Methylation epigenotypes and genetic features in colorectal laterally spreading tumors

Shimizu, Eiji; Ohata, Ken; Chiba, Hideyuki; Matsuhashi, Nobuyuki; Doi, Noriteru; Fukushima, Junichi; Endo, Hideki; Takahashi, Hirokazu; Tsuji, Shingo; Yagi, Koichi; Matsusaka, Keisuke; Aburatani, Hiroyuki; Kaneda, Atsushi

doi:10.1002/ijc.28814

Cited by 24 publications

(72 citation statements)

References 52 publications

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“…The 24 tumor samples in Cluster-A significantly correlated with the presence of KRAS mutation ( P = 1×10 -4 ), and proximal location ( P = 3×10 -6 ) (Figure 2A). To evaluate methylation epigenotype of this cluster by comparison with the previously established methylation epigenotypes of sporadic CRC [12, 28], their methylation status was examined with 45 sporadic CRC samples, including 15 high-, 15 intermediate-, and 15 low-methylation epigenotypes, which had been previously evaluated [12]. Hierarchical clustering analysis revealed that all 24 tumor samples in Cluster-A were clustered into intermediate-methylation epigenotype (Figure 2B).…”

Section: Resultsmentioning

confidence: 96%

“…As detected in intermediate-methylation sporadic CRC [12, 28, 31], it suggested that methylation accumulation and KRAS -mutation(+) are mostly completed by the adenoma stage.…”

Section: Resultsmentioning

confidence: 97%

“…To confirm that the difference of intermediate- and low-methylation epigenotypes in FAP tumors was due to differences in the methylation levels in Group-2 markers, which is feature of sporadic CRC [12, 28], their methylation levels in intermediate- and low-methylation tumors were compared (Figure 3). While all Group-1 markers (≅ CIMP markers) showed low methylation levels in both intermediate- and low-methylation tumors, all Group-2 markers showed significantly higher methylation levels in intermediate-methylation samples when compared to the low-methylation samples.…”

Section: Resultsmentioning

confidence: 99%

“…The frequency of KRAS mutation was not different between adenoma and cancer. Methylation levels did not significantly increase from adenoma to cancer either, suggesting that methylation accumulation to form intermediate-methylation epigenotype and KRAS mutation was mostly completed by the adenoma stage, which resembles sporadic colorectal tumors [28, 31]. …”

Section: Discussionmentioning

confidence: 99%

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Two subtypes of colorectal tumor with distinct molecular features in familial adenomatous polyposis

et al. 2016

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While sporadic colorectal cancer (CRC) is classified into several molecular subtypes, stratification of familial colorectal tumors is yet to be well investigated. We previously established two groups of methylation markers through genome-wide DNA methylation analysis, which classified sporadic CRC and adenoma into three distinct subgroups: high-, intermediate-, and low-methylation epigenotypes. Here, we investigated familial adenomatous polyposis (FAP), through quantitative methylation analysis of 127 samples (16 cancers, 96 adenomas, and 15 benign mucosa from 14 patients with FAP) using six Group-1 and 14 Group-2 methylation markers, APC, BRAF, and KRAS mutation analysis, and CTNNB1 and TP53 immunohistochemical analysis. All the 14 patients presented with APC germline mutation. Three were from the same family and presented the same APC mutation. FAP tumors lacked BRAF-mutation(+) high-methylation epigenotype and were classified into two methylation epigenotypes. While 24 of 112 tumor samples showed intermediate-methylation epigenotype significantly correlating with KRAS-mutation(+) (P=3×10-4), 88 tumor samples showed low-methylation epigenotype correlating with the absence of KRAS- and BRAF-mutations. Similar to sporadic CRC, CTNNB1 was frequently activated at the adenoma stage, and TP53 mutation occurred during cancer development from adenoma. Whereas some patients showed a single epigenotype in all tumors throughout the colon, tumors with two distinct epigenotypes developed within a family with the same APC mutation or even within one patient. Methylation accumulation significantly correlated with proximal location and older age. These results indicate that there are at least two distinct molecular subtypes of FAP tumors, resembling sporadic CRC and independent from the APC germline mutation status.

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Section: Resultsmentioning

confidence: 96%

“…As detected in intermediate-methylation sporadic CRC [12, 28, 31], it suggested that methylation accumulation and KRAS -mutation(+) are mostly completed by the adenoma stage.…”

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Two subtypes of colorectal tumor with distinct molecular features in familial adenomatous polyposis

et al. 2016

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“…Although the molecular mechanism involved in the development of LSTs is not fully understood, several studies reported frequent detection of KRAS mutation and CIMP in LSTs [25,26]. A more recent study showed that LST-G is associated with KRAS mutation and the intermediate-methylation epigenotype, while LST-NG is characterized by catenin beta-1 (CTNNB1) mutation and a low-methylation epigenotype [27].…”

Section: Epigenetic Silencing Of Neurotensin Receptor 1 Is Associatedmentioning

confidence: 99%

Integrated Analysis of the Endoscopic, Pathological and Molecular Characteristics of Colorectal Tumorigenesis

et al. 2018

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Background: Colorectal cancers (CRCs) develop through the accumulation of genetic and epigenetic alterations of oncogenes and tumor suppressor genes. In addition to the well-characterized adenoma-carcinoma sequence, the serrated neoplasia pathway is now recognized as an alternative pathway for CRC development. Summary: Through analysis of the colonoscopic, pathological, and molecular features of colorectal tumors, we identified a novel microsurface structure characteristic of serrated lesions. The Type II-Open (Type II-O) pit pattern is highly specific to sessile serrated adenoma/polyps (SSA/Ps), and Type-II-O-positive tumors frequently exhibit v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and 5′-C-phosphate-G-3′ (CpG) island hypermethylation. By screening DNA methylation associated with the development of serrated lesions, we detected methylation of secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding 1 (SMOC1) in traditional serrated adenomas (TSAs). Epigenetic silencing of SMOC1 is prevalent among TSAs but it is rarely observed in SSA/Ps, which suggests SMOC1 could be a useful diagnostic marker of serrated lesions. We also searched for epigenetic alterations associated with the growth pattern of colorectal tumors and found that methylation of neurotensin receptor 1 is associated with lateral and non-invasive tumor growth. Key Message: Through the summarized studies, we have been able to identify novel morphological and molecular features that could contribute to a better understanding of colorectal tumors and to improved clinical diagnosis.

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DNA methylation epigenotype and clinical features of NRAS‐mutation(+) colorectal cancer

et al. 2017

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Sporadic colorectal cancer (CRC) is classified into several molecular subtypes. We previously established two groups of DNA methylation markers through genome‐wide DNA methylation analysis to classify CRC into distinct subgroups: high‐, intermediate‐, and low‐methylation epigenotypes (HME, IME, and LME, respectively). HME CRC, also called CpG island methylator phenotype (CIMP)‐high CRC, shows methylation of both Group 1 markers (CIMP markers) and Group 2 markers, while IME/CIMP‐low CRC shows methylation of Group 2, but not of Group 1 markers, and LME CRC shows no methylation of either Group 1 or Group 2 markers. While BRAF‐ and KRAS‐mutation(+) CRC strongly correlated with HME and IME, respectively, clinicopathological features of NRAS‐mutation(+) CRC, including association with DNA methylation, remain unclear. To characterize NRAS‐mutation(+) CRC, the methylation levels of 19 methylation marker genes (6 Group 1 and 13 Group 2) were analyzed in 61 NRAS‐mutation(+) and 144 NRAS‐mutation(−) CRC cases by pyrosequencing, and their correlation with clinicopathological features was investigated. Different from KRAS‐mutation(+) CRC,NRAS‐mutation(+) CRC significantly correlated with LME. NRAS‐mutation(+) CRC showed significantly better prognosis than KRAS‐mutation(+) CRC (P = 3 × 10−4). NRAS‐mutation(+) CRC preferentially occurred in elder patients (P = 0.02) and at the distal colon (P = 0.006), showed significantly less lymph vessel invasion (P = 0.002), and correlated with LME (P = 8 × 10−5). DNA methylation significantly accumulated at the proximal colon. NRAS‐mutation(+) CRC may constitute a different subgroup from KRAS‐mutation(+) CRC, showing significant correlation with LME, older age, distal colon, and relatively better prognosis.

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Methylation epigenotypes and genetic features in colorectal laterally spreading tumors

Cited by 24 publications

References 52 publications

Two subtypes of colorectal tumor with distinct molecular features in familial adenomatous polyposis

Two subtypes of colorectal tumor with distinct molecular features in familial adenomatous polyposis

Integrated Analysis of the Endoscopic, Pathological and Molecular Characteristics of Colorectal Tumorigenesis

DNA methylation epigenotype and clinical features of NRAS‐mutation(+) colorectal cancer

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