Abstract 1197: Chromosomal aberrations implicated in colorectal adenoma to carcinoma progression as markers of high risk colorectal adenomas.

Background: Colorectal adenomas are precursor lesions of colorectal cancer. About 5% of colorectal adenomas are estimated to progress to colorectal cancer (CRC). The currently used histo-pathological characteristics to identify adenomas at risk of malignant progression, i.e. scoring of size ≥ 10mm, villous component or high grade dysplasia, are not sufficiently sensitive and specific and prone to inter-observer variability. Integrating molecular markers reflecting the underlying biology of CRC into the current classification system is expected to better characterize adenomas at high-risk of progression. Aim: Here we compared the prevalence of genetic changes, in particular DNA copy number changes, between advanced and non-advanced adenomas. Methods: Formalin-fixed paraffin-embedded tissue samples from 121 patients (mean age 65.4±11.6, 52.9% male) with colorectal adenomas (63 non-advanced adenomas and 58 advanced adenomas) were retrospectively collected from the archives of the department of pathology of the VU - University medical center (VUmc), Amsterdam, the Netherlands. DNA was extracted and DNA copy number analysis was performed using Multiplex Ligation-dependent Probe Amplification (MLPA), focusing on 7 chromosomal regions previously associated with adenoma-to-carcinoma progression, namely 8p, 15q, 17p and 18q loss and 8q,13q and 20q gain (1). Comparison of DNA copy number aberrations between sub-groups was done using a Chi-square test, or Fisher9s exact test when appropriate. For multivariate analysis logistic regression was used. Data analysis was performed using SPSS version 22 (IBM SPSS Statistics) and p-values below 0.05 were considered to be statistically significant (using two-sided tests). Results: Of the adenomas analyzed 23.1% (28/121) showed at least one gain or loss of the investigated chromosomal regions. Two or more chromosomal aberrations were present in 22.4 % (13/58) of the advanced adenomas and 1.6% (1/63) of the non-advanced adenomas (p=0,001). Since advanced colorectal adenomas are defined based on their histological characteristics ((tubulo)villous component and/or high degree dysplasia and/or ≥ 10mm), we searched for associations of these histological features with the analyzed chromosomal aberrations (CAE9s). Multivariate analysis showed that only gains of 13q and 20q were significantly associated with adenomas ≥ 10mm (p=0.01 and p=0.003, respectively) and losses of 18q were significantly associated with high-grade dysplasia (p=0.04). Conclusion: Our data indicate that DNA copy number alterations are not as frequent as expected in advanced adenomas and are also found in non-advanced and diminutive lesions. Combining histological and molecular features in adenoma follow-up studies could increase the knowledge on malignant potential of adenomas. (1) Hermsen et al, Gastroenterology, 2002; 123:1109-1119 Citation Format: Beatriz Carvalho, Begona Diosdado, Jochim S. Terhaar Sive Droste, Anne S. Bolijn, Meike de Wit, Myrthe van Burink, Remond JA Fijneman, Nicole CT van Grieken, Gerrit A. Meijer. Chromosomal aberrations implicated in colorectal adenoma to carcinoma progression as markers of high-risk colorectal adenomas. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A04.