Introduction: Colorectal cancer (CRC) continues to rank as one of the most common cancers in the U.S. and around the world. Colorectal adenoma is the well-established precursor of CRC, yet only a very small proportion of adenomas progress to CRC. Therefore, identification of biomarker associated with adenoma progression is vital for risk stratification and development of intervention strategies. We hypothesize that genomic analysis of adenoma will lead to better understanding of tumorigenesis and identification of novel biomarkers.
Methods: We carried out whole exome sequencing (WES) on tissues and paired blood in 14 sessile serrated adenoma (SSA) and 36 tubulovillous adenoma (TVA) patients. Frequently mutated genes from TVA along with significantly mutated genes of TCGA colorectal adenocarcinoma were further investigated in an additional 100 pairs of TVA by targeted sequencing.
Results: 1) WES revealed similar somatic mutation frequency but distinctive mutated genes in TVA and SSA. 2) All adenomas included in WES were non-hypermutators with mutation frequency ranged from 0.55 to 3.71 (average: 1.49) non-silent somatic mutations per million base, which is significantly lower than that of TCGA non-hypermutators that ranged from 0.48 to 10.11 (average 4.47, p < 2.2×10⁁-16). 3) MutSigCV v1.4 discovered shared and unique significantly-mutated genes (SMG) in TVA and SSA reflecting difference in biology. 4) Targeted sequencing confirmed the findings in WES with a better estimate of population frequency for genes of interest. 5) Unsupervised clustering achieved high discrimination between adenoma and adenocarcinoma. 6) A subset of mutations that best discriminate adenoma and adenocarcinoma were identified by random Forest.
Conclusions: We discovered a set of genes with distinctive mutation pattern between adenoma and adenocarcinoma. We are conducting functional analysis to explore the potential of these genes as progression driver and risk predictors. We predict that the findings of this project will help lay the foundation to inform development of surveillance program and preventive intervention in CRC.
Citation Format: Shu-Hong Lin, Gottumukkala S. Raju, Chad Huff, Jian Gu, Jiun-Shen Chen, Scott Kopetz, David G. Menter, Ernest Hawk, Lopa Mishra, Yuanquing Ye, Xifeng Wu. Mutational landscape of colorectal adenomas reveals potential signatures for progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 143.