p16 a biomarker of aging and tolerance for cancer therapy

Muss, Hyman B.; Smitherman, Andrew B.; Wood, William A.; Nyrop, Kirsten A.; Tuchman, Sascha A.; Randhawa, Paramjeet; Entwistle, Amy; Mitin, Natalia; Shachar, Shlomit Strulov

doi:10.21037/tcr.2020.03.39

Cited by 35 publications

(33 citation statements)

References 78 publications

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“…In the current study, among the cross-sectional cohort of young adult survivors who were treated for a broad range of cancers, the mean p16 level (9.6 log 2 p16 units) was 0.7 log 2 units higher than that of age-matched controls. On the basis of analyses of p16 expression by age in a cohort of 536 donors either without a history of cancer or without a history of chemotherapy exposure, 21 a 0.7-log 2 -unit increase in p16 expression is equivalent to an advancement of 25 years in chronological age. Increased senescence related to cytotoxic chemotherapy has been observed previously in multiple human tumor cell lines, in mouse models (for reviews, see Spallarossa et al 22 and Marcoux et al 22,23 ), and among older adults 12,13 ; however, to our knowledge, this is the first report of such findings among young adult survivors of childhood, adolescent, and young adult cancers.…”

Section: Discussionmentioning

confidence: 99%

“…In other cases, differences in p16 levels were converted to chronological years to conceptualize the degree of age acceleration. The version of the assay used in this study has a p16 expression versus age correlation slope with a mean increase of 0.028 log 2 units per year of chronological age 21 . Therefore, conversion of the change in log 2 p16 units to years of chronological aging in this study was calculated using the following formula: ∆log 2 p16/0.028, consistent with the assay version used.…”

Section: Methodsmentioning

confidence: 99%

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Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16^INK4a and frailty

Smitherman

Wood

Mitin

et al. 2020

Cancer

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BACKGROUND: Cellular senescence, measured by expression of the cell cycle kinase inhibitor p16 INK4a , may contribute to accelerated aging in survivors of childhood, adolescent, and young adult cancer. The authors measured peripheral blood T-lymphocyte p16 INK4a expression among pediatric and young adult cancer survivors, hypothesizing that p16 INK4a expression is higher after chemotherapy and among frail survivors. METHODS: A cross-sectional cohort of young adult survivors and age-matched, cancer-free controls were assessed for p16 INK4a expression and frailty. Newly diagnosed pediatric patients underwent prospective measurements of p16 INK4a expression before and after cancer therapy. Frailty was measured with a modified Fried frailty phenotype evaluating sarcopenia, weakness, slowness, energy expenditure, and exhaustion. RESULTS: The cross-sectional cohort enrolled 60 survivors and 29 age-matched controls with a median age of 21 years (range, 17-29 years). The prospective cohort enrolled 9 newly diagnosed patients (age range, 1-18 years). Expression of p16 INK4a was higher among survivors compared with controls (9.6 vs 8.9 log 2 p16 units; 2-sided P = .005, representing a 25-year age acceleration in survivors) and increased among newly diagnosed patients from matched pretreatment to posttreatment samples (7.3-8.9 log 2 p16 units; 2-sided P = .002). Nine survivors (16%) were frail and had higher p16 INK4a expression compared with robust survivors (10.5 [frail] vs 9.5 [robust] log 2 p16 units; 2-sided P = .055), representing a 35-year age acceleration among frail survivors. CONCLUSIONS: Chemotherapy is associated with increased cellular senescence and molecular age in pediatric and young adult cancer survivors. Frail survivors, compared with robust survivors, exhibit higher levels of p16 INK4a , suggesting that cellular senescence may be associated with early aging in survivors. Cancer 2020;126:4975-4983.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16^INK4a and frailty

Smitherman

Wood

Mitin

et al. 2020

Cancer

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“…All analyses were conducted using SAS statistical software v9.4 (Cary, NC). Conversion of change in log2 p16 to years of chronologic aging was calculated using the formula: Δlog2p16/0.028 derived from a 633-patient cohort ( 32 ). All statistical tests were 2-sided, and a P value of less than .05 was considered statistically significant.…”

Section: Methodsmentioning

confidence: 99%

Effects of Breast Cancer Adjuvant Chemotherapy Regimens on Expression of the Aging Biomarker, p16INK4a

Shachar

Deal

Reeder‐Hayes

et al. 2020

JNCI Cancer Spectrum

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Background While chemotherapy saves lives, increasing evidence shows that chemotherapy accelerates aging. We previously demonstrated that mRNA expression of p16INK4a, a biomarker of senescence and molecular aging, increased early and dramatically after beginning adjuvant anthracycline-based regimens in early-stage breast cancer patients. Here, we determined if changes in p16INK4a expression vary by chemotherapy regimen among early-stage breast cancer patients. Methods We conducted a study of Stage I-III breast cancer patients receiving adjuvant or neoadjuvant chemotherapy. p16INK4a expression was analyzed pre-chemotherapy and post-chemotherapy (median 6.2 months after the last chemotherapy) in peripheral blood T-lymphocytes. Chemotherapy-induced change in p16INK4a expression was compared among regimens. All statistical tests were two-sided. Results In 146 women, chemotherapy was associated with a statistically significant increase in p16INK4a expression (accelerated aging of 17 years; p<.001). Anthracycline-based regimens were associated with the largest increases (accelerated aging of 23 to 26 years; p≤.008). Non-anthracycline-based regimens demonstrated a much smaller increase (accelerated aging of 9 to 11 years; p≤.15). In addition to the type of chemotherapy regimen, baseline p16INK4a levels, but not chronologic age or race, were also associated with the magnitude of increases in p16INK4a. Patients with lower p16INK4a levels at baseline were more likely to experience larger increases. Conclusions Our findings suggest that the aging effects of chemotherapy may be influenced by both chemotherapy type and the patient’s baseline p16INK4a level. Measurement of p16INK4a expression is not currently available in the clinic, but non-anthracycline regimens offering similar efficacy as anthracycline regimens might be favored.

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“…p16Age Gap calculation P16 expression levels were converted into equivalent years of aging (p16Age) using a linear regression formula derived from analysis of p16 expression in 633 subjects 48 . The p16 value corresponding to the participants' chronological age at the start of chemotherapy was then subtracted from p16Age to calculate p16Age Gap.…”

Section: P16 Expression Levelsmentioning

confidence: 99%

A biomarker of aging, p16, predicts peripheral neuropathy in women receiving adjuvant taxanes for breast cancer

Mitin

Nyrop

Strum

et al. 2022

Preprint

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Importance: Identifying patients at higher risk of chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet need in oncology given its high incidence and persistence into survivorship. Objective: To determine if expression of p16, a biomarker of aging and cellular senescence, predicts CIPN. Design: Prospective observational cohort study including one hundred fifty-two participants enrolled between January 2014 and August 2018 and followed during the course of adjuvant chemotherapy. Expression of p16 was measured prior to and at the end of chemotherapy. Side effects, including peripheral neuropathy, were assessed prior to each chemotherapy cycle. Setting: A multi-center study including four major academic hospitals and five community oncology clinics. Participants: Women with newly diagnosed with stage I to III breast cancer to receive chemotherapy including a taxane. Main Outcomes and Measure: Development of grade 2+ (moderate or worse) CIPN during the course of chemotherapy treatment. CIPN symptoms were graded by participants oncology clinician using the NCI-CTCAE v5 system. Expression of p16 mRNA was measured by qPCR in T-lymphocytes isolated from fresh peripheral blood. Results: A multivariate model including taxane regimen type and p16Age Gap, a measure of discordance between chronological age and p16 expression, identified risk factors for CIPN. Participants with higher chronological age but lower p16 expression prior to chemotherapy (molecularly young) were at the highest risk. Incidence of CIPN positively correlated with chemotherapy-induced increase in p16 expression, with the largest increase seen in participants with the lowest p16 expression prior to treatment. Conclusions and Relevance: This is the first report describing a model to identify patients at risk for taxane-induced CIPN. Studies to confirm and validate our findings are ongoing. When validated, a p16Age Gap-based model can be used to guide chemotherapy selection in patients with early breast cancer, given that chemotherapy regimens for this indication usually employ one of two taxanes (paclitaxel or docetaxel) with similar efficacy but different risks of CIPN.

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p16 a biomarker of aging and tolerance for cancer therapy

Cited by 35 publications

References 78 publications

Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16^INK4a and frailty

Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16^INK4a and frailty

Effects of Breast Cancer Adjuvant Chemotherapy Regimens on Expression of the Aging Biomarker, p16INK4a

A biomarker of aging, p16, predicts peripheral neuropathy in women receiving adjuvant taxanes for breast cancer

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p16 a biomarker of aging and tolerance for cancer therapy

Cited by 35 publications

References 78 publications

Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16INK4a and frailty

Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16INK4a and frailty

Effects of Breast Cancer Adjuvant Chemotherapy Regimens on Expression of the Aging Biomarker, p16INK4a

A biomarker of aging, p16, predicts peripheral neuropathy in women receiving adjuvant taxanes for breast cancer

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Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16^INK4a and frailty

Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16^INK4a and frailty