Epigenetic aging in older breast cancer survivors and noncancer controls: preliminary findings from the Thinking and Living with Cancer Study

Rentscher, Kelly E.; Bethea, Traci N.; Zhai, Wanting; Small, Brent J.; Zhou, Xingtao; Ahles, Tim A.; Ahn, Jaeil; Breen, Elizabeth C.; Cohen, Harvey Jay; Extermann, Martine; Graham, Deena; Jim, Heather; McDonald, Brenna C.; Nakamura, Zev M.; Patel, Sunita K.; Root, James C.; Saykin, Andrew J.; Dyk, Kathleen Van; Mandelblatt, Jeanne S.; Carroll, Judith

doi:10.1002/cncr.34818

Cited by 17 publications

(21 citation statements)

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“…Differences in EAA of this magnitude were associated with functional decline and mortality among adult patients with cancer undergoing chemotherapy. 29,30 This study provided novel evidence of a linear association between the DAI, a clinically validated marker of aging, and epigenetic markers of biological aging, suggesting substantial aging-related biological process underlying the DAI. This finding is consistent with a prior report showing that the DAI was associated with mortality in young adult cancer survivors.…”

Section: Discussionmentioning

confidence: 68%

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Deficit Accumulation Index and Biological Markers of Aging in Survivors of Childhood Cancer

Williams,

Mandelblatt,

Wang

et al. 2023

JAMA Netw Open

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ImportanceSurvivors of childhood cancer experience premature aging compared with community controls. The deficit accumulation index (DAI) uses readily available clinical data to measure physiological age in survivors; however, little data exist on how well deficit accumulation represents underlying biological aging among survivors of cancer.ObjectiveTo examine the associations between the DAI and epigenetic age acceleration (EAA) and mean leukocyte telomere length (LTL).Design, Setting, and ParticipantsThis cross-sectional study analyzed data from the St Jude Lifetime Cohort, an assessment of survivors of childhood cancer who were treated at St Jude Children’s Research Hospital in Memphis, Tennessee. Data were collected between 2007 and 2016, assayed between 2014 and 2019, and analyzed between 2022 and 2023. Participants were adult survivors who were diagnosed between 1962 and 2012 and who survived 5 years or more from time of diagnosis. The analyses were restricted to survivors with European ancestry, as there were too few survivors with non-European ancestry.ExposuresThe DAI included 44 aging-related items, such as chronic health conditions and functional, psychosocial, and mental well-being. Item responses were summed and divided by the total number of items, resulting in a ratio ranging from 0 to 1. These DAI results were categorized based on reported associations with hospitalization and mortality: low, defined as a DAI less than 0.2; medium, defined as a DAI of 0.2 to less than 0.35; and high, defined as a DAI of 0.35 or higher.Main Outcomes and MeasuresGenome-wide DNA methylation was generated from peripheral blood mononuclear cell–derived DNA. The EAA was calculated as the residuals from regressing the Levine epigenetic age on chronological age. The mean LTL was estimated using whole-genome sequencing data.ResultsThis study included 2101 survivors of childhood cancer (1122 males [53.4%]; mean [SD] age, 33.9 [9.1] years; median [IQR] time since diagnosis, 25.1 [18.7-31.9] years) with European ancestry. Compared with survivors in the low DAI group, those in the high DAI group experienced 3.7 more years of EAA (β = 3.66; 95% CI, 2.47-4.85; P &lt; .001), whereas those in the medium DAI group experienced 1.8 more years of EAA (β = 1.77; 95% CI, 0.84-2.69; P &lt; .001), independent of treatment exposures. The EAA and DAI association was consistent across 3 common diagnoses (acute lymphoblastic leukemia, Hodgkin lymphoma, and central nervous system tumors) and across chronological age groups. For example, among acute lymphoblastic leukemia survivors, those in the medium DAI group (β = 2.27; 95% CI, 0.78-3.76; P = .001) experienced greater EAA vs those in the low DAI group. Similarly, among survivors younger than 30 years, the high DAI group experienced 4.9 more years of EAA vs the low DAI group (β = 4.95; 95% CI, 2.14-7.75; P &lt; .001). There were no associations between mean LTL residual and the DAI.Conclusions and RelevanceThis cross-sectional study of survivors of childhood cancer showed that the DAI was associated with EAA, suggesting an underlying biological process to the accumulation of deficits. Both the DAI and EAA were effective at identifying aging phenotypes, and either may be used to measure aging and response to interventions targeting aging pathways.

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Section: Discussionmentioning

confidence: 68%

“…This pattern was consistent across age groups. Differences in EAA of this magnitude were associated with functional decline and mortality among adult patients with cancer undergoing chemotherapy …”

Section: Discussionmentioning

confidence: 98%

Deficit Accumulation Index and Biological Markers of Aging in Survivors of Childhood Cancer

Williams,

Mandelblatt,

Wang

et al. 2023

JAMA Netw Open

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“…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 …”

Section: Resultsmentioning

confidence: 99%

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

Sayer,

Ng,

Chan

et al. 2024

Cancer Medicine

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IntroductionIdentifying reliable biomarkers that reflect cancer survivorship symptoms remains a challenge for researchers. DNA methylation (DNAm) measurements reflecting epigenetic changes caused by anti‐cancer therapy may provide needed insights. Given lack of consensus describing utilization of DNAm data to predict survivorship issues, a review evaluating the current landscape is warranted.ObjectiveProvide an overview of current studies examining associations of DNAm with survivorship burdens in cancer survivors.MethodsA literature review was conducted including studies if they focused on cohorts of cancer survivors, utilized peripheral blood cell DNAm data, and evaluated the associations of DNAm and survivorship issues.ResultsA total of 22 studies were identified, with majority focused on breast (n = 7) or childhood cancer (n = 9) survivors, and half studies included less than 100 patients (n = 11). Survivorship issues evaluated included those related to neurocognition (n = 5), psychiatric health (n = 3), general wellness (n = 9), chronic conditions (n = 5), and treatment specific toxicities (n = 4). Studies evaluated epigenetic age metrics (n = 10) and DNAm levels at individual CpG sites or regions (n = 12) for their associations with survivorship issues in cancer survivors along with relevant confounding factors. Significant associations of measured DNAm in the peripheral blood samples of cancer survivors and survivorship issues were identified.Discussion/ConclusionStudies utilizing epigenetic age metrics and differential methylation analysis demonstrated significant associations of DNAm measurements with survivorship burdens. Associations were observed encompassing diverse survivorship outcomes and timeframes relative to anti‐cancer therapy initiation. These findings underscore the potential of these measurements as useful biomarkers in survivorship care and research.

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“…There is a considerable interest in the potential of epigenetic dysregulation as biomarkers and therapeutic targets in BC. The association between epigenetic aging and clinical outcomes has been recently evaluated in longer term BC survivors to guide cancer care for older women ( 10 ). Epigenetic malfunctions can potentially be restored to their normal phenotypes through epigenetic-based therapies ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic modulation of antitumor immunity and immunotherapy response in breast cancer: biological mechanisms and clinical implications

Yin,

Gu,

Chaudhry

et al. 2024

Front. Immunol.

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Breast cancer (BC) is the most common non-skin cancer and the second leading cause of cancer death in American women. The initiation and progression of BC can proceed through the accumulation of genetic and epigenetic changes that allow transformed cells to escape the normal cell cycle checkpoint control. Unlike nucleotide mutations, epigenetic changes such as DNA methylation, histone posttranslational modifications (PTMs), nucleosome remodeling and non-coding RNAs are generally reversible and therefore potentially responsive to pharmacological intervention. Epigenetic dysregulations are critical mechanisms for impaired antitumor immunity, evasion of immune surveillance, and resistance to immunotherapy. Compared to highly immunogenic tumor types, such as melanoma or lung cancer, breast cancer has been viewed as an immunologically quiescent tumor which displays a relatively low population of tumor-infiltrating lymphocytes (TIL), low tumor mutational burden (TMB) and modest response rates to immune checkpoint inhibitors (ICI). Emerging evidence suggests that agents targeting aberrant epigenetic modifiers may augment host antitumor immunity in BC via several interrelated mechanisms such as enhancing tumor antigen presentation, activation of cytotoxic T cells, inhibition of immunosuppressive cells, boosting response to ICI, and induction of immunogenic cell death (ICD). These discoveries have established a highly promising basis for using combinatorial approaches of epigenetic drugs with immunotherapy as an innovative paradigm to improve outcomes of BC patients. In this review, we summarize the current understanding of how epigenetic processes regulate immune cell function and antitumor immunogenicity in the context of the breast tumor microenvironment. Moreover, we discuss the therapeutic potential and latest clinical trials of the combination of immune checkpoint blockers with epigenetic agents in breast cancer.

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Epigenetic aging in older breast cancer survivors and noncancer controls: preliminary findings from the Thinking and Living with Cancer Study

Cited by 17 publications

References 94 publications

Deficit Accumulation Index and Biological Markers of Aging in Survivors of Childhood Cancer

Deficit Accumulation Index and Biological Markers of Aging in Survivors of Childhood Cancer

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

Epigenetic modulation of antitumor immunity and immunotherapy response in breast cancer: biological mechanisms and clinical implications

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