Mutational Profiles Reveal an Aberrant TGF-β-CEA Regulated Pathway in Colon Adenomas.
Mutational processes and signatures that drive early tumorigenesis are centrally important for early cancer prevention. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. Here, we describe surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Transitional single nucleotide substitutions of C:G>T:A predominate in the adenoma mutational spectrum. Strikingly, we observe mutations in the TGF-β pathway and CEA-associated genes in 4 out of 11 adenomas, overlapping with the Wnt pathway. Immunohistochemical labeling reveals a nearly 5-fold increase in CEA levels in 23% of adenoma samples with a concomitant loss of TGF-β signaling. We also define a functional role by which the CEA B3 domain interacts with TGFBR1, potentially inactivating the tumor suppressor function of TGF-β signaling. Our study uncovers diverse mutational processes underlying the transition from early adenoma to cancer. This has broad implications for biomarker-driven targeting of CEA/TGF-β in high-risk adenomas and may lead to early detection of aggressive adenoma to CRC progression.
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Jian
J
Chen
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Gottumukkala S
GS
Raju
Institute of Clinical Research, Veterans Affairs Medical Center, Washington DC, United States of America.
Wilma
W
Jogunoori
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Vipin
V
Menon
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Avijit
A
Majumdar
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Jiun-Sheng
JS
Chen
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Young Jin
YJ
Gi
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Yun Seong
YS
Jeong
Departments of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Liem
L
Phan
Institute of Clinical Research, Veterans Affairs Medical Center, Washington DC, United States of America.
Mitchell
M
Belkin
Center for Translational Medicine, Department of Surgery and George Washington Cancer Center, George Washington University, Washington DC, United States of America.
Shoujun
S
Gu
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Suchin
S
Kundra
Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Nipun A
NA
Mistry
Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Jianping
J
Zhang
Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Xiaoping
X
Su
Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Shulin
S
Li
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Sue-Hwa
SH
Lin
Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Milind
M
Javle
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
John S
JS
McMurray
Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Thomas F
TF
Rahlfs
Institute of Clinical Research, Veterans Affairs Medical Center, Washington DC, United States of America.
Bibhuti
B
Mishra
Institute of Clinical Research, Veterans Affairs Medical Center, Washington DC, United States of America.
Jon
J
White
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Asif
A
Rashid
Goodman Cancer Research Centre and Departments of Biochemistry, Medicine and Oncology, McGill University, Montreal, Canada.
Nicole
N
Beauchemin
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Brian R
BR
Weston
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Mehnaz A
MA
Shafi
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
John R
JR
Stroehlein
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Marta
M
Davila
Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Rehan
R
Akbani
Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
John N
JN
Weinstein
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Xifeng
X
Wu
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Institute of Clinical Research, Veterans Affairs Medical Center, Washington DC, United States of America.|Center for Translational Medicine, Department of Surgery and George Washington Cancer Center, George Washington University, Washington DC, United States of America.
Lopa
L
Mishra
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002272:Carcinoembryonic Antigen / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D009154:Mutation / Q000235:genetics*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; D016212:Transforming Growth Factor beta