MHC class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinoma.

Abstract

Colorectal tumorigenesis has been associated with the progressive acquisition of a variety of genetic alterations. These include mutations of the Ki-ras proto-oncogene in codons 12 and 13, which account for 85% of genetic changes in colorectal cancer. In murine in vitro models of oncogenic transformation, an association between ras-mediated transformation and downregulation of different components of the MHC class I antigen processing machinery (APM) has been described. In order to investigate whether this association also exists in human tumors, 10 cases of high-grade intraepithelial neoplasia (HIN), as well as primary tumors and autologous lymph node metastases from 42 patients with colorectal carcinoma, were monitored by allele-specific restriction analysis for Ki-ras mutations. In parallel, APM component expression and tumor cell proliferation were analyzed by immunohistochemistry. In comparison to autologous colorectal mucosa, TAP1, LMP2 and tapasin loss was found in 68%, 67% and 80% of HIN, respectively. In contrast, impaired TAP1, LMP2 and tapasin expression was found in 42%, 42% and 63% of primary adenocarcinomas of stage III disease and in 63%, 47% and 79% of the matched lymph node metastases, respectively. More than 60% of colorectal tumor lesions with TAP1, LMP2 and/or tapasin defects displayed Ki-ras mutations. The frequency of TAP1, LMP2 and tapasin loss varied between 33% of primary adenocarcinomas, 40% of HIN to approximately 67% of metastases. These data suggest that i) APM component deficiencies occur more frequently in Ki-ras-mutated colorectal carcinoma lesions and ii) APM abnormalities in conjunction with Ki-ras mutations appear to be associated with disease stage. These findings support the hypothesis that Ki-ras mutations may contribute to immune escape mechanisms of tumors by downregulating the MHC class I APM component expression.

• Authors: Derek Atkins, Aldona Breuckmann, Gerd E Schmahl, Priska Binner, Soldano Ferrone, Frank Krummenauer, Stephan Störkel, Barbara Seliger
• Journal: International journal of cancer (Int J Cancer) Vol. 109 Issue 2 Pg. 265-73 (Mar 20 2004) ISSN: 0020-7136 [Print] United States
• PMID: 14750179 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 2
• ATP Binding Cassette Transporter, Subfamily B, Member 3
• ATP-Binding Cassette Transporters
• Histocompatibility Antigens Class I
• Ki-67 Antigen
• MAS1 protein, human
• Multienzyme Complexes
• Proto-Oncogene Mas
• TAP1 protein, human
• LMP-2 protein
• TAP2 protein, human
• Cysteine Endopeptidases
• LMP7 protein
• Proteasome Endopeptidase Complex

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 2
• ATP Binding Cassette Transporter, Subfamily B, Member 3
• ATP-Binding Cassette Transporters (genetics)
• Adenocarcinoma (genetics, metabolism, pathology)
• Adult
• Aged
• Aged, 80 and over
• Antigen Presentation (genetics)
• Carcinoma in Situ (genetics, metabolism, pathology)
• Cell Division
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Cysteine Endopeptidases (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Genes, ras (genetics)
• Histocompatibility Antigens Class I (genetics, metabolism)
• Humans
• Ki-67 Antigen (metabolism)
• Lymphatic Metastasis
• Male
• Middle Aged
• Multienzyme Complexes
• Mutation (genetics)
• Neoplasm Staging
• Proteasome Endopeptidase Complex
• Proto-Oncogene Mas