Age-dependent clinical prognostic value of histone modifications in colorectal cancer

Aging is one of the prime risk factors for the development of cancer. Expression patterns of epigenetic regulators, including histone modification levels, are altered during aging of normal cells, a phenomenon referred to as epigenetic drift. Furthermore, it is known that epigenetic mechanisms are involved in the development of cancer. We hypothesized that expression of histone modifications, acetylation of histone 3 lysine 9 (H3K9Ac) and trimethylation of histone 3 lysine 27 (H3K27me3), with reported normal age-related expression patterns might show an age-dependent prognostic value in colorectal cancer (CRC). To quantify expression, we performed immunohistochemical staining of these histone modifications on a tissue microarray containing colorectal tissues of the 254 patients with TNM stage I-Ill CRC. Stratification of patients according to survival status revealed age-related tumor expression patterns of both H3K9Ac and H3K27me3. Decreased expression with advancing age was observed in patients who were alive after follow-up (no-event group), whereas increased expression with advancing age was observed in patients who presented with a recurrence or death in follow-up (event group). These opposite expression patterns translated into an age-dependent prognostic value in CRC for the individual histone modifications and their combination. The prognostic value reverses with advancing age, high nuclear expression associated with good clinical outcome in young adults, and, in contrast, with worse clinical outcome in elderly patients. In conclusion, for the first time, we demonstrated prognostic impact of epigenetic biomarkers that reverses with advancing age. This new insight supports the hypothesis that CRC biology is different in young vs elderly patients and emphasizes the importance of focusing on age-related effects in CRC.