Distinct DNA methylation signatures associated with blood lipids as exposures or outcomes among survivors of childhood cancer: a report from the St. Jude lifetime cohort

Abstract

Background DNA methylation (DNAm) plays an important role in lipid metabolism, however, no epigenome-wide association study (EWAS) of lipid levels has been conducted among childhood cancer survivors. Here, we performed EWAS analysis with longitudinally collected blood lipid data from survivors in the St. Jude lifetime cohort study. Methods Among 2052 childhood cancer survivors of European ancestry (EA) and 370 survivors of African ancestry (AA), four types of blood lipids, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG), were measured during follow-up beyond 5-years from childhood cancer diagnosis. For the exposure EWAS (i.e., lipids measured before blood draw for DNAm), the DNAm level was an outcome variable and each of the blood lipid level was an exposure variable; vice versa for the outcome EWAS (i.e., lipids measured after blood draw for DNAm). Results Among EA survivors, we identified 43 lipid-associated CpGs in the HDL (n = 7), TC (n = 3), and TG (n = 33) exposure EWAS, and 106 lipid-associated CpGs in the HDL (n = 5), LDL (n = 3), TC (n = 4), and TG (n = 94) outcome EWAS. Among AA survivors, we identified 15 lipid-associated CpGs in TG exposure (n = 6), HDL (n = 1), LDL (n = 1), TG (n = 5) and TC (n = 2) outcome EWAS with epigenome-wide significance (P < 9 × 10−8). There were no overlapping lipids-associated CpGs between exposure and outcome EWAS among EA and AA survivors, suggesting that the DNAm changes of different CpGs could be the cause or consequence of blood lipid levels. In the meta-EWAS, 12 additional CpGs reached epigenome-wide significance. Notably, 32 out of 74 lipid-associated CpGs showed substantial heterogeneity (Phet < 0.1 or I2 > 70%) between EA and AA survivors, highlighting differences in DNAm markers of blood lipids between populations with diverse genetic ancestry. Ten lipid-associated CpGs were cis-expression quantitative trait methylation with their DNAm levels associated with the expression of corresponding genes, out of which seven were negatively associated. Conclusions We identified distinct signatures of DNAm for blood lipids as exposures or outcomes and between EA and AA survivors, revealing additional genes involved in lipid metabolism and potential novel targets for controlling blood lipids in childhood cancer survivors.

Current evidence supporting associations of DNA methylation measurements with survivorship burdens in cancer survivors: A scoping review

“…In total, 22 studies were discovered meeting inclusion criteria for this review (Table S3 ). 19 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 …”

“…Cancer sub‐types within study populations included: nine (40.8%) childhood/young adult cancer populations, 45 , 46 , 47 , 48 , 49 , 54 , 55 , 59 , 60 seven (31.8%) breast cancer patient populations, 19 , 40 , 41 , 42 , 43 , 50 , 57 two (9.1%) head and neck cancer populations, 51 , 58 and four studies classified as other or non‐specific cancer sub‐types 44 , 52 , 53 , 56 (Table 1 ; Figure 2 ; Table S3 ). Population sizes ranged from 20 to 2846 cancer patients; there were 11 (50%) studies with cohorts of 100 or less cancer patients 19 , 40 , 41 , 42 , 43 , 44 , 49 , 50 , 54 , 57 , 60 (Table 1 , Figure 2 , Table S3 ).…”

“…Population sizes ranged from 20 to 2846 cancer patients; there were 11 (50%) studies with cohorts of 100 or less cancer patients 19 , 40 , 41 , 42 , 43 , 44 , 49 , 50 , 54 , 57 , 60 (Table 1 , Figure 2 , Table S3 ). Control subjects were recruited in 10 total (45.5%) studies, with eight (36.4%) studies recruiting healthy matched controls 40 , 41 , 45 , 46 , 47 , 48 , 49 , 59 and two (13.6%) recruiting asymptomatic cancer patients (asymptomatic relative to survivorship burden) 19 , 55 (Table 1 ). With respect to treatment exposures, four (18.2%) studies limited their sample to patients treated with specific chemotherapies, 19 , 54 , 55 , 56 three (13.6%) limited their samples to patients receiving radiation therapy, 51 , 54 , 58 while most studies did not limit patient populations based on treatment exposures (Table 1 ).…”

“…Survivorship outcomes were assessed in patients through a combination of objective assessments in seven studies 42 , 43 , 44 , 46 , 49 , 54 , 55 (31.8%), medical record review for four studies 45 , 47 , 59 , 60 (18.2%), and patient self‐reported responses in 13 studies (59.1%) studies 19 , 40 , 41 , 44 , 47 , 49 , 50 , 51 , 52 , 53 , 56 , 57 , 58 (Table 1 ). Survivorship burdens related to cognition were evaluated in five studies, including outcomes related to self‐perceived cognitive decline evaluated with validated surveys and computerized cognitive assessments evaluating domains like psychomotor speed, learning and memory, attention, processing speed and executive function, and cumulative neurocognitive index.…”

“…Examples of comorbidities included: chronic cardiovascular diseases, obesity, diabetes, chronic obstructive pulmonary disease, asthma, and reproductive health issues. 45 , 46 , 47 , 56 , 59 Lastly, four studies examined survivorship burdens related to treatment specific toxicities with anticancer therapies captured with clinical assessments and chart review. Examples include methotrexate and mucositis, anthracyclines and cardiomyopathy, ototoxicity and cisplatin, and chemotherapy with gastrointestinal distress (Figure 3 ).…”