Oncotarget

Research Papers:

Comprehensive molecular analysis based on somatic copy number alterations in intramucosal colorectal neoplasias and early invasive colorectal cancers

Tamotsu Sugai _, Makoto Eizuka, Wataru Habano, Yasuko Fujita, Ayaka Sato, Ryo Sugimoto, Kouki Otsuka, Eiichiro Yamamoto, Takayuki Matsumoto and Hiromu Suzuki

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Oncotarget. 2018; 9:22895-22906. https://doi.org/10.18632/oncotarget.25112

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Abstract

Tamotsu Sugai1, Makoto Eizuka1, Wataru Habano2, Yasuko Fujita1, Ayaka Sato1, Ryo Sugimoto1, Kouki Otsuka3, Eiichiro Yamamoto4, Takayuki Matsumoto5 and Hiromu Suzuki4

1Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan

2Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Morioka, Japan

3Department of Surgery, Iwate Medical University, School of Medicine, Iwate Medical University, Morioka, Japan

4Department of Molecular Biology, Sapporo Medical University, School of Medicine, Cyuuouku, Sapporo, Japan

5Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan

Correspondence to:

Tamotsu Sugai, email: [email protected]

Keywords: colorectal cancer; comprehensive genomic analysis; colorectal adenoma; copy number alteration; microsatellite instability

Received: February 09, 2018    Accepted: March 15, 2018    Published: May 01, 2018

ABSTRACT

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 (KRAS, BRAF), 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 KRAS 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.


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