Mutations of the Ki‐ras, p53 and APC genes in adenocarcinomas of the human small intestine

Arai, Masami; Shimizu, Seiichirou; Imai, Yoshihiko; Nakatsuru, Yoko; Oda, Hideaki; Oohara, Takeshi; Ishikawa, Takatoshi

doi:10.1002/(sici)1097-0215(19970207)70:4<390::aid-ijc3>3.3.co;2-s

Cited by 27 publications

(43 citation statements)

References 13 publications

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“…Although a few previous studies of small intestinal adenocarcinomas have examined KRAS and/or BRAF mutations, which are well-known oncogenes in colorectal cancer, most of these analyses were performed on small numbers of patients (Table 9). 1,3,[10][11][12][13][14][15][16][17][18][19][20] The frequency of KRAS mutations among small intestinal adenocarcinomas ranged from 9 to 83% in the previous studies. Previous studies from Japan with homogeneous ethnic groups showed a wide range of frequencies of KRAS mutation (9-71%), [13][14][15]19 and other studies with heterogeneous ethnic groups, such as studies from USA, also reported various frequencies of KRAS mutation (14-83%).…”

Section: Discussionmentioning

confidence: 99%

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Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

Jun

Kim

et al. 2016

Modern Pathology

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Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) chemotherapy in colorectal cancer. But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas. In this work, the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables, including survival of the patients, was analyzed. KRAS or BRAF mutations were observed in 63 (33%) cases. Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive. The majority of KRAS mutations were G4A transition (43/61 cases, 71%) or p.G12D (31/61 cases, 51%). The patients with mutant KRAS tended to have higher pT classifications (P = 0.034) and more frequent pancreatic invasion (P = 0.020) than those with wild-type KRAS. Multivariate logistic regression analysis showed that certain mutated KRAS subtypes (G4A transitions and G12D mutations) were significantly correlated with higher pT classification (P = 0.015 and 0.004, respectively) than wild-type KRAS and other KRAS mutations. The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF (P = 0.148), but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival (median, 46.0 months; P = 0.046) than those with wild-type KRAS (85.4 months) in lower pT classification (pT1-pT3) group. In summary, KRAS and, infrequently, BRAF mutations are observed in a subset of small intestinal adenocarcinomas, and are associated with higher pT classification and more frequent pancreatic invasion. KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors. Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal adenocarcinoma patients, namely those with wildtype KRAS and BRAF if they have metastatic disease, similar to colorectal cancer patients.

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Section: Discussionmentioning

confidence: 99%

“…1,3,[10][11][12][13][14][15][16][17][18][19][20] In addition, because most of these few analyses were performed on only small numbers of small intestinal adenocarcinoma patients, they need to be validated.…”

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confidence: 99%

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

Jun

Kim

et al. 2016

Modern Pathology

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“…In the study by Rashid and Hamilton, 15 allelic loss at chromosome 5q, the region of the adenomatous polyposis coli gene, was found to be extremely rare, detected in only one of 21 small intestinal adenocarcinomas (5%). Arai et al 16 and Bläker et al 17 demonstrated mutations in the adenomatous polyposis coli gene in 3 of a total of 36 small intestinal adenocarcinomas (8%) they examined. Furthermore, Wheeler et al 18 did not find any mutation in 21 cases.…”

Section: Discussionmentioning

confidence: 99%

“…30 Similar to that occurring in the adenoma-carcinoma sequence of colorectal tumorigenesis, 31,32 p53 mutation has been proposed as a late event during the development of small intestinal adenocarcinoma, which may serve a role in tumor progression. 15,33 The reported frequency of p53 mutation in small intestinal adenocarcinoma ranges from 0 to 43% by DNA-based analysis, 15,16,34,35 and 24 to 65% by immunohistochemistry. 15,18,23,33,36 Our data are in line with these observations and further demonstrate that in both small intestinal and colorectal adenocarcinomas, p53 overexpression, an indirect indication of p53 gene mutation, occurs only rarely in microsatellite instable tumors.…”

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confidence: 99%

Immunohistochemical investigation of tumorigenic pathways in small intestinal adenocarcinoma: a comparison with colorectal adenocarcinoma

2006

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Small intestinal adenocarcinoma is an uncommon neoplasm morphologically similar to or indistinguishable from colorectal adenocarcinoma. Although much has been learned about genetic pathways critical to colorectal tumorigenesis, little is known about molecular alterations involved in the development of small intestinal adenocarcinoma. In this study, we immunohistochemically compared non-ampullary small intestinal adenocarcinomas with sporadic colorectal adenocarcinomas for the expression of several proteins known to serve pivotal roles in colorectal tumorigenesis. These included adenomatous polyposis coli and b-catenin involved in the Wnt signaling pathway, and DNA mismatch repair enzymes hMLH1, hMSH2 and hMSH6 involved in the microsatellite instability pathway. The expression of two important tumor suppressors, p53 and RB, was also examined. The results show that complete loss of adenomatous polyposis coli immunoreactivity, presumably resulting from its gene mutations, was observed in eight of 26 (31%) small intestinal adenocarcinomas and 36 of 51 (71%) colorectal adenocarcinomas (P ¼ 0.0008). Nuclear localization of b-catenin, an indirect evidence of deregulated Wnt signaling pathway, was observed in 5 (19%) small intestinal adenocarcinomas and 36 (71%) colorectal adenocarcinomas (Po0.0001). Total lack of nuclear staining for one or more of the DNA mismatch repair enzymes occurred in a similar low frequency in both small intestinal and colorectal adenocarcinomas, seen in two of 25 (8%) and 10 of 47 (21%) cases, respectively (P ¼ 0.1958). The frequencies of aberrant p53 and RB expression were also similar between small intestinal and colorectal adenocarcinomas. These observations indicate that defects in the Wnt and microsatellite instability pathways occur in over 90% of colorectal adenocarcinomas, but in only 40% of small intestinal adenocarcinomas. Small intestinal tumorigenesis appears to follow a distinct, yet unidentified, molecular pathway(s) from its colorectal counterpart despite their morphologic similarity.

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“…[2][3][4] Recent studies, however, provide evidence for a somewhat different molecular pathogenesis of the majority of sporadic carcinomas in both locations. [5][6][7][8][9] Microsatellite and chromosomal instability (MSI and CIN) are two divergent types of genomic instability found in adenocarcinomas throughout the gastrointestinal tract, including the small intestine. 6,7,[9][10][11][12] MSI is caused by inactivation of the DNA mismatch repair system that may either result from promoter hypermethylation of the DNA mismatch repair gene MLH1 in sporadic carcinogenesis, 13 or following germline mutations in DNA mismatch repair system genes in hereditary nonpolyposis colorectal cancer.…”

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confidence: 99%

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

et al. 2011

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Characterization of tumor genetics and epigenetics allows to stratify a tumor entity according to molecular pathways and may shed light on the interactions of different types of DNA alterations during tumorigenesis. Small intestinal adenocarcinoma is rare, and to date the interrelation of genomic instability and epigenetics has not been investigated in this tumor type. We therefore analyzed 37 primary small bowel carcinomas with known microsatellite instability and KRAS status for chromosomal instability using comparative genomic hybridization, for the presence of aberrant methylation (CpG island methylation phenotype) by methylation-specific polymerase chain reaction, and for BRAF mutations. Chromosomal instability was detected in 22 of 37 (59%) tumors (3 of 9 microsatellite instable, and 19 of 28 microsatellite stable carcinomas). Nine carcinomas (24%) were microsatellite and chromosomally stable. High-level DNA methylation was found in 16% of chromosomal instable tumors and in 44% of both microsatellite instable and microsatellite and chromosomally stable carcinomas. KRAS was mutated in 55, 0, and 10% of chromosomal instable, microsatellite instable, and microsatellite and chromosomally stable tumors, respectively whereas the frequencies of BRAF mutations were 6% for chromosomal instable and 22% for both microsatellite instable and microsatellite and chromosomally stable carcinomas. In conclusion, in this study we show that chromosomal instable carcinomas of the small intestine are distinguished from microsatellite instable and microsatellite and chromosomally stable tumors by a high frequency of KRAS mutations, low frequencies of CpG island methylation phenotype, and BRAF mutations. In microsatellite instable and microsatellite and chromosomally stable cancers, CpG island methylation phenotype and BRAF/KRAS mutations are similarly distributed, indicating common mechanisms of tumor initiation or progression in their molecular pathogenesis.

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Mutations of the Ki‐ras, p53 and APC genes in adenocarcinomas of the human small intestine

Cited by 27 publications

References 13 publications

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

Immunohistochemical investigation of tumorigenic pathways in small intestinal adenocarcinoma: a comparison with colorectal adenocarcinoma

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

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