Analysis of K‐ras mutations and expression of cyclooxygenase‐2 and gastrin protein in laterally spreading tumors

Mukawa, Kenichiroh; Fujii, Shigehiko; Takeda, Jun; Kitajima, Kazuaki; Tominaga, Keiichi; Chibana, Yoko; Fujita, Mikio; Ichikawa, Kazuhito; Tomita, Shigeki; Ono, Yuko; Imura, Johji; Kawamata, Hitoshi; Chiba, Tsutomu; Hiraishi, Hideyuki; Terano, Akira; Fujimori, Takahiro

doi:10.1111/j.1440-1746.2005.03897.x

Cited by 24 publications

(19 citation statements)

References 29 publications

(65 reference statements)

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“…Furthermore, experimental evidence for the link between flat lesions and colitis-associated colorectal neoplasia comes from the dextran sulphate sodium colitis mouse model in which flat lesions were associated with more severe inflammation than polypoid lesions by several groups (54)(55)(56). A potential factor could be COX-2, which is proinflammatory and has been shown to be higher expressed in flat lesions compared with polypoid lesions (57). These findings support the hypothesis that, especially in relation to 5q loss, flat colorectal adenomas are more similar to colitis-associated colorectal neoplasia, than to polypoid adenomas.…”

Section: Discussionmentioning

confidence: 99%

Chromosome 5q Loss in Colorectal Flat Adenomas

Voorham

Carvalho

Spiertz

et al. 2012

Clinical Cancer Research

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Purpose: Flat adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behavior compared with their polypoid counterparts. Here, we aimed to compare one of the molecular changes most explicitly associated with adenoma to carcinoma progression, that is, chromosomal instability, between flat and polypoid colorectal adenomas.Experimental Design: Consecutive series of 83 flat and 35 polypoid adenomas were analyzed for DNA copy number changes using a high-resolution array comparative genomic hybridization platform, microsatellite instability (MSI) status, and for mutations in the adenomatous polyposis coli (APC) gene. Immunohistochemical stainings for CD3, CD8, and FoxP3 expression were carried out.Results: Patterns of DNA copy number changes differed between the two phenotypes, with significantly more frequent loss of 5q14.3 and 5q15-q31.1 in flat adenomas, whereas losses of 1p36.32-p35.3, 10q25.3, 17p12, and chromosome 18 were more frequent in polypoid adenomas (false discovery rate < 0.2). MSI was observed in one flat adenoma. As the 5q15-q31.1 region harbors the APC locus, APC mutation status was investigated, showing significantly less mutations in flat adenomas (P ¼ 0.04). An initial exploration of a possible association of 5q loss with inflammation indicated that tumor-infiltrating lymphocytes were more abundant in the stroma of flat adenomas compared with that of polypoid adenomas.Conclusion: Flat and polypoid adenomas have partially distinct chromosomal profiles, consistent with differences in the biology underlying these phenotypes. Alterations more specific to flat adenomas, in particular 5q loss, may be associated with inflammation.

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Section: Discussionmentioning

confidence: 99%

Chromosome 5q Loss in Colorectal Flat Adenomas

Voorham

Carvalho

Spiertz

et al. 2012

Clinical Cancer Research

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“…Although more than 10 years have passed since Kudo 6 advocated the new category 'laterally spreading tumor', only a few genetic alterations of laterally spreading tumors such as KRAS, b-catenin and p53 mutations, 5,8,10,11 and overexpression of COX-2 7 and gastrin protein 8 have been reported. laterally spreading tumors are defined as lesions 410 mm in diameter with a low vertical axis that extend laterally along the luminal wall, 6 and most of them remain as adenoma or early invasive cancer.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8][9][10] Laterally spreading tumors are superficial neoplasms that spread laterally over the mucosa, and these have recently received significant attention from gastroenterologists. However, the accurate frequencies of these genetic and epigenetic alterations in flat-type colorectal tumors have remained largely unknouwn.…”

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confidence: 99%

Flat-type colorectal advanced adenomas (laterally spreading tumors) have different genetic and epigenetic alterations from protruded-type advanced adenomas

et al. 2007

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Morphologically, colorectal adenomas can be divided into two groups, protruded-type and flat-type. However, the accurate frequencies of genetic and epigenetic alterations in flat-type colorectal advanced adenomas (laterally spreading tumors) have remained largely unknown. In the current study, we investigated genetic and epigenetic alterations in 101 flat-type colorectal advanced adenomas and 68 protruded-type colorectal advanced adenomas by using direct DNA sequencing and quantitative real-time PCR (MethyLight), respectively. KRAS mutation was detected in a significantly higher percentage of flat-type adenomas (35%) than in protruded-type adenomas (13%). When the samples were limited to the tumors in the distal colon, the difference of KRAS mutation was still significant. KRAS mutation in G-to-A transitions at codons 12 and 13 was detected in a significantly higher percentage of flat-type adenomas (26%) than in protruded-type adenomas (9%). BRAF and b-catenin mutations were detected in 3 and 8% of the 101 flat-type adenomas, respectively. No significant difference was found between frequencies of those mutations in flat-type adenomas and protruded-type adenomas. Methylations of MGMT, CDKN2A (p16) and MLH1 were detected in 28, 33 and 9% of the 101 flat-type adenomas, respectively. CDKN2A methylation was detected in a significantly lower percentage of flat-type adenomas than in protruded-type adenomas (63%). Methylation of at least one gene was detected in a significantly lower percentage of flat-type adenomas (54%) than in protruded-type adenomas (78%). In conclusion, KRAS mutation was frequently detected in flat-type advanced adenomas and the mutational patterns in most of them with KRAS mutations were a transition from G-to-A. Therefore, these genetic alterations seem to play an important role in the development of flat-type advanced adenomas, especially in the distal colon. Epigenetic alterations infrequently occurred in flat-type advanced adenomas, suggesting that they have different genetic and epigenetic alterations from those of protruded-type advanced adenomas.

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“…3,3′-Diaminobenzidine was used as the chromogen. Slides were counterstained with hematoxylin, dehydrated in a graded series of ethanol, mounted on slides, and coverslipped (Mukawa et al 2005). For negative controls, according to different primary antibodies, normal rabbit or mouse serum was added instead of the primary antibody.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Increased Expression of β-Catenin, Phosphorylated Glycogen Synthase Kinase 3β, Cyclin D1, and c-myc in Laterally Spreading Colorectal Tumors

Wang

Gong

et al. 2008

J Histochem Cytochem.

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S U M M A R Y Laterally spreading tumors (LSTs) are considered a special subtype of superficial colorectal tumor. This study was performed to characterize the clinicopathological features and examine activation of the Wnt/b-catenin pathway in LSTs and protruded-type colorectal adenomas (PAs). Fifty LSTs and 54 PAs were collected, and their clinicopathological characteristics were compared. The expression of E-cadherin, b-catenin, glycogen synthase kinase-3b (GSK-3b), phosphorylated GSK-3b, (phospho-GSK-3b), cyclin D1, and c-myc was investigated by immunohistochemical staining on serial sections. Patients with LSTs were significantly older than those bearing PAs (63.4 vs 47.4 years old; p,0.001). The mean size of LSTs was significantly larger than that of PAs (27.0 mm vs 14.6 mm; p,0.01). Forty-eight percent of LSTs were located in the proximal colon, which was significantly higher than that of PAs (18.5%; p,0.05). Expression of b-catenin, phospho-GSK-3b, cyclin D1, and c-myc was significantly increased in LSTs compared with PAs (p,0.05). However, E-cadherin and total GSK-3b expression was not significantly different between the two groups. The level of b-catenin expression correlated strongly with phospho-GSK-3b, cyclin D1, and c-myc expression in LSTs but not in PAs. Our findings suggest that activation of the Wnt/b-catenin pathway is more prevalent in LSTs than in PAs, suggesting that phosphorylation-dependent inactivation of GSK-3b may be involved in LST carcinogenesis.

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Analysis of K‐ras mutations and expression of cyclooxygenase‐2 and gastrin protein in laterally spreading tumors

Abstract: These results show that LST-G and LST-NG have different genetic alterations.

Cited by 24 publications

References 29 publications

Chromosome 5q Loss in Colorectal Flat Adenomas

Chromosome 5q Loss in Colorectal Flat Adenomas

Flat-type colorectal advanced adenomas (laterally spreading tumors) have different genetic and epigenetic alterations from protruded-type advanced adenomas

Increased Expression of β-Catenin, Phosphorylated Glycogen Synthase Kinase 3β, Cyclin D1, and c-myc in Laterally Spreading Colorectal Tumors

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