Integrin alpha-2 and beta-3 gene polymorphisms and colorectal cancer risk.

BACKGROUND AND AIMS: Integrins such as alpha(2)beta(1), alpha(IIb)beta(3), and alpha(v)beta(3) have been suggested as key players for cancer development and progression. Several polymorphisms affecting these molecules, two in integrin alpha(2) (ITGA2 807C>T and 1648G>A) and one in beta(3) (ITGB3 176T>C), influence their levels, structure, and possibly their function. To analyze the role of ITGA2 and ITGB3 polymorphisms for colorectal cancer risk and clinical presentation, we performed a case-control study. MATERIALS AND METHODS: Four hundred thirty-three colorectal cancer patients and 433 healthy sex- and age-matched control subjects were investigated. ITGA2 and ITGB3 polymorphisms were determined by 5'-nuclease assays. RESULTS/FINDINGS: The ITGA2 807C>T polymorphism was associated with reduced colorectal cancer risk. In a codominant model, the odds ratio for each additional 807-T allele for colorectal cancer was 0.77 (95% confidence interval 0.64-0.94; p = 0.011). The ITGA2 1648G> and the ITGB3 176T>C polymorphism were not associated with colorectal cancer. None of the three polymorphisms investigated was associated with tumor size, histological grade, presence of primary lymph node metastases, tumor stage, or age at diagnosis. INTERPRETATION/CONCLUSION: We conclude that the ITGA2 807C>T polymorphism may be associated with reduced colorectal cancer risk.

The cyclooxygenase-2 (PTGS2) 8473T>C polymorphism is associated with breast cancer risk.

Cyclooxygenase-2 (COX-2) is involved in carcinogenesis, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis. The gene for COX-2, designated as PTGS2, carries a common polymorphism at position 8473 in the 3'-untranslated region (PTGS2 8473T>C), which has been associated with susceptibility to malignant disease. To investigate the role of this polymorphism for breast cancer, we determined the prevalence of PTGS2 genotypes in 500 women with breast cancer and 500 sex- and age-matched healthy control subjects. Homozygous carriers of the 8473-CC genotype were more frequent among patients (12.4%) than among controls (6.6%; P = 0.002). The odds ratio for carriers of this genotype for breast cancer was 2.1 (95% confidence interval, 1.3-3.3). Among patients, estrogen receptor positivity was less frequent among carriers of a CC genotype (63.9%) than among carriers of a TT or TC genotype (76.9%; P = 0.028). Tumor size, histologic grade, presence of primary lymph node metastases, progesterone receptor positivity, or age at diagnosis were not associated with PTGS2 genotypes. We conclude that the homozygous PTGS2 8473-CC genotype may be associated with breast cancer risk.

A multigenic approach to predict breast cancer risk.

In the biology of complex disorders, such as breast cancer, interactions among genetic factors may play an important role and theoretical considerations suggest that gene-gene interactions are quite common in such diseases. In this case-control study with 500 breast cancer patients and 500 population-based healthy sex- and age-matched control subjects, we applied a multigenic approach to examine the associations with breast cancer risk of a comprehensive panel of 16 selected polymorphisms in a variety of pathways using classification tree analysis (CART). Overall, 79.6% of all breast cancer patients and 80.6% of all control subjects were correctly classified on the basis of their individual genetic profile by the classification procedure. CART analysis of the data identified the heterozygous vascular endothelial growth factor (VEGF) and matrix metalloproteinase 3 (MMP3) genotype and homozygous cyclooxygenase-2 (PTGS2) mutant as the initial splits, indicating that these genotypes exert the greatest impact on the classification process. Breast cancer patients were primarily indicated by 30 distinct genetic profiles. The odds ratio of these genetic risk profiles for breast cancer was 16.12 (95% confidence interval 11.09-23.49). Five genetic profiles formed homogenous breast cancer subgroups and represented highest risk genetic profiles. This is the first comprehensive study to use a multigenic analysis for breast cancer and the data suggest that individuals with distinct genetic profiles are at an increased risk for breast cancer, confirming the importance of taking a multigenic approach for risk assessment.

Genetic variants of the sulfotransferase 1A1 and breast cancer risk.

Sulfotransferase 1A1 (SULT1A1), also designated as phenol-preferring sulfotransferase, is involved in the bioactivation and detoxification of a variety of potential carcinogens, including iodothyronines, hydroxylated aromatic amines, and phenolic xenobiotics. A common arginine (R) to histidine (H) polymorphism at amino acid position 213 influences SULT1A1 activity and has been suggested as risk factor for a different types of cancers. To investigate the role of this polymorphism for breast cancer risk, SULT1A1 genotype was determined in 500 women with clinically verified breast cancer and 500 female age-matched healthy control subjects. Frequencies of heterozygous (controls: 42.5% patients: 50.2%) or homozygous (controls: 12.6%; patients: 9.4%) carriers of the 213H variant were not significantly different between groups. The SULT1A1 genotype was furthermore not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. The SULT1A1 213H variant was associated with the presence of lymph node metastases (p = 0.002). We conclude that the SULT1A1 R213H polymorphism is not a general risk factor for breast cancer, but may be involved in lymph node metastazing in breast cancer patients.

The common 677C>T gene polymorphism of methylenetetrahydrofolate reductase gene is not associated with breast cancer risk.

Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and plays a role in DNA biosynthesis, methylation, and repair in actively dividing cells. A common 677C>T polymorphism in the gene for MTHFR, leading to a thermolabile enzyme with decreased activity, has been associated with reduced plasma folate levels and elevated homocysteine levels and could be a risk factor for breast cancer. In the present case-control study, MTHFR genotype was determined in 500 women with clinically verified breast cancer and 500 female age-matched healthy control subjects. The homozygous TT genotype was found in 13.0% patients and 13.1% controls (P = n.s.). The odds ratio of TT homozygotes for breast cancer was 0.99 (95% confidence interval 0.68-1.43). The MTHFR genotype was furthermore not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. In a subgroup of 116 premenopausal patients, no increased frequency of the homozygous 677T genotype was found (13.8%). Therefore, we conclude that the MTHFR 677C>T polymorphism is not associated with individual susceptibility to breast cancer.

The 870G>A polymorphism of the cyclin D1 gene is not associated with breast cancer.

A common 870G > A polymorphism in the gene for cyclin D1, CCND1, has been linked to alternative splicing and cancer susceptibility. To analyze its role for breast cancer, we determined the CCND1 genotype in 500 breast cancer patients and 500 controls. CCND1 genotype frequencies were similar among patients and controls. The CCND1 genotype was furthermore not associated with tumor characteristics. We conclude that the CCND1 870G > A polymorphism is not associated with breast cancer.