIs	CH+	Reduced OS in RCC, NSCLC, melanoma, glioma, H&N, EG, CUP, breast, bladder; no impact in colorectal cancer.	Hsiehchen D, et al., 2022 [77].
FIRE‐3 trial with ICIs	CH‐DNMT3A wildtype, CH‐DNMT3A mutations	DNMT3A mutations associated with improved survival in metastatic CRC.	Arends CM, et al., 2022 [78].
Surgery + adjuvant therapy	CH+	Markedly lower survival in NSCLC.	Yun JK, et al., 2023 [64].
First‐line chemo ± ICIs (CRC/EG)	CH+, CH‐PD+	No association with PFS, leukocyte counts, or G‐CSF requirement.	Diplas TH, et al., 2023 [58].
PREMIS trial (ICIs)	CHIP+	No significant difference in PFS or in OS.	Rodriguez JE, et al., 2024 [79].
PREDiCT‐1 study (chemo)	CHIP+	Decreased PFS.	Krishnan T, et al., 2025 [71].
PA.7 trial (ICIs in pancreatic cancer)	CHIP+	Improved PFS.	Krishnan T, et al., 2025 [71].

Abbreviations: CH, clonal hematopoiesis; CH‐PD+, CH with pathogenic driver mutations; chemo, chemotherapy; CHIP, clonal hematopoiesis of indeterminate potential; CRC, colorectal cancer; CUP, cancer of unknown primary; EG, esophagogastric cancer; G‐CSF, granulocyte colony‐stimulating factor; H&N, head and neck cancer; ICIs, Immune checkpoint inhibitors; NSCLC, non–small cell lung cancer; OS, overall survival; PFS, progression‐free survival.

5. Future Directions

The impact of CH varies depending on the mutation type, tumor type, immune context, and treatment modality [1, 2, 7, 12, 13, 15, 65]. Understanding the role of CH clones in shaping the immune response within the solid tumor microenvironment is essential for informing treatment options, identifying new therapeutic targets, and improving outcome prediction in patients with solid tumors. Large‐scale studies are needed to evaluate the impact of CH on treatment regimens and to assess and mitigate the risk of secondary disorders, such as tMN and CVD. Currently, the management of individuals with CH is being explored as a diagnostic and prognostic tool. The integration of genomic testing, including circulating tumor DNA analysis, into routine care may pave the way for personalized preventive medicine.

CH mutations are no longer seen as a process confined to hematologic malignancies. Their role in solid cancers is becoming increasingly clear, with mutations in HSCs influencing tumor growth, immune evasion, and angiogenesis. Further research into the molecular mechanisms linking CH to solid tumor progression will be critical for developing novel therapies and improving cancer treatment strategies.

Author Contributions

Yen T. M. Nguyen: visualization, writing – original draft. Manabu Fujisawa: writing – original draft, writing – review and editing. Shumpei Ishikawa: writing – review and editing. Mamiko Sakata‐Yanagimoto: conceptualization, writing – review and editing.

Ethics Statement

The authors have nothing to report.

Informed Consent: N/A.

Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.

Conflicts of Interest

The authors declare no conflicts of interest. Dr. Ishikawa, Shumpei and Dr. Sakata‐Yanagimoto, Mamiko, are editorial board members of Cancer Science.