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Functional analysis of low-penetrance breast cancer susceptibility genes

Putative low penetrance cancer susceptibility genes may have under appreciated role in the overall genetic predisposition to breast cancer and other common malignancies. To test their possible functional role, we used a variety of approaches to examine several candidate breast cancer susceptibility genes, including BACH1 (Lei and Vorechovsky, 2003; Luo et al., 2002), CDH (Lei et al., 2002b; Salahshor et al., 2001), ATM (Lei et al., 2002a; Stankovic et al., 2001) and MMP3 (Lei et al., 2002c). The methods employed mutation analysis (Luo et al., 2002; Vorechovsky, 2002), analysis of alternative pre-mRNA splicing (Kralovicova et al., 2004), subcellular localization (Lei and Vorechovsky, 2003), promoter activity assays (Lei et al., 2002b), haplotype analysis (Stankovic et al., 2001) and allelic association (Lei et al., 2002c). Full details are described in references below:

- Kralovicova, J., Houngninou-Molango, S., Kramer, A., and Vorechovsky, I. (2004). Branch sites haplotypes that control alternative splicing. Hum Mol Genet 18, in press.

- Lei, H., Pospisilova, D., Lindblom, A., and Vorechovsky, I. (2002a). Re: Dominant Negative ATM Mutations in Breast Cancer Families. J Natl Cancer Inst 94, 951-952.

- Lei, H., Sjoberg-Margolin, S., Salahshor, S., Werelius, B., Jandakova, E., Hemminki, K., Lindblom, A., and Vorechovsky, I. (2002b). CDH1 mutations are present in both ductal and lobular breast cancer, but promoter allelic variants show no detectable breast cancer risk. Int J Cancer 98, 199-204.

- Lei, H., and Vorechovsky, I. (2003). BACH 517C->T transition impairs protein translocation to nucleus: a role in breast cancer susceptibility? Int J Cancer 104, 389-391.

- Lei, H., Zaloudik, J., and Vorechovsky, I. (2002c). Lack of association of the -1171 (5A) allele of the MMP3 promoter with breast cancer. Clin Chem 48, 798-799.

- Luo, L., Lei, H., Du, Q., von Wachenfeldt, A., Kockum, I., Luthman, H., Vorechovsky, I., and Lindblom, A. (2002). No mutations in the BACH1 gene in BRCA1 and BRCA2 negative breast-cancer families linked to 17q22. Int J Cancer 98, 638-639.

- Salahshor, S., Haixin, L., Huo, H., Kristensen, V. N., Loman, N., Sjoberg-Margolin, S., Borg, A., Borresen-Dale, A. L., Vorechovsky, I., and Lindblom, A. (2001). Low frequency of E-cadherin alterations in familial breast cancer. Breast Cancer Res 3, 199-207.

- Stankovic, T., Taylor, A. M., Yuille, M. R., and Vorechovsky, I. (2001). Recurrent ATM mutations in T-PLL on diverse haplotypes: no support for their germline origin. Blood 97, 1517-1518.

- Vorechovsky, I. (2002). Mutation analysis of large genomic regions in tumor DNA using single-strand conformation polymorphism. Lessons from the ATM gene. Methods Mol Med 68, 115-124.


Igor VORECHOVSKY, (Lecturer)
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