MUC1 is immunogenic in vivo

No abstract

Matrix metalloproteinase (MMP)-1 and MMP-3 genes are associated with tumor cell invasion and metastasis with their promoter polymorphisms influencing the level of transcription. Our study explored the association of these polymorphisms with colorectal cancer risk in a Japanese population. DNA was extracted from peripheral blood of 101 patients with colorectal cancer and 127 age-and gender-matched healthy volunteers. Genotyping was carried out using PCR-RFLP and direct sequencing. In the MMP-1 gene polymorphism, the frequency of the 2G/2G genotype that is associated with higher enzyme activity was significantly increased in colorectal cancer patients when compared to controls (p ‫؍‬ 0.0067; OR ‫؍‬ 2.077; 95% CI ‫؍‬ 1.221-3.534). With regard to the MMP-3 polymorphism, unexpectedly, the frequency of the 6A/6A genotype causing lower enzyme activity was significantly increased in patients (p ‫؍‬ 0.0129; OR ‫؍‬ 2.110; 95% CI ‫؍‬ 1.165-3.822). Because the loci for the 2 MMP genes are closely linked, we examined linkage disequilibrium between the 2 loci using expectation-maximization algorithm. We found that the 2 loci were in linkage disequilibrium and that 2G-6A haplotype was significantly increased in patients compared to controls (p ‫؍‬ 0.0010; OR ‫؍‬ 1.949; 95% CI ‫؍‬ 1.305-2.911). Our present data suggest that the MMP-1 and MMP-3 promoter polymorphisms may be associated with a colorectal cancer susceptibility in Japanese.

Purpose: Early events in colorectal tumorigenesis include mutation of the adenomatous polyposis coli (APC) gene and epigenetic hypermethylation with transcriptional silencing of the O 6 -methylguanine DNA methyltransferase (MGMT), human mut L homologue 1 (hMLH1), and P16/CDKN2A genes. Epigenetic alterations affect genetic events: Loss of MGMT via hypermethylation reportedly predisposes to guanine-to-adenine or cytosine-to-thymine (G:C!A:T) transition mutations in KRAS and P53, and silencing of hMLH1 leads to high levels of microsatellite instability (MSI-H)/mutator phenotype, suggesting that epigenetic-genetic subtypes exist. Experimental Design: We evaluated the relationships of aberrant methylation of APC, MGMT, hMLH1, P16, N33, and five MINTs to mutations in APC, KRAS, BRAF, and P53 in 208 colorectal carcinomas. Results: We found that APC hypermethylation was age related (P = 0.04), in contrast to the other genes, and did not cluster with CpG island methylator phenotype (CIMP) markers. Hypermethylation of APC concurrently with either MGMT or hMLH1 was strongly associated with occurrence of G-to-A transitions in APC [odds ratio (OR), 26.8; P < 0.0002 from multivariable logic regression model], but C-to-T transitions had no associations. There was no relationship of hypermethylation of any gene, including MGMT, with G-to-A or C-to-T transitions in KRAS or P53, although APC hypermethylation was associated with P53 mutation (P < 0.0002). CIMP with MSI-H due to hMLH1 hypermethylation, or CIMP with loss of MGMT expression in nonM SI-H tumors, was associated with BRAF mutation (OR, 4.5; P < 0.0002). CIMP was also associated with BRAF V600E T-to-A transversion (OR, 48.5; P < 0.0002).Conclusions: Our findings suggest that the heterogeneous epigenetic dysregulation of promoter methylation in various genes is interrelated with the occurrence of mutations, as manifested in epigenetic-genetic subgroups of tumors.The development of most colorectal carcinomas (CRC) is thought to be initiated by inactivation of the APC/b-catenin/ Wnt signaling pathway, usually by mutation of one copy of the APC gene followed by a second event that inactivates the other allele (1-4). The second inactivating event is usually described as allelic deletion or mutation but can be epigenetic methylation of cytosines in CpG islands of the promoter region of APC that results in transcriptional silencing (5, 6). Altered APC has wideranging downstream effects on cell-cell adhesion, transcriptional regulation, chromosomal instability, cell migration, proliferation and cell cycle control, differentiation, and apoptosis (1-4).Somatic APC mutation is associated with the development of intraepithelial neoplasia (dysplasia) in aberrant crypt foci and early adenomas (7). The initiating alterations in APC in these early lesions persist whereas additional genetic and epigenetic events accumulate and drive tumor progression. Somatic mutation in the APC gene is present in as many as 80% of sporadic colorectal adenomas and carcinomas (7 -9), and a mutati...

These data suggest that the MIF -173 G/C polymorphism may be related to the extent of disease in UC in a Japanese population.

A nonsynonymous single nucleotide polymorphism (Asp299Gly) in the Toll-like receptor-4 (TLR-4) gene affects the responsiveness to lipopolysaccharide in humans. To analyze this important polymorphism more efficiently, we developed a simple polymerase chain reaction (PCR) restriction length fragment polymorphism (RFLP) assay and examined the Asp299Gly allele frequency in a Japanese population. The PCR primer was designed with 1- or 2-bp mismatches, creating the recognition sequence for restriction enzyme BsaBI or BstXI, allowing RFLP analysis of the digested products. Genotyping was carried out with this assay for 275 DNA specimens from 107 healthy volunteers and 168 patients with various diseases, including ulcerative colitis (n = 86). The Asp299Gly allele of the TLR-4 gene was not detected in any of the specimens, suggesting that it is very rare in Japanese.

Our data suggest that the expression of MUC1 may be related to the progression of pancreatic cancer.

Breast cancer resistance protein (BCRP), the second member of the ATP-binding cassette membrane transporter family, has a single nucleotide polymorphism, C421A (resulting in Q141K), that is of functional importance. Our aim was to explore the relationship between this polymorphism of the BCRP gene and the risk of renal cell carcinoma (RCC) development. For a case-control study, DNA samples from 200 nonpapillary RCC patients and 200 healthy control subjects were analyzed using the TaqMan technique. The genotypic frequencies of the BCRP C421A polymorphism were compared between RCC patients and control subjects. The frequency of the C/C genotype was significantly higher in RCC patients than in control subjects (age-and gender-adjusted OR 5 1.96, 95% CI 1.32-2.93). No associations were observed between the BCRP C421A polymorphism and clinicopathologic or epidemiologic factors, including age, gender, tumor grade, stage, cigarette smoking, family history of cancer and body mass index. Carriers with the C/C genotype of the BCRP C421A polymorphism are at risk of developing nonpapillary RCC. These data suggest that BCRP is a candidate RCC susceptibility gene. ' 2005 Wiley-Liss, Inc.Key words: breast cancer resistance protein; single nucleotide polymorphism; renal cell carcinoma RCC is the most common malignancy of human adult kidneys and accounts for 2-3% of all cancers. Approximately 80% of all RCCs belong to the clear cell subtype, originating from the proximal epithelia.1 The prevalence of RCC is increasing, 2,3 probably for the following reasons: (i) an improved detection rate arising from the widespread use of noninvasive imaging procedures, such as ultrasonography, CT and MRI; (ii) prolongation of the life span in developed countries; and (iii) increases in environmental risk factors, especially exogenous carcinogens derived from various foods and industrial processes. Regarding the metabolism of such xenobiotics, genetically polymorphic enzymes such as cytochrome P-450, glutathione S-transferase and N-acetyltransferase have been reported to modulate renal cancer risk.4-6 Detection of high-risk groups based on the knowledge of cancer-susceptibility genes is clearly important for further improvement in the early diagnosis and prevention of RCC.Accumulating evidence has revealed that transporter molecules involved in the distribution, delivery and penetration of environmental agents into cellular and subcellular compartments may also play roles in the risk of renal cancer development.7,8 P-gp (MDR1/ABCB1), MRP2 (ABCC2) and BCRP (ABCG2) are members of the ABC transporter family, which function in the uptake, binding, transport and distribution of xenobiotics. P-gp is a plasma membrane transporter encoded by MDR1. Studies have shown that these proteins are expressed not only in cancer cells for effluxing multi-anticancer agents but also in the apical membrane of normal enterocytes, where they presumably act as ''gatekeepers'', controlling the oral availability of many substances. 9This hypothesis could be applicable t...