TP53 mutation at early stage of colorectal cancer progression from two types of laterally spreading tumors.
TP53 mutation at early stage of colorectal cancer progression from two types of laterally spreading tumors.
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DOI：
10.1111/cas.12930
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发表时间：
2016-06
期刊：
影响因子：
5.7
通讯作者：
Kaneda A
中科院分区：
文献类型：
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作者：
Sakai E;Fukuyo M;Matsusaka K;Ohata K;Doi N;Takane K;Matsuhashi N;Fukushima J;Nakajima A;Kaneda A
虽然大多数散发性结直肠癌（CRC）被认为是通过腺瘤-癌序列从突出的腺瘤发展而来，但一些CRC是通过平坦的病变发展而来，即所谓的横向扩散肿瘤（LST）。我们之前分析了LST的表观遗传畸变，发现LST明确分为两种分子亚型：中间甲基化与KRAS突变和低甲基化与无癌基因突变。中甲基化LST多为颗粒型LST (LST‐G)，低甲基化LST多为非颗粒型LST （LST‐NG）。在本研究中，我们对38个候选CRC驱动基因进行了靶向外显子测序研究，以深入了解这些基因如何调节LST的发展。尽管LST - G和LST - NG在总突变频率上没有显著差异，但我们在每个样本中平均鉴定出11.5个可疑的非多态性变异，包括索引和非同义突变。与RTK/RAS信号通路相关的基因在LST‐G中的突变频率高于LST‐NG (P = 0.004)，特别是KRAS突变在LST‐G中的发生率为70%(30/43)，而在LST‐NG中的发生率为26% (13/50)（P < 0.0001）。两种LST均表现出高频率的APC突变，即使在腺瘤阶段，这表明它参与了LST的起始阶段，因为它通过腺瘤-癌序列参与了结肠直肠癌的早期发生。TP53突变从未在腺瘤中观察到，但在癌症样本中被特异性检测到。在LST‐NG中，TP53突变发生在粘膜内癌的发展过程中，而在LST‐G中，TP53突变发生在粘膜下浸润癌的发展过程中。这表明，TP53突变发生在LST‐G和LST‐NG的腺瘤发展的早期阶段，但在LST‐NG的早期阶段参与。
Although most sporadic colorectal cancers (CRC) are thought to develop from protruded adenomas through the adenoma–carcinoma sequence, some CRC develop through flat lesions, so‐called laterally spreading tumors (LST). We previously analyzed epigenetic aberrations in LST and found that LST are clearly classified into two molecular subtypes: intermediate‐methylation with KRAS mutation and low‐methylation with absence of oncogene mutation. Intermediate‐methylation LST were mostly granular type LST (LST‐G) and low‐methylation LST were mostly non‐granular LST (LST‐NG). In the present study, we conducted a targeted exon sequencing study including 38 candidate CRC driver genes to gain insight into how these genes modulate the development of LST. We identified a mean of 11.5 suspected nonpolymorphic variants per sample, including indels and non‐synonymous mutations, although there was no significant difference in the frequency of total mutations between LST‐G and LST‐NG. Genes associated with RTK/RAS signaling pathway were mutated more frequently in LST‐G than LST‐NG (P = 0.004), especially KRAS mutation occurring at 70% (30/43) of LST‐G but 26% (13/50) of LST‐NG (P < 0.0001). Both LST showed high frequency of APC mutation, even at adenoma stage, suggesting its involvement in the initiation stage of LST, as it is involved at early stage of colorectal carcinogenesis via adenoma‐carcinoma sequence. TP53 mutation was never observed in adenomas, but was specifically detected in cancer samples. TP53 mutation occurred during development of intramucosal cancer in LST‐NG, but during development of cancer with submucosal invasion in LST‐G. It is suggested that TP53 mutation occurs in the early stages of cancer development from adenoma in both LST‐G and LST‐NG, but is involved at an earlier stage in LST‐NG.