Expression of the senescence biomarker p16INK4a among childhood, adolescent, and young adult cancer survivors.

Abstract

10556 Background: The mechanism of accelerated aging among survivors of childhood, adolescent, and young adult cancer is not clearly understood. Cellular senescence may contribute to this process. We measured peripheral blood T lymphocyte p16INK4a expression, a biomarker of cellular senescence and aging, among pediatric and young adult cancer survivors hypothesizing that p16INK4a expression is higher due to chemotherapy exposure and among frail survivors. Methods: Two cohorts were enrolled from January 2018 to December 2019 at an academic medical center. One, a cross-sectional cohort of young adult cancer survivors and age-matched, cancer-free controls in whom we assessed p16INK4a expression and clinical frailty. Frailty was measured with the modified Fried Frailty Index that evaluates skeletal muscle index, weakness, slowness, leisure energy expenditure, and exhaustion. A second cohort underwent prospective measurement of p16INK4a expression before and after cancer chemotherapy. Eligibility among survivors and newly diagnosed patients required treatment with an alkylating agent, an anthracycline / anthracenedione, or both. Multivariable linear regression was used to model expression of p16INK4a by patient age at assessment, treatment intensity, and frailty status. Results: The cross-sectional cohort enrolled 60 young adult survivors and 29 age-matched, cancer-free controls with median age 21 years and range 17-29 years for both groups. Survivors were a median of 5.5 years from end of treatment. The prospective cohort enrolled nine newly diagnosed patients (range 1-18 years). Expression of p16INK4a was higher among young adult cancer survivors as compared to age-matched controls (9.6 v. 8.9 log2 p16 units, p < 0.01) representing a 25-year age acceleration in the survivors. Expression of p16INK4a increased among newly diagnosed patients from matched pre- to post-treatment samples (7.3 to 8.9 log2 p16 units, p = 0.002). Nine survivors (16%) met criteria for being frail and had higher p16INK4a expression as compared to robust survivors (10.5 [frail] v. 9.5 [robust] log2 p16 units, p = 0.055). Conclusions: Chemotherapy is associated with increased cellular senescence in pediatric and young adult cancer survivors as reflected in expression of p16INK4a indicating an increase in molecular age following chemotherapy exposure. The large proportion of frail survivors in this study also exhibited higher levels of p16INK4a suggesting that cellular senescence may be associated with early aging observed among these survivors.