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

Int J Cancer. 2004 Mar 20;109(2):265-73. doi: 10.1002/ijc.11681.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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
  • Multienzyme Complexes
  • TAP1 protein, human
  • LMP-2 protein
  • TAP2 protein, human
  • Cysteine Endopeptidases
  • LMP7 protein
  • Proteasome Endopeptidase Complex