Chen Jian, Raju Gottumukkala S, Jogunoori Wilma, Menon Vipin, Majumdar Avijit, Chen Jiun-Sheng, Gi Young Jin, Jeong Yun Seong, Phan Liem, Belkin Mitchell, Gu Shoujun, Kundra Suchin, Mistry Nipun A, Zhang Jianping, Su Xiaoping, Li Shulin, Lin Sue-Hwa, Javle Milind, McMurray John S, Rahlfs Thomas F, Mishra Bibhuti, White Jon, Rashid Asif, Beauchemin Nicole, Weston Brian R, Shafi Mehnaz A, Stroehlein John R, Davila Marta, Akbani Rehan, Weinstein John N, Wu Xifeng, Mishra Lopa
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.
PLoS One. 2016 Apr 21;11(4):e0153933. doi: 10.1371/journal.pone.0153933. eCollection 2016.
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.
驱动早期肿瘤发生的突变过程和特征对于早期癌症预防至关重要。然而，迄今为止，那些过度且迅速发展为结肠癌的息肉（腺瘤）的生物标志物和风险因素仍未明确界定。在此，我们通过全基因组序列（WGS）分析，在4对良性结直肠腺瘤组织样本中的2对中描述了惊人的高突变谱。对另外7对腺瘤进行的无监督分层聚类转录组分析显示，无论腺瘤大小，都存在明显不同的突变特征。腺瘤突变谱中以C:G>T:A的转换型单核苷酸替换为主。引人注目的是，我们在11个腺瘤中的4个中观察到TGF-β通路和CEA相关基因的突变，这些突变与Wnt通路重叠。免疫组织化学标记显示，在23%的腺瘤样本中，CEA水平几乎增加了5倍，同时伴有TGF-β信号的丧失。我们还确定了CEA B3结构域与TGFBR1相互作用的功能作用，这可能会使TGF-β信号的肿瘤抑制功能失活。我们的研究揭示了从早期腺瘤向癌症转变背后的多种突变过程。这对于在高危腺瘤中以生物标志物为导向靶向CEA/TGF-β具有广泛的意义，并且可能导致对侵袭性腺瘤向结直肠癌进展的早期检测。
