GU Cancers 2018 | Molecular aging and p16INK4a in testicular cancer survivors

Maria Teresa Bourlon

Maria Teresa Bourlon, MD, MS, of Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico, discusses the link between chemotherapy and premature ageing, via the biomarker p16INK4a, in testicular cancer survivors at the Genitourinary Cancers Symposium 2018, held in San Francisco, CA. Although testicular cancer patients can be cured successfully with chemotherapy, they still suffer from the long-term effects of the treatment. The results of Dr Bourlon’s research show an increased expression of the p16INK4a senescence protein in patients exposed to chemotherapy. p16INK4a has been found to inhibit CDK4/6 and promote p53 degradation, essentially causing premature senescence. Consequently, testicular cancer survivors may have an increased cancer risk, risk of infection and a weaker response to vaccinations, which is concerning for survivors.

Transcript (edited for clarity):

Testicular cancer patients, even if they present in advanced stages, can be cured with chemotherapy. But we know that testicular cancer survivors, after chemotherapy, struggle with long-term side effects. One of the side effects that hasn’t been described is if chemotherapy induces early aging.

In the study, we found that p16, which is an aging biomarker, is elevated in those patients who have been previously exposed to chemotherapy compared to normal controls of the same age. The implication of this is that their immune system may age earlier than healthy individuals. We know that several aggressors may induce senescence; this includes the inactivation of oncogenes, radiation and also chemotherapy. They might produce p16 expression which inhibits cyclin dependent kinases 4/6 and dephosphorylates retinoblastoma. At the same time, it may also induce p14 which promotes p53 degradation. Retinoblastoma may be dephosphorylated by either the p16 pathway or the p53/p21 pathway. We know retinoblastoma is a main activator of senescence so chemotherapy can potentially induce premature aging.

What we know about this study is that testicular cancer survivors, after chemotherapy, exhibit an increased expression of the aging biomarker p16 and they also exhibit an immunophenotype that is associated with premature senescence. This is the first time this is reported in this population and the implication of premature aging could increase risk of infection, give a poor response to vaccination and may increase the risk of cancer in the elderly. It’s something that warrants further investigation because our survivors might be at increased risk of developing these complications or long-term toxicity which is premature aging.

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