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Search for susceptibility loci and candidate genes for breast cancer
Breast cancer is the most frequent cancer among women in the western world. Family history is a wellestablished and important risk factor for breast cancer. Both a population-based twin study and a study based on a large family cancer database have suggested that hereditary factors account for about a quarter of breast cancers. The well-established high penetrance genes, e.g. BRCA1 and BRCA2, only account for less than 5% of all breast cancer cases. In attempts to identify further genetic factors, two common approaches have been used. One is linkage analysis, which is used to pinpoint the putative moderate/high susceptibility loci. The other is an association study, which is thought to be more powerful in the search for low-penetrance alleles in candidate genes.
Here, we explored the susceptibility loci in chromosomes 1, 13, 16, and 17 in Swedish monozygotic twins, concordant for breast cancer, using loss of heterozygosity (LOH) analysis (Paper I). We also carried out association studies (Papers II–IV) to investigate the contribution of functional polymorphisms in putative breast cancer susceptibility genes to the risk of breast cancer, using both unselected and familial breast cancer cases. The use of familial cases can significantly increase the power of the association studies. The genes selected were the sex hormone binding globulin (SHBG) gene, genes involved in transforming growth factor beta (TGFbeta) signaling pathway, and the vascular endothelial growth factor (VEGF) gene.
· In the LOH study (Paper I), our hypothesis was that loss of the same allele at a specific genomic region in both of the twins might suggest a tumor suppressor gene that confers a strong predisposition to breast cancer. From the analysis, we found that 16qtel and 17p13 were the two main candidate regions in the twins. 16q22.1, 17q21 and 13q14 may also be involved in a subset of the twins. Chromosome 1 did not seem to carry any important tumor suppressor gene in our sample set.
· Estradiol is one of the strongest risk factors for breast cancer. SHBG is a plasma carrier of estradiol and it is involved in regulation of the bioavailability of estradiol to target cells. In Paper II, we analyzed three functional coding-region polymorphisms in the SHBG gene. One of them appeared to have a small protective effect on breast cancer risk, both in the unselected and the high risk breast cancer populations. The effect became significant when all breast cancer cases were compared to all of the controls.
· In Paper III, five polymorphisms in the TGFb1 gene, one polymorphism in the TGFbbetaRI gene and two polymorphisms in the TGFbetaRII gene were analyzed. In normal human breast epithelial cells and during the early stages of breast cancer development, TGFbeta1 acts as a growth inhibitor but with progression as a tumor promoter. Genotype and haplotype analyses were carried out on the polymorphisms in the TGFbeta1 gene, and a genotype combination analysis on the polymorphisms in the TGFbeta1 and its receptor genes. Only carriers of the rare 6A/6A genotype in the TGFbetaR1 gene were suggested to be at an increased risk of breast cancer.
· Formation of new blood vessels (angiogenesis) is an important step during the development of cancer. VEGF is a major mediator of breast cancer angiogenesis. In Paper IV, altogether four polymorphisms in the VEGF gene were studied in both familial and unselected breast cancer cases, together with corresponding controls. None of the polymorphisms, nor any haplotype alone, were significantly associated with either familial or unselected breast cancer. However, when we investigated the VEGF genotypes in relation to the clinical characteristics in the unselected breast cancers, some of the genotypes and haplotypes showed significant association with altered tumor aggressiveness.
In summary, we found that 16qtel and 17p13 are the two main candidate breast tumor suppressor gene regions among the chromosomes studied in Swedish monozygotic twins. Some of the genetic polymorphisms in the genes that were studied may influence the risk of breast cancer. Furthermore, some genotypes and haplotypes appear to affect the development of breast tumors.
List of scientific papers
I. Forsti A, Jin Q, Sundqvist L, Soderberg M, Hemminki K (2001). Use of monozygotic twins in search for breast cancer susceptibility loci. Twin Res. 4(4): 251-9.
https://pubmed.ncbi.nlm.nih.gov/11665305
II. Forsti A, Jin Q, Grzybowska E, Soderberg M, Zientek H, Sieminska M, Rogozinska-Szczepka J, Chmielik E, Utracka-Hutka B, Hemminki K (2002). Sex hormone-binding globulin polymorphisms in familial and sporadic breast cancer. Carcinogenesis. 23(8): 1315-20.
https://pubmed.ncbi.nlm.nih.gov/12151349
III. Jin Q, Hemminki K, Grzybowska E, Klaes R, Soderberg M, Zientek H, Rogozinska-Szczepka J, Utracka-Hutka B, Pamula J, Pekala W, Forsti A (2004). Polymorphisms and haplotype structures in genes for transforming growth factor beta1 and its receptors in familial and unselected breast cancers. Int J Cancer. 112(1): 94-9.
https://pubmed.ncbi.nlm.nih.gov/15305380
IV. Jin Q, Hemminki K, Enquist K, Lenner P, Grzybowska E, Klaes R, Chen B, Pamula J, Pekala W, Zientek H, Rogozinska-Szczepka J, Utracka-Hutka B, Hallmans G, Forsti A (2004). Vascular endothelial growth factor polymorphisms in breast cancer with evidence of influence on tumor development. [Submitted]
History
Defence date
2004-12-17Department
- Department of Medicine, Huddinge
Publication year
2004Thesis type
- Doctoral thesis
ISBN-10
91-7140-030-3Number of supporting papers
4Language
- eng