Abstract 67: Genomic and mutational profiling of human colon adenomas reveals early driver mutations and a TGF-β-CEA regulated profile

Abstract

Abstract Introduction: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world with 143,700 newly diagnosed cases in 2012. The rapid development of cancers in small, sessile adenomas could be a contributing factor that may have been overlooked. Identifying high risk patients through genomic analysis of adenomas could potentially lead to an early intervention therapy. Methods: Whole Genome Sequence (WGS) and Whole Exome Sequence (WES) analyses were performed for 4 pairs of normal controls (two from proximal colon and two from the distal colon) and colorectal adenomas (2 sessile serrated (SSA) and 2 tubulovillous adenomas (TVA) less than 1 cm in size). Transcriptome sequence analysis was performed in seven pairs of control-test matched adenomas (6 TVA and 1 SSA). Expression level of CEA and TGF-β pathway members were carried out on 30 non dysplastic adenomas and normal colon tissues by immunohistochemistry. Results: 1. Hyper-mutator profiles were observed in two of the samples (1 SSA and 1 TVA) by WGS with 1709 mutations after normalization with normal paired samples. 2. The samples showed an average mutation frequency of 0.55 mutations per 106 bases. 3. Aberrant mutational profiles was detected in seven of the eleven adenomas, with distinct mutational signatures among the samples, two with high, two intermediate and three low mutational rates. 4. Six of the eleven adenomas (1 SSA and 4 TVAs) showed alteration in the Wnt and p53 pathway. 5. Transitional single nucleotide substitutions of C:T>G:A in the mutational spectrum were observed in 37% of the samples. 6. Subtle localized hyper mutation (kataegis) was observed among two of the samples. 7. Five out of eleven adenomas showed mutations in the TGF-β (transforming growth factor-β) and CEA pathways members, overlapping with Wnt/p53 mutations in four adenomas. 8. Analyses of expression level of CEA and TGF-β pathway members in 30 non dysplastic tissues revealed a marked increase (over 8 fold) in CEA expression in 25% of adenoma samples which was linked to concomitant loss of TGF-β signaling. 9. Further functional studies revealed that CEA associated with TGF-β Type I receptor and disruption of TGF-β tumor suppressor signaling with activation of STAT3. Conclusions: Our studies indicate that small adenomas both TVAs and SSAs can resemble CRCs in genomic profiling and may reflect a high risk population. Genetic and mechanistic analyses reveal that disruption of CEA/TGF-β pathway in early adenomas may reflect a new and early role for these pathways in CRC. This study further supports the biomarker driven targeting of CEA/TGF-β in high risk adenomas and can be used as a prognostic marker for early detection of aggressive adenoma-CRC progression. Citation Format: Vipin K. Menon, Raju S. Gottumukkala, Jian Chen, Xiaoping Su, Nipun Mistry, Avijit Majumdar, Ji-Hyun Shin, Shulin Li, Kirti Shetty, Xifeng Wu, Brian Weston, Ethan Miller, John R. Stroehlein, Marta L. Davila, Mehnaz A. Shafi, Asif Rashid, Bhaskar V. Kallakury, Selvi Thirumurthi, John S. McMurray, Sue-Hwa Lin, Wilma Jogunoori, Lopa Mishra. Genomic and mutational profiling of human colon adenomas reveals early driver mutations and a TGF-β-CEA regulated profile. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 67. doi:10.1158/1538-7445.AM2015-67