Genetic epidemiology of mutated K-rasproto-oncogene, altered suppressor genes, and microsatellite instability in colorectal adenomas

Abstract

Background-The genetic epidemiology of colorectal adenomas has not been studied prospectively in colonoscopy patients without cancer. Aims-To study genetic alterations in colorectal adenomas and correlate these with patient demographics and adenoma characteristics. Methods-Mutations and allelic deletions in 201 adenomas from 60 patients were compared with demographic features, adenoma characteristics, and family history. Results-The most common alteration was K-ras proto-oncogene mutation, present in 35% of adenomas and 65% of patients. Patients 65 years of age and older had a decreased probability of K-ras mutations (26% versus 45%). Overexpression of p53 gene product was present in only 6% of adenomas but was more frequent in villous or tubulovillous adenomas (19% versus 3%). Allelic loss of chromosome 18q was present in only 2% of adenomas and was significantly less frequent than p53 overexpression. DNA replication errors (RER) were present in 7% of adenomas and 15% of patients, including multiple adenomas in four patients (two with hereditary non-polyposis colorectal cancer syndrome). Only 36% of RER positive adenomas had alteration of BAT-26 alleles, none had alteration of BAT-25, and only one (8%) had mutation in the transforming growth factor type II receptor gene. RER positive adenomas were more likely to have a K-ras mutation. In patients with multiple adenomas, there was concordance of p53 overexpression and RER but not of K-ras mutations. Conclusions-Genetic progression in colorectal adenomas is heterogeneous, involving factors related to patient age and the presence of RER for the occurrence of ras mutations, but diVerent intraindividual characteristics for the occurrence of p53 alterations and RER. (Gut 1999;44:826-833) Keywords: K-ras mutation; p53 gene; loss of 18q; microsatellite instability; replication error; TGF RII Colorectal cancer is the second most common cause of cancer deaths in the USA. Most colorectal cancers develop from adenomatous polyps, and morphological and genetic progression in an adenoma-adenocarcinoma sequence and in hereditary colorectal cancer is well described.

The colorectal adenoma–carcinoma sequence

“…The relatively high frequency of ras mutated adenomas supports the hypothesis of this oncogene as an early participant in the adenoma± carcinoma sequence. However, as K-ras mutation is less common in small adenomas 38,63,74,75 , it seems that while this alteration confers a growth advantage it is unlikely to be an initiating factor in colorectal tumorigenesis.…”

“…All known carcinogenic mutations of the K-ras oncogene affect codons in the GTP-binding domain, decrease its GTPase activity, and result in a constitutively active ras protein 68 . Activating K-ras mutations occur in 35±42 per cent of colorectal carcinomas 38,70±73 and are observed at a similar frequency in large adenomas 38,74,75 . The relatively high frequency of ras mutated adenomas supports the hypothesis of this oncogene as an early participant in the adenoma± carcinoma sequence.…”

“…The relatively high frequency of ras mutated adenomas supports the hypothesis of this oncogene as an early participant in the adenoma± carcinoma sequence. However, as K-ras mutation is less common in small adenomas 38,63,74,75 , it seems that while this alteration confers a growth advantage it is unlikely to be an initiating factor in colorectal tumorigenesis.Jen and colleagues 63 analysed small hyperplastic and adenomatous polyps from cancer-bearing colon for APC and K-ras mutations. APC mutations were found to be closely associated with dysplasia, as 82 per cent of adenomas and no hyperplastic polyps had detectable mutations.…”

Estudo da relação entre a imunoexpressão das proteínas caderina-E e DCC com o grau de diferenciação celular e o estadiamento TNM do adenocarcinoma colorretal

“…Pacientes portadores de carcinoma colorretal em estádios iniciais apresentam bom prognóstico, porém, nos estádios avançados da doença, há uma notável redução da sobrevida (20% em cinco anos) (26) . Entretanto, alguns pacientes com doença localizada morrem por recidiva tumoral mesmo recebendo o tratamento adequado (31) .…”

“…Evidências indicam que a perda da função da caderina-E está relacionada com o processo de diferenciação e metás-tases no carcinoma de mama e de esôfago (22,26) .…”