The Relationship Between Cancer Risk and Epigenetic Age Acceleration After Stroke

Neurology Biochemistry Basic Medical Sciences Life Sciences Immunology Environmental and Public Health Oncology Medicine Cell Biology
stroke cancer risk epigenetic clock DNA methylation biological age acceleration

Study on the Association Between Long-Term Cancer Risk and Epigenetic Age in Stroke Survivors

Background and Significance

Cancer and stroke are leading global causes of morbidity and mortality, with their association being increasingly recognized. Statistics show that about 6% of cancer patients experience a stroke during their lifetime, while stroke survivors have double the risk of developing cancer compared to the general population. Furthermore, studies indicate that stroke (whether ischemic or hemorrhagic) can precede cancer diagnoses. This complex pathological relationship highlights the need to understand the underlying mechanisms.

DNA methylation (DNAm), a core area of epigenetic research, assesses the methylation status of specific CpG sites to construct epigenetic clocks. These clocks accurately predict biological age (B-age) and are closely associated with cancer and stroke risk. However, the potential relationship between B-age acceleration and post-stroke cancer risk remains unexplored.

This study, conducted by Suárez-Pérez et al. and published in Genome Medicine, aims to investigate the association between post-stroke cancer risk and B-age acceleration, validating the potential utility of epigenetic markers in predicting health outcomes.

Study Source

The study was conducted at Hospital del Mar in Barcelona, Spain, along with its affiliated research institute. Key authors include Antoni Suárez-Pérez, Adrià Macias-Gómez, and Jordi Jiménez-Conde. The data was sourced from the long-term follow-up of the BASICMAR stroke registry, covering cases from 2005 to 2014, with follow-up concluding in January 2023.

Methods and Workflow

Study Design

This prospective observational cohort study analyzed 940 cases from the BASICMAR registry. Patients with a history of cancer, a cancer diagnosis within three months of stroke onset, or follow-up durations under three months were excluded, resulting in 648 eligible patients. The primary endpoint was cancer incidence during the follow-up period.

Data Collection and Processing

  1. DNA Methylation Analysis:

    • Whole blood samples were collected within 24 hours of stroke onset, and DNAm was analyzed using Illumina 450K and Epic Beadchip platforms.
    • Quality control was performed to exclude low-quality CpG sites and samples, followed by data normalization using Noob and BMIQ methods.

  2. Epigenetic Clock Calculation:

    • Five epigenetic clocks (Hannum, Horvath, PhenoAge, Zhang BLUP/EN, and EpiToc) were used to estimate B-age.
    • Extrinsic epigenetic age acceleration (EEAA) and intrinsic epigenetic age acceleration (IEAA) were calculated, with adjustments for immune cell counts to reduce confounding.

  3. Follow-Up and Cancer Diagnosis:

    • Follow-up data were collected from medical records and patient interactions, with cancer diagnoses confirmed by oncologists.

Statistical Analysis

  • Cox regression and Fine-Gray subdistribution models were employed to assess associations between EEAA, IEAA, EpiToc estimates, and cancer risk, adjusting for confounders like sex, stroke type, and lifestyle factors.
  • Multiple testing corrections were applied using the Benjamini-Hochberg method.

Results

Population Characteristics and Cancer Incidence

  • Of the 648 patients (median follow-up: 8.15 years), 83 (12.8%) developed cancer, predominantly gastrointestinal tumors (41%).
  • Cancer incidence was higher in males (71.1% vs. 57.7%) and those with higher alcohol consumption (41.0% vs. 28.5%).

Epigenetic Age and Cancer Risk

  1. EEAA and Cancer Risk:

    • Hannum’s clock EEAA showed a significant association with cancer risk. Each additional year of EEAA increased cancer risk by 6% (HR = 1.06, 95% CI: 1.02–1.10, p = 0.002).
    • Zhang and EpiToc clocks showed significant associations in univariate analysis, with marginal significance in competing-risk models.

  2. IEAA Analysis:

    • IEAA findings were consistent with EEAA, reinforcing the role of epigenetic age acceleration in cancer risk.

  3. EpiToc Clock:

    • EpiToc values (raw and age-adjusted) were associated with a 27.6% and 28.8% increased cancer risk, respectively, though results were marginally significant after adjustments.

Impact of Sex and Stroke Type

  • Zhang clock’s EEAA was significantly associated with cancer in females but not in males.
  • Stroke type (ischemic or hemorrhagic) did not significantly affect the relationship between epigenetic age and cancer risk.

Conclusion and Implications

This study is the first to identify an independent association between accelerated epigenetic age (particularly Hannum’s EEAA) and increased cancer risk in stroke survivors. The findings highlight the potential of epigenetic markers in predicting health outcomes post-stroke and suggest integrating epigenetic data into high-risk patient screening.

The study also emphasizes the need for further research into sex-specific differences, cancer subtypes, and stroke types. Future studies should include larger sample sizes and longitudinal data collection to validate these findings.

Study Limitations

  • Limited sample size restricted the identification of additional associations and subgroup analyses for cancer subtypes.
  • DNAm analysis relied solely on peripheral blood, which may not fully capture tissue-specific methylation patterns.
  • Acute-phase sampling might have influenced B-age estimates.

Despite these limitations, the study provides robust evidence through its 15-year follow-up and comprehensive epigenetic analyses, offering new insights into the cancer-stroke relationship and paving the way for potential clinical applications of epigenetic clocks.