Unique SNP in CD 44 Intron 1 and its Role in Breast Cancer Development

In the current study, we investigated if CD44 polymorphisms are associated with increased susceptibility to breast cancer. Direct nucleotide sequencing analysis identified a novel and unique single nucleotide polymorphism (SNP, designated as CD44 Ex2+14 A>G) in the CD44 intron 1 region in 84% of breast cancer patients, which was significantly higher than that seen in normal donors. Moreover, the breast cancer patients with homozygous unique SNP in CD44 intron 1 had breast cancer at earlier ages, larger tumor burden, more regional lymph node metastases at the time of diagnosis, and higher cancer recurrence rate. There was a strong association between the unique SNP in CD44 intron 1 and CD44 expression on peripheral blood mononuclear cells. Our results suggest that CD44 polymorphism is associated with breast cancer development, and CD44 polymorphism analysis may be effectively used in the risk assessment, prediction, prevention, diagnosis and genetic epidemiological analysis of breast cancer. Breast cancer is a leading cause of cancer-related deaths in women in the United States and worldwide. One of the most important risk factors for breast cancer is family history of the disease, indicating that genetic factors may be important determinants of breast cancer risk. A number of breast cancer susceptibility genes have been identified. The two most important breast cancer susceptibility genes, BRCA1 and BRCA2, accounted for approximately 15% of breast cancer cases due to inherited mutations or alterations (1, 2). However, BRCA1 and BRCA2 mutations are present in far less than 1% of the general population (3). In addition to BRCA1 and BRCA2, five other genes, TP53, PTEN, LKB1, ATM and CHEK2, are also well established as breast cancer susceptibility genes (4). The proportion of breast cancers in the general population explained by these germline gene mutations is very small. It is estimated that all the currently known breast cancer susceptibility genes account for less than 25% of the familial aggregation of breast cancer (5). The evidence to date strongly suggests that majority of the familial clustering of breast cancer is unexplained and other breast cancer susceptibility genes still remain to be identified. Inherited genetic variations, or gene polymorphisms, are viewed as major factors in breast cancer prevalence. However, the data thus far have been inconclusive. After reviewing a substantial number of studies that have investigated candidate genes for low-penetrance breast cancer susceptibility alleles, Dunning et al. (1999) concluded that there is no clear evidence that any of these polymorphisms are strongly associated with breast cancer risk (6). Recent findings on the associations between polymorphisms and breast cancer susceptibility have also been controversial. For instance, a previous study suggested that BRCA1 carriers with longer lengths of the CAG repeat in the androgen receptor gene are at increased risk of breast cancer (3). However, a subsequent study failed to find any significant association of the androgen receptor repeat polymorphisms with risk of breast cancer in either BRCA1/2 carriers or in noncarriers (7). Several reports documented that progesterone receptor gene polymorphism is associated with an increased breast cancer risk (8, 9). In contrast, other studies failed to show any significant associations between breast cancer risk and progesterone receptor polymorphisms (10-12). It is more likely, however, that the lack of correlation between polymorphisms and susceptibility to breast cancer may be due to genes that have yet to be identified or tested (6). Lately, analysis of 9 selected single nucleotide polymorphisms (SNPs) in a large 1263 Correspondence to: Dr. Mitzi Nagarkatti, Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, 6439 Garners Ferry Road, Columbia, SC 29209, U.S.A. Tel: +1 803 7333258, Fax: +1 803 7331515, e-mail: Mitzi.Nagarkatti@ uscmed.sc. edu