Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors.
Laterally spreading tumors (LST) are colorectal adenomas that develop into extremely large lesions with predominantly slow progression to cancer, depending on lesion subtype. Comparing and contrasting the molecular profiles of LSTs and colorectal cancers offers an opportunity to delineate key molecular alterations that drive malignant transformation in the colorectum. In a discovery cohort of 11 LSTs and paired normal mucosa, we performed a comprehensive and unbiased screen of the genome, epigenome, and transcriptome followed by bioinformatics integration of these data and validation in an additional 84 large, benign colorectal lesions. Mutation rates in LSTs were comparable with microsatellite-stable colorectal cancers (2.4 vs. 2.6 mutations per megabase); however, copy number alterations were infrequent (averaging only 1.5 per LST). Frequent genetic, epigenetic, and transcriptional alterations were identified in genes not previously implicated in colorectal neoplasia (ANO5, MED12L, EPB41L4A, RGMB, SLITRK1, SLITRK5, NRXN1, ANK2). Alterations to pathways commonly mutated in colorectal cancers, namely, the p53, PI3K, and TGFβ pathways, were rare. Instead, LST-altered genes converged on axonal guidance, Wnt, and actin cytoskeleton signaling. These integrated omics data identify molecular features associated with noncancerous LSTs and highlight that mutation load, which is relatively high in LSTs, is a poor predictor of invasive potential.



The novel genetic, epigenetic, and transcriptional changes associated with LST development reveal important insights into why some adenomas do not progress to cancer. The finding that LSTs exhibit a mutational load similar to colorectal carcinomas has implications for the validity of molecular biomarkers for assessing cancer risk. Mol Cancer Res; 14(12); 1217-28. ©2016 AACR.
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia. l.hesson@unsw.edu.au r.ward@uq.edu.au.
Luke B
LB
Hesson
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
Benedict
B
Ng
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
Peter
P
Zarzour
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.|Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India.
Sameer
S
Srivastava
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
Chau-To
CT
Kwok
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
Deborah
D
Packham
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
Andrea C
AC
Nunez
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
Dominik
D
Beck
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
Regina
R
Ryan
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
Ashraf
A
Dower
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
Caroline E
CE
Ford
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
John E
JE
Pimanda
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
Mathew A
MA
Sloane
School of Medical Sciences, UNSW Australia, Kensington, Sydney, Australia.
Nicholas J
NJ
Hawkins
Department of Gastroenterology, Westmead Hospital, Sydney, New South Wales, Australia.
Michael J
MJ
Bourke
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
Jason W H
JW
Wong
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia. l.hesson@unsw.edu.au r.ward@uq.edu.au.|Level 3 Brian Wilson Chancellery, The University of Queensland, Brisbane, Queensland, Australia.
Robyn L
RL
Ward
D000236:Adenoma / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study / Q000379:methods; D023281:Genomics / Q000379:methods*; D006801:Humans; D009154:Mutation; D017423:Sequence Analysis, RNA / Q000379:methods