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

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

doi:10.18632/oncotarget.25112

Ayaka Sato, Hiromu Suzuki + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.25112

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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.

Highlights

Colorectal cancer (CRC) is the third most common form of cancer and the second leading cause of cancerrelated death worldwide [1]
Hierarchical clustering analysis based on the CNA pattern, including gains, LOHs, and copy-neutral LOHs, was carried out to examine differences in genetic alterations in samples from patients with colorectal intramucosal neoplasia (IMN) and colorectal cancer (CRC) that may have invaded into the muscular layer
Eizuka et al indicated that there were significant differences based on somatic copy number alterations (SCNAs) patterns among lowgrade adenoma (LGA), high-grade adenoma (HGA), and intramucosal adenocarcinoma (IMA) [15]

Summary

Introduction

Colorectal cancer (CRC) is the third most common form of cancer and the second leading cause of cancerrelated death worldwide [1]. Most sporadic CRCs arise through the adenoma-carcinoma sequence [2, 3]. The identification of early molecular alterations in early colorectal lesions (colorectal adenoma [low grade and high grade], intramucosal cancer, and CRC with early invasion) is important. To improve the diagnosis and treatment outcomes in patients with CRC, it will be necessary to elucidate the molecular alterations associated with early-stage colorectal lesions. Recent studies have shown that there are two major molecular alterations in cancers, i.e., chromosomal instability (CIN or microsatellite stable [MSS]) and microsatellite instability (MSI; MIN) [3, 4]. Recent evidence suggests that there may be overlap between the two types of CRC, it is believed that CIN (or MSS) and MIN (or MSI) types are mutually exclusive [3, 4, 8]

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