Mutations of the Ki-ras, p53 andAPC genes in adenocarcinomas of the human small intestine

Abstract

In contrast to the origins of colorectal carcinomas, the mechanisms of carcinogenesis in the small intestine remain unclear. We therefore analyzed the mutational status of the Ki-ras, p53, and adenomatous polyposis coli (APC) genes in primary carcinomas of the small intestine and compared the mutation patterns with those established for colorectal cancers. DNA was extracted from 15 formalin-fixed, paraffinembedded lesions. Codons 12, 13 and 61 of the Ki-ras gene, exons 5-8 of the p53 gene, and codons 1268-1569, which contain the mutation cluster region (MCR) of the APC gene, were amplified by means of PCR, subcloned and sequenced. Mutations of the Ki-ras and p53 genes were observed in 8 (53.3%) and 4 lesions (26.7%), respectively. The mutational frequency of the Ki-ras gene in the present series of small intestinal carcinomas was similar, while that of the p53 gene was slightly lower than the reported frequencies for colorectal carcinomas. Only one case showed a mutation of the APC gene, involving an insertional mutation of an adenine at codons 1554-1556 with formation of a stop codon immediately downstream. Since the occurrence of an APC mutation is considered an early event in colorectal carcinogenesis, our findings indicating an extremely low frequency of such changes in and around the MCR suggest that carcinomas of the small intestine arise via a genetic pathway distinct from that involved in the development of carcinomas of the colorectum. Int.

Genetics of adenocarcinomas of the small intestine: frequent deletions at chromosome 18q and mutations of the SMAD4 gene

“…The wild type sequence is given in the upper row, the mutated sequence in the lower row other chromosomes (4q, 6q, 8p, 15q). Thus, con®rming previous data (Rashid and Hamilton, 1997, Arai et al, 1997) the presently investigated sporadic carcinomas lack evidence of a signi®cant role of APC inactivation in their development. This is intriguing because the elevated risk of small intestinal carcinomas in patients with familial adenomatous polyposis and the high incidence of small intestinal tumours in mice with germline APC mutations (Moser et al, 1990) suggest a role of APC in the maintenance of regular cell growth in the small intestine.…”

“…By microsatellite analysis they have found low frequencies of deletions at chromosomal arms 5q, the location of the APC gene, and at 18q, where the DCC-, and DPC4/SMAD4 genes are located. The frequency of replication errors, k-ras mutations, and deletions at 17p, the location of the p53 gene, were reported to be similar to the frequency in colorectal carcinomas (Rashid and Hamilton, 1997;Sutter et al, 1996;Arber et al, 2000), while mutational analysis of APC showed infrequent genetic inactivation of this gene in small intestinal carcinomas (Arai et al, 1997).…”

“…Several authors describe k-ras mutations with a frequency ranging from 36 ± 84% (Sutter et al, 1996;Rashid and Hamilton, 1997;Arber et al, 2000). In a series of 15 small intestinal adenocarcinomas Arai et al (1997) have found p53 and APC mutations in 27 and 7%, respectively. More recently, Murata et al (2000) describe a deletion within exon 3 of the b-catenin oncogene in one case.…”

Adenocarcinoma with adenoma in the jejunum suggesting an adenoma-carcinoma sequence in the small bowel: A case report

“…Nishiyama et al (7) and Arai et al (8) reported that 40–50% of cases of PSBA overexpress the p53 protein, suggesting that p53 may have a major role in the progression of carcinoma of the small bowel (7,8). In the present case, no p53-positive epithelial cells were found in the normal mucosa; however, p53-expressing cells were observed in the adenoma tissue and the level of p53 expression and the number of p53-expressing cells was higher in the adenocarcinoma tissue, consistent with previous findings (7,8).…”

Small Bowel Adenocarcinoma

“…This hyperproliferative mucosa then undergoes additional genetic ''hits'' that eventually result in malignant transformation, and ultimately tumor invasion and metastasis [6]. Despite the understanding gained from min mouse model, APC mutations in human SBA are actually uncommon [7]. Other mutations found to occur include abnormalities in the K-ras and p53 genes, though the frequency of abnormalities in the p53 gene is much lower than that observed in human colon cancer [8].…”