Somatically acquired genetic alterations in flat colorectal neoplasias

Olschwang, Sylviane; Slezak, P; Roze, M.; Jaramillo, Edgar; Nakano, Hiroshi; Koizumi, Koichi; Rubio, Carlos A.; Laurent‐Puig, Pierre; Thomas, Gilles

doi:10.1002/(sici)1097-0215(19980729)77:3<366::aid-ijc10>3.0.co;2-6

Cited by 35 publications

(22 citation statements)

References 18 publications

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“…Similarly, an inverse correlation between RASSF1A silencing and K-ras activation is present in pancreatic cancer (Dammann et al, 2003a). Flat-type colorectal cancer has a low frequency of K-ras mutations, and we detected K-ras mutations in only seven of 48 (14.6%) cases, which is similar to previous reports Minamoto et al, 1994;Olschwang et al, 1998). On the other hand, the frequency of RASSF1A methylation (81.3%) was among the highest among tumors previously analysed.…”

Section: Discussionsupporting

confidence: 90%

“…Genetic studies on flat colorectal tumors are scarce. The frequency of K-ras mutations is less than that of conventional sporadic colorectal tumors mostly derived from an exophytic adenoma-carcinoma sequence Minamoto et al, 1994;Olschwang et al, 1998). Also, flat tumors frequently demonstrate early inactivation of p53 with concomitant allelic loss of 17p (Yukawa et al, 1994;Rubio and Rodensjo, 1996;Mueller et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors

et al. 2004

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Flat colorectal tumors, characterized by high-grade dysplasia from early small flat mucosal lesions, exhibit a relatively aggressive clinical behavior and are known for their infrequent K-ras mutations. In this study, we investigated the methylation status of the RASSF1A promoter in association with 3p LOH and K-ras mutations in 48 flat colorectal tumors (39 early carcinomas and nine intramucosal high-grade dysplasias). RASSF1A hypermethylation was detected in 39 of 48 (81.3%) tumors and RASSF1A methylation was also detected in 19 of 39 (49%) normal colonic mucosal tissues. 3p21.3 LOH was detected in 20 of 42 (47.6%) cases, but RASSF1 methylation was detected in cases with LOH (14 cases) and retention of 3p21.3 (20 cases). K-ras mutations were detected in seven of 48 (14.6%) tumors and the concordant occurrence of K-ras mutation and RASSF1A methylation was detected in three of 48 cases (6.3%). Overall, there was a statistically significant mutually exclusive relationship between K-ras mutations and RASSF1A methylation. In conclusion, promoter hypermethylation of RASSF1A is a frequent event and may start early in the background normal mucosa in this tumor type. An alternative cascade of abnormalities in RAS transduction pathways may be responsible for the flat morphology and aggressive nature of flat colorectal neoplasms.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors

et al. 2004

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“…23,24 For nonpolypoid adenomas and carcinomas ex-nonpolypoid adenomas such genetic changes are widely unknown for the adenoma-carcinoma sequence. The low incidence of KRAS mutations reported for nonpolypoid colorectal adenomas 10,11,13 suggested a different genetic basis for the transformation process in these lesions. Also RAS mutations, a frequent genetic change in early colorectal tumor development of polypoid origin 8,25 have been reported to be not involved in the carcinogenesis of exnonpolypoid adenoma.…”

Section: Discussionmentioning

confidence: 98%

“…Other studies have focused on the replication error status and transforming growth factor-␤RII mutations paying attention also to mutations of APC and K-RAS. 13 A recent publication reports on the aberrant expression of G 1 phase cell-cycle regulators in nonpolypoid and polypoid colorectal adenomas.…”

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confidence: 99%

Distinct Chromosomal Imbalances in Nonpolypoid and Polypoid Colorectal Adenomas Indicate Different Genetic Pathways in the Development of Colorectal Neoplasms

Richter¹,

Slezak

Walch

et al. 2003

The American Journal of Pathology

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Cytogenetic changes are widely unknown for nonpolypoid (synonymously termed as "flat" or "depressed") colorectal adenomas. A comparison with polypoid adenomas will contribute to the discussion whether different genetic pathways for colorectal tumorigenesis depending on its origin from nonpolypoid or polypoid adenomas exist. Tissue samples of nonpolypoid (n ‫؍‬ 22), polypoid (n ‫؍‬ 28) adenomas, carcinomas ex-nonpolypoid adenomas (n ‫؍‬ 9), carcinomas ex-polypoid adenomas (n ‫؍‬ 14), and normal colonic mucosa (n ‫؍‬ 9) were investigated by comparative genomic hybridization of whole genomic DNA. Chromosomal imbalances were detected from average comparative genomic hybridization profiles for each entity. Nonpolypoid adenomas show recurrent chromosomal losses on chromosomes 16, 17p, 18, 20, and 22 and gains on chromosomes 2q, 4q, 5, 6, 8q, 12q, and 13q. In polypoid adenomas losses of whole chromosomes 16, 18, and 22 and gains of chromosomes 7q and 13 were detected. The frequency of copy number changes was higher in nonpolypoid compared to polypoid adenomas and early onset of chromosomal changes became apparent in low-grade dysplasias of nonpolypoid adenomas. Gains on chromosomes 2q, 5, 6, 8q, and 12q and losses on chromosomes 17p and 20 occurred exclusively in nonpolypoid adenomas, whereas 16p dele-

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“…Recently, flat-type colorectal tumours have been reported not only in Japan (Sakashita et al, 2000) but also in Western countries (Olschwang et al, 1998). Previous studies showed that flat-type colorectal tumours tended to reach deeper layers earlier and to show higher rates of lymphatic invasion and lymph node metastasis than did protruded-type tumours (Kuramoto and Oohara, 1989;Mueller et al, 1998).…”

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confidence: 99%

Gene expression profiling of colorectal adenomas and early invasive carcinomas by cDNA array analysis

et al. 2005

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It is generally accepted that most colorectal carcinomas arise in pre-existing adenomas. Morphologically, colorectal adenomas can be divided into two groups, protruded type and flat type. The aim of this study was to clarify relevant alterations of gene expression associated with the early stage of colorectal carcinogenesis. Using cDNA array, we analysed the expression profiles of 550 cancerrelated genes in 36 colorectal adenomas (18 flat-type and 18 protruded-type adenomas) and 14 early invasive carcinomas. Among the 550 genes, we chose 32 genes the average expression levels of which were at least three-fold up-or downregulated in tumour tissues compared with levels in matched normal tissues. A total of 13 and 19 genes were identified as up-and downregulated genes in tumour tissues, respectively. Among the upregulated genes, the average expression levels of E1AF, bone morphogenic protein (BMP)-4, insulin-like growth factor (IGF)-2, inducible nitric oxide synthase (iNOS), tissue inhibitors of metalloproteinase (TIMP)-1, Smad4, and nm23 in tumour tissues were over five times higher than those in matched normal tissues. Colorectal adenomas and early invasive carcinomas were divided into two major clusters by clustering analysis. Moreover, flat-and protruded-type adenomas were divided into two major clusters by clustering analysis. The expression profiles obtained by the cDNA array clearly indicate that colorectal adenomas and early invasive carcinomas have specific expression profiles. Likewise, the gene expression profiles of flat-and protruded-type adenomas are different. These results indicate that molecular classification of early colorectal tumours by a cDNA array is feasible.

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Somatically acquired genetic alterations in flat colorectal neoplasias

Cited by 35 publications

References 18 publications

Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors

Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors

Distinct Chromosomal Imbalances in Nonpolypoid and Polypoid Colorectal Adenomas Indicate Different Genetic Pathways in the Development of Colorectal Neoplasms

Gene expression profiling of colorectal adenomas and early invasive carcinomas by cDNA array analysis

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