Sugai Tamotsu, Eizuka Makoto, Habano Wataru, Fujita Yasuko, Sato Ayaka, Sugimoto Ryo, Otsuka Kouki, Yamamoto Eiichiro, Matsumoto Takayuki, Suzuki Hiromu
Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan.
Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Morioka, Japan.
Oncotarget. 2018 May 1;9(33):22895-22906. doi: 10.18632/oncotarget.25112.
It is unclear whether somatic copy number alterations (SCNAs) contribute to the development of colorectal cancer (CRC). Here, we aimed to identify the molecular profiles of early colorectal carcinogenesis based on SCNAs and determine the associations of other molecular abnormalities for the detection of neoplasia in both intramucosal neoplasia (IMN) and invasive CRC with invasion into the muscular layer without metastasis (early invasive CRC). A single nucleotide polymorphism array was used to examine 100 colorectal IMNs (low-grade adenoma [LGA], 40; high-grade adenoma [HGA], 25; intramucosal adenocarcinoma [IMA], 35) and early invasive CRC (20 tumors). In addition, genetic mutations (, ), TP53 overexpression, microsatellite instability (MSI), and DNA methylation (low, intermediate, high) were examined. Hierarchical clustering analysis based on the SCNA pattern was carried out to identify molecular profiles in IMNs and early invasive CRC. Colorectal tumors were classified into three subgroups based on SCNA patterns. Subgroup 1 was characterized by multiple SCNAs, subgroup 3 was closely associated with infrequent SCNAs, and subgroup 2 was an intermediate subgroup in SCNA pattern between subgroups 1 and 3. Although mutations in were commonly found in all three subgroups, overexpression of TP53 was observed primarily in subgroup 1 and 2. DNA methylation showed a low/intermediate type. Finally, no MSI was detected. Each subgroup was correlated with histology (subgroup 1, early invasive CRC; subgroup 2, LGA; subgroups 2 and 3, HGA and IMA). Considerable SCNAs may be required for acquisition of invasive ability in CRC. Our results provide novel insights into early CRC.
目前尚不清楚体细胞拷贝数改变（SCNAs）是否促成结直肠癌（CRC）的发生发展。在此，我们旨在基于SCNAs确定早期结直肠癌发生的分子特征，并确定其他分子异常与检测黏膜内瘤变（IMN）和无转移的肌层浸润性结直肠癌（早期浸润性CRC）中肿瘤形成的关联。使用单核苷酸多态性阵列检测100例结直肠IMN（低级别腺瘤[LGA]，40例；高级别腺瘤[HGA]，25例；黏膜内腺癌[IMA]，35例）和早期浸润性CRC（20个肿瘤）。此外，检测了基因突变（，）、TP53过表达、微卫星不稳定性（MSI）和DNA甲基化（低、中、高）。基于SCNA模式进行层次聚类分析，以识别IMN和早期浸润性CRC中的分子特征。根据SCNA模式将结直肠肿瘤分为三个亚组。亚组1的特征是多个SCNAs，亚组3与罕见的SCNAs密切相关，亚组2是亚组1和3之间SCNA模式的中间亚组。尽管在所有三个亚组中都普遍发现了 中的突变，但TP53过表达主要在亚组1和2中观察到。DNA甲基化显示为低/中间类型。最后，未检测到MSI。每个亚组与组织学相关（亚组1，早期浸润性CRC；亚组2，LGA；亚组2和3，HGA和IMA）。CRC获得侵袭能力可能需要相当数量的SCNAs。我们的结果为早期CRC提供了新的见解。
