PLoS ONE (Jan 2016)

Mutational Profiles Reveal an Aberrant TGF-β-CEA Regulated Pathway in Colon Adenomas.

  • Jian Chen,
  • Gottumukkala S Raju,
  • Wilma Jogunoori,
  • Vipin Menon,
  • Avijit Majumdar,
  • Jiun-Sheng Chen,
  • Young Jin Gi,
  • Yun Seong Jeong,
  • Liem Phan,
  • Mitchell Belkin,
  • Shoujun Gu,
  • Suchin Kundra,
  • Nipun A Mistry,
  • Jianping Zhang,
  • Xiaoping Su,
  • Shulin Li,
  • Sue-Hwa Lin,
  • Milind Javle,
  • John S McMurray,
  • Thomas F Rahlfs,
  • Bibhuti Mishra,
  • Jon White,
  • Asif Rashid,
  • Nicole Beauchemin,
  • Brian R Weston,
  • Mehnaz A Shafi,
  • John R Stroehlein,
  • Marta Davila,
  • Rehan Akbani,
  • John N Weinstein,
  • Xifeng Wu,
  • Lopa Mishra

DOI
https://doi.org/10.1371/journal.pone.0153933
Journal volume & issue
Vol. 11, no. 4
p. e0153933

Abstract

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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.