Concomitant RASSF1A hypermethylation and KRAS/BRAF mutations occur preferentially in MSI sporadic colorectal cancer View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2005-07-11

AUTHORS

Carla Oliveira, Sérgia Velho, Enric Domingo, Ana Preto, Robert M W Hofstra, Richard Hamelin, Hiroyuki Yamamoto, Raquel Seruca, Simo Schwartz

ABSTRACT

Methylation-associated inactivation of RASSF1A has frequently been observed in several human malignancies including sporadic colorectal and gastric cancer. However, nothing is known about the RASSF1A methylation status in the setting of MMR-deficient gastrointestinal tumours. In this study, we analysed systematically alterations in KRAS, BRAF and RASSF1A, in order to define the frequency and the pattern of these genetic/epigenetic alterations in three distinct subsets of MSI gastrointestinal tumours. Further, an association study was performed between RASSF1A methylation and the clinicopathological parameters in order to determine the profile of tumours harbouring this epigenetic event. A total of 56 MSI sporadic gastrointestinal tumours (31 colorectal and 25 gastric) and 20 MSI HNPCC analysed for KRAS/BRAF were analysed for RASSF1A promoter hypermethylation by MSP and DNA sequencing. No significant differences were found between the frequency of RASSF1A methylation in sporadic MSI colorectal and gastric carcinomas and HNPCC carcinomas (P=0.31). Methylation of RASSF1A was present in 16 of 31 (52%) sporadic MSI colorectal and 11 of 25 (44%) MSI gastric carcinomas, and in six of 20 (30%) HNPCC carcinomas. Nearly 36% of MSI sporadic colorectal carcinomas (CRCs) had RASSF1A methylation and activating mutations at KRAS and/or BRAF. In contrast, only 10 and 8% of HNPCC and sporadic gastric carcinomas, respectively, had concomitant KRAS mutations and RASSF1A methylation. The MSI sporadic gastric and CRCs with RASSF1A methylation were preferentially poorly differentiated (P=0.03, 0.05, respectively). We show that the profile of alterations RASSF1A, KRAS/BRAF is different among the three groups of MSI gastrointestinal tumours. Further, we demonstrate that MSI sporadic CRCs accumulated significantly more epigenetic/genetic alterations in RASSF1A, KRAS/BRAF than MSI sporadic gastric or HNPCC carcinomas (P=0.016). These results are likely to have therapeutic implications in the near future, due to the possibilities of using specific kinase inhibitors alone or in association with demethylating agents in MSI tumour types harbouring KRAS or BRAF mutations and RASSF1A methylation. More... »

PAGES

7630-7634

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1208906

DOI

http://dx.doi.org/10.1038/sj.onc.1208906

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1001626065

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/16007118


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40 KRAS/BRAF mutations
41 MSP
42 RASSF1A
43 RASSF1A hypermethylation
44 RASSF1A methylation
45 RASSF1A methylation status
46 RASSF1A promoter hypermethylation
47 agents
48 alterations
49 association
50 association studies
51 cancer
52 carcinoma
53 clinicopathological parameters
54 colorectal
55 colorectal cancer
56 colorectal carcinoma
57 concomitant KRAS mutation
58 contrast
59 differences
60 distinct subsets
61 epigenetic alterations
62 epigenetic events
63 events
64 frequency
65 future
66 gastric
67 gastric cancer
68 gastric carcinoma
69 gastrointestinal tumors
70 genetic alterations
71 group
72 human malignancies
73 hypermethylation
74 implications
75 inactivation
76 inhibitors
77 kinase inhibitors
78 malignancy
79 methylation
80 methylation of RASSF1A
81 methylation status
82 methylation-associated inactivation
83 mutations
84 near future
85 order
86 parameters
87 patterns
88 possibility
89 profile
90 profiles of tumors
91 promoter hypermethylation
92 results
93 sequencing
94 setting
95 significant differences
96 specific kinase inhibitors
97 sporadic colorectal
98 sporadic colorectal cancer
99 sporadic colorectal carcinomas
100 sporadic gastric
101 sporadic gastric carcinomas
102 status
103 study
104 subset
105 therapeutic implications
106 total
107 tumor types
108 tumors
109 types
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