42. Epigenomic profiling of anal cancer: does size matter? An RTOG 98-11 specimen study

Abstract

Background Anal cancer accounts for 4% of all lower gastrointestinal tract malignancies in the US. One of the most important predictors of prognosis among anal cancer patients is the size of the primary tumour. Tumours with diameters >5 cm have poorer disease-free survival than those with smaller tumours. Understanding the biological changes associated with tumour growth may provide information to guide therapy and improve patient outcomes. DNA methylation changes are critical epigenetic events in cancer development. Methods: In this study we sought to characterise the epigenomic signatures associated with anal cancer tumour size (≤5 cm vs >5 cm) in FFPE tissues from 121 patients (≤5 cm = 88; >5 cm = 33) who participated in the RTOG 98–11 cooperative group anal cancer clinical trial. Differential methylation, examined at >450 000 CpG loci using the Illumina Human Methylation 450 Array, were compared between the two groups using Mann–Whitney test (significance = P < 0.001 and difference in methylation β-value >0.1). Results: This study included 74 women and 47 men with a median age of 54 years. A total of 86 CpG loci were differentially methylated (78 increased and 8 decreased) in large vs small tumours. Genes harbouring CpG sites that were among the most highly differentially methylated included those associated with WNT signalling (FZD10, WNT9A), microRNAs (MIR200A) and novel methylated targets (PON3). Conclusions: These data provide evidence that epigenetic events likely play a significant role in the progression of anal SCC and may serve as biomarkers of prognosis. Similar epigenomic approaches may be useful at earlier stages of anal neoplastic progression for application in screening and early detection.