Studies of twins indicate that approximately 27% of breast cancers and 35% of colorectal cancers are inherited (Lichtenstein, Holm et al. 2000). High-penetrance tumor susceptibility genes only account for a small fraction of these common cancers. The remainder of the unexplained familial risk is presumably due to other high penetrance genes, but polygenic mechanisms and low penetrance tumor susceptibility genes are likely to account for a greater proportion of familial breast and colorectal cancers. In a search for mutations of the type I TGF-β receptor (TGFBR1), we have identified a common variant, TGFBR1*6A, which has a deletion of three GCG triplets coding for alanine within a nine alanine (9A) repeat of the TGFBR1 signal sequence (Pasche, Luo et al. 1998, Pasche, Kolachana et al. 1999, Pasche, Knobloch et al. 2005). In normal epithelial cells, TGFBR1*6A mediates TGF-β growth inhibitory signals less effectively than TGFBR1, and in cancer cells it may switch growth-inhibitory signals into growth-stimulatory signals. This important allele has emerged as a common cancer susceptibility allele, which has been confirmed in several meta-analyses(Liao, Mao et al. 2010, Wang, Qi et al. 2012). Using a novel mouse model of Tgfbr1 haploinsufficiency, we have shown that constitutively decreased Tgfbr1 signaling is a potent modifier of colorectal cancer in mice (Zeng, Phukan et al. 2009) and humans(Valle, Serena-Acedo et al. 2008). This led to the identification of human TGFBR1 haplotypes associated with hypomorphic TGF-ß signaling, as well as colorectal cancer (Pasche, Wisinski et al. 2010) and non-small cell lung cancer risk (Lei, Liu et al. 2009). We are currently studying the molecular mechanisms of naturally occurring variants and genotypes of the TGF-ß signaling pathway using knock-in and knock-out mouse models, as well as various in vitro models. We are also conducting genetic epidemiology studies of variants of the TGF-ß signaling pathway in the adiponectin pathway as they relate to risk of colorectal cancer and breast cancer.
TGF-ß and cancer susceptibility
Using patient-based discovery methods(Pasche, Jimenez et al. 2015), we have pioneered the use of low levels amplitude-modulated radiofrequency electromagnetic fields as a novel targeted therapy in oncology(Jimenez, Blackman et al. 2018). We have demonstrated that tumor-specific modulation frequencies are capable of blocking tumor growth in patients(Barbault, Costa et al. 2009, Costa, de Oliveira et al. 2011) and in cancer cells(Zimmerman, Pennison et al. 2012). We have developed novel in vitro(Zimmerman, Pennison et al. 2012) and in vivo(Capstick, Gong et al. 2016) models of radiofrequency electromagnetic fields exposure to assess the mechanism of action of amplitude-modulated electromagnetic fields in cancer. Our current research efforts focus on dissecting the mechanism of action of this new targeted therapy for cancer, which received European regulatory approval for the treatment of advanced hepatocellular carcinoma in 2018.
Amplitude modulated radiofrequency electromagnetic fields
Barbault, A., F. P. Costa, B. Bottger, R. F. Munden, F. Bomholt, N. Kuster and B. Pasche (2009). "Amplitude-modulated electromagnetic fields for the treatment of cancer: discovery of tumor-specific frequencies and assessment of a novel therapeutic approach." J Exp Clin Cancer Res28(1): 51.
Capstick, M., Y. Gong, B. Pasche and N. Kuster (2016). "An HF exposure system for mice with improved efficiency." Bioelectromagnetics37(4): 223-233.
Costa, F. P., A. C. de Oliveira, R. Meirelles, M. C. C. Machado, T. Zanesco, R. Surjan, M. C. Chammas, M. de Souza Rocha, D. Morgan, A. Cantor, J. Zimmerman, I. Brezovich, N. Kuster, A. Barbault and B. Pasche (2011). "Treatment of advanced hepatocellular carcinoma with very low levels of amplitude-modulated electromagnetic fields." Br J Cancer105(5): 640-648.
Jimenez, H., C. Blackman, G. Lesser, W. Debinski, M. Chan, S. Sharma, K. Watabe, H. W. Lo, A. Thomas, D. Godwin, W. Blackstock, A. Mudry, J. Posey, R. O'Connor, I. Brezovich, K. Bonin, D. Kim-Shapiro, A. Barbault and B. Pasche (2018). "Use of non-ionizing electromagnetic fields for the treatment of cancer." Front Biosci (Landmark Ed)23: 284-297.
Lei, Z., R. Y. Liu, J. Zhao, Z. Liu, X. Jiang, W. You, X. F. Chen, X. Liu, K. Zhang, B. Pasche and H. T. Zhang (2009). "TGFBR1 Haplotypes and Risk of Non-Small-Cell Lung Cancer." Cancer Research69(17): 7046-7052.
Liao, R. Y., C. Mao, L. X. Qiu, H. Ding, Q. Chen and H. F. Pan (2010). "TGFBR1*6A/9A polymorphism and cancer risk: a meta-analysis of 13,662 cases and 14,147 controls." Mol Biol Rep.37(7): 3227-3232.
Lichtenstein, P., N. V. Holm, P. K. Verkasalo, A. Iliadou, J. Kaprio, M. Koskenvuo, E. Pukkala, A. Skytthe and K. Hemminki (2000). "Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland." N Engl J Med343(2): 78-85.
Pasche, B., H. Jimenez, J. Zimmerman, M. Pennison, M. Wang, J. Posey, A. Forrero-Torres, J. T. Carpenter, I. Brezovich, A. W. Blackstock, F. P. Costa and A. Barbault (2015). Systemic treatment of cancer with low and safe levels of radiofrequency electromagnetic fields amplitude-modulated at tumor-specific frequencies. Bioelectromagnetic and Subtle Energy Medicine. P. J. Rosch. Boca Raton, FL, CRC Press: 299-305.
Pasche, B., T. J. Knobloch, Y. Bian, J. Liu, S. Phukan, D. Rosman, V. Kaklamani, L. Baddi, F. S. Siddiqui, W. Frankel, T. W. Prior, D. E. Schuller, A. Agrawal, J. Lang, M. E. Dolan, E. E. Vokes, W. S. Lane, C. C. Huang, T. Caldes, A. Di Cristofano, H. Hampel, I. Nilsson, G. von Heijne, R. Fodde, V. V. V. S. Murty, A. de la Chapelle and C. M. Weghorst (2005). "Somatic Acquisition and Signaling of TGFBR1*6A in Cancer." JAMA: The Journal of the American Medical Association294(13): 1634-1646.
Pasche, B., P. Kolachana, K. Nafa, J. Satagopan, Y. G. Chen, R. S. Lo, D. Brener, D. Yang, L. Kirstein, C. Oddoux, H. Ostrer, P. Vineis, L. Varesco, S. Jhanwar, L. Luzzatto, J. Massague and K. Offit (1999). "T beta R-I(6A) is a candidate tumor susceptibility allele." Cancer Research59(22): 5678-5682.
Pasche, B., Y. Luo, P. H. Rao, S. D. Nimer, E. Dmitrovsky, P. Caron, L. Luzzatto, K. Offit, C. Cordon-Cardo, B. Renault, J. M. Satagopan, V. V. Murty and J. Massague (1998). "Type I transforming growth factor beta receptor maps to 9q22 and exhibits a polymorphism and a rare variant within a polyalanine tract." Cancer Res.58(13): 2727-2732.
Pasche, B., K. B. Wisinski, M. Sadim, V. Kaklamani, M. J. Pennison, Q. Zeng, N. Bellam, J. Zimmerman, N. Yi, K. Zhang, J. Baron, D. O. Stram and M. G. Hayes (2010). "Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs." J Exp.Clin Cancer Res.29: 57.
Valle, L., T. Serena-Acedo, S. Liyanarachchi, H. Hampel, I. Comeras, Z. Li, Q. Zeng, H. T. Zhang, M. J. Pennison, M. Sadim, B. Pasche, S. M. Tanner and A. de la Chapelle (2008). "Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer." Science321(5894): 1361-1365.
Wang, Y. Q., X. W. Qi, F. Wang, J. Jiang and Q. N. Guo (2012). "Association between TGFBR1 polymorphisms and cancer risk: a meta-analysis of 35 case-control studies." PLoS ONE7(8): e42899.
Zeng, Q., S. Phukan, Y. Xu, M. Sadim, D. S. Rosman, M. Pennison, J. Liao, G. Y. Yang, C. C. Huang, L. Valle, A. Di Cristofano, A. de la Chapelle and B. Pasche (2009). "Tgfbr1 Haploinsufficiency Is a Potent Modifier of Colorectal Cancer Development." Cancer Research69(2): 678-686.
Zimmerman, J. W., M. J. Pennison, I. Brezovich, N. Yi, C. T. Yang, R. Ramaker, D. Absher, R. M. Myers, N. Kuster, F. P. Costa, A. Barbault and B. Pasche (2012). "Cancer cell proliferation is inhibited by specific modulation frequencies." Br J Cancer106(2): 307-313.