Racial Disparities in Clonal Hematopoiesis Among Solid Cancer Patients with Cardiovascular Diseases

Introduction

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular disease, higher all-cause mortality, and elevated likelihood of developing hematological malignancies. Prior studies reported CHIP at a higher prevalence in solid cancer patients (~25-30%), possibly due to increased exposure to mutagenic/epigenetic stressors inherent in this population, common risk factors shared between solid cancers and CHIP or the oncogenic therapies they receive. Environmental factors may influence the epigenetic landscape, impacting the progression of CHIP to myeloid neoplasms (MN), including AML. Despite many studies, there is little known about the patterns of CHIP/CCUS among BAA and other minority groups. By assessing critical mutations in precursor conditions, we aim to improve health outcomes by preventing their clonal progression, given their poorer prognosis in overt disease stages. Notably, BAA AML patients have historically low survival rates due to socioeconomic, healthcare disparities, and biological factors. We here conducted a population sequencing study in our catchment area to study the prevalence of CHIP lesions in a racially distinct solid cancer population.

Methods

76 adult female cancer patients (breast, endometrial, ovarian, uterine) with a history of cardiometabolic disease (Hx of HTN, HLD, DM, PVD, CAD) who were treated at Karmanos Cancer Institute with curative intent for solid cancer were sampled at their diagnosis prior to exposure to cytotoxic chemo or radiotherapy. The study was supported under the overarching proposal of ACHIEVE GreatER: Addressing Cardiometabolic Health Inequities by Early PreVEntion in the Great LakEs Region (NIH/NIMHD Grant #5P50MD017351). Race/ethnicity data was self-reported. Whole exome sequencing was used to identify CHIP mutation and single-nucleotide polymorphism (SNP) array data. A variant calling pipeline with Genome Analysis ToolKit was used to identify somatic variants, including variant quality score recalibration method for quality filtering and minimum variant allele frequency (VAF) of 0.02. Putative somatic CHIP mutations were further filtered using a list of commonly identified CHIP genes based on prior literature. Likely germline variants, defined as single nucleotide variants with VAF > 0.3, were excluded. Based on the literature, the following were exceptions and counted as somatic: DNMT3A R882, SRSF2 P95, SF3B1 K666 and K700, JAK2 V617. Chi-square and t-tests were used for univariate statistical analyses; logistic regression was used for multivariate analysis.

Results

Among the total cohort, the median age was 63 (IQR 56-68 ys). 35 (46%) patients had breast, 22 (29%) had endometrial, 14 (18%) had ovarian, 1 (1%) patient had cervical, 1 (1%) had uterine cancer, and 3 (4%) had benign endometrial/ovarian/cervical disease. The known cardiometabolic association was seen in 54% of patients, and a majority of patients had risk factors for coronary artery disease, including hypertension (84%), diabetes (42%), hyperlipidemia (37%), and smoking (39%). 45 patients (59%) had a known family history of malignancy. 45 (59%) patients were BAA, 25 (33%) were Non-BAA, and 6 (8%) were other races.

After filtering germline variants, we focused our analysis on somatic mutations comparing disparities between BAA and Non-BAA patients. There was numerical enrichment of IDH2^MT in BAA patients (9% vs. 3% in non-BAA, p=0.3). Notably, KMT2C mutation was significantly enriched in BAA patients compared to non-BAA (67 vs 23%, p=0.0002) and was independently associated with age (p<0.05), race (p=0.003), and known cardiac disorder (p<0.05). There were notable differences in other myeloid genes between races, including GATA2, STAG2, NPM1, DNMT3A, and others that were not statistically significant due to low sample size. In multivariate logistic regression analysis, both race and age were important factors in determining KMT2C mutation status (Non-BAA race, OR=0.20, p=0.009; age OR=1.07, p=0.051), and cardiac disorder trended toward KMT2C association (OR=2.82, p=0.062).

Conclusion

Our study is one of the first to evaluate the racial disparity in CHIP prevalence among solid cancer patients. Given the prognostic relevance of the presence of IDH2/1 mutations in overt disease stages like AML, these enriched mutations in BAA sets a premise for intervention to prevent clonal evolution.

Balasubramanian:Alexion AstraZeneca: Speakers Bureau; Kura Oncology: Research Funding.