Strong Impact of TGF-β1 Gene Polymorphisms on Breast Cancer Risk in Indian Women: A Case-Control and Population-Based Study

Abstract

IntroductionTGF-β1 is a multi-functional cytokine that plays an important role in breast carcinogenesis. Critical role of TGF-β1 signaling in breast cancer progression is well documented. Some TGF-β1 polymorphisms influence its expression; however, their impact on breast cancer risk is not clear.MethodsWe analyzed 1222 samples in a candidate gene-based genetic association study on two distantly located and ethnically divergent case-control groups of Indian women, followed by a population-based genetic epidemiology study analyzing these polymorphisms in other Indian populations. The c.29C>T (Pro10Leu, rs1982073 or rs1800470) and c.74G>C (Arg25Pro, rs1800471) polymorphisms in the TGF-β1 gene were analyzed using direct DNA sequencing, and peripheral level of TGF-β1 were measured by ELISA.Resultsc.29C>T substitution increased breast cancer risk, irrespective of ethnicity and menopausal status. On the other hand, c.74G>C substitution reduced breast cancer risk significantly in the north Indian group (p = 0.0005) and only in the pre-menopausal women. The protective effect of c.74G>C polymorphism may be ethnicity-specific, as no association was seen in south Indian group. The polymorphic status of c.29C>T was comparable among Indo-Europeans, Dravidians, and Tibeto-Burmans. Interestingly, we found that Tibeto-Burmans lack polymorphism at c.74G>C locus as true for the Chinese populations. However, the Brahmins of Nepal (Indo-Europeans) showed polymorphism in 2.08% of alleles. Mean TGF-β1 was significantly elevated in patients in comparison to controls (p<0.001).Conclusionc.29C>T and c.74G>C polymorphisms in the TGF-β1 gene significantly affect breast cancer risk, which correlates with elevated TGF-β1 level in the patients. The c.29C>T locus is polymorphic across ethnically different populations, but c.74G>C locus is monomorphic in Tibeto-Burmans and polymorphic in other Indian populations.

c.29C>T polymorphism in the transforming growth factor-β1 (TGFB1) gene correlates with increased risk of urinary bladder cancer

“…Other populations in India and outside need to be studied before concluding about the relationship between the TGFB1 polymorphisms and bladder cancer risk. Since in our earlier study [33], we observed a significant association between the c.29C>T substitution and breast cancer risk, it remains to be analyzed if this substitution increases cancer risk in general. Our data would provoke further research in evaluating the association of cytokine levels and cytokine gene polymorphisms with cancer of bladder or other organs.…”

No Association of the TGF-β1 29T/C Polymorphism with Breast Cancer Risk in Caucasian and Asian Populations: Evidence from a Meta-Analysis Involving 55, 841 Subjects

“…A total of thirty-one research articles involving 24021 cases and 31820 controls were finally included in the present meta-analysis based on our selection (inclusionexclusion) criteria (Ziv et al, 2001;Dunning et al, 2003;Hishida et al, 2003;Krippl et al, 2003;Quarmby et al, 2003;Jin et al, 2004;Le Marchand et al, 2004;Saha et al, 2004;Shu et al, 2004;Kaklamani et al, 2005;Lee et al, 2005;Shin et al, 2005;Feigelson et al, 2006;Scola et al, 2006;Cox et al, 2007a;2007b;Gonullu et al, 2007;Rajkumar et al, 2008;Chen et al, 2011;Joshi et al, 2011;Pooja et al, 2013) (Figure 1). The major characteristics of selected studies are summarized in Table 1.…”

The association of functional polymorphisms in genes encoding growth factors for endothelial cells and smooth muscle cells with the severity of coronary artery disease

“…TGF-β1 is also found in blood serum, although studies aiming to compare TGF-β1 levels and CAD severity yielded conflicting results [5, 40–42]; additionally, TGF-β1 levels depend on genetic factors [43–46]. Some researchers have associated the C alleles with higher TGF-β1 levels [44–46], whereas other authors have postulated higher levels in T/T homozygotes [44]. In our study, we did not observe any relationship between rs1800470 in the gene coding for TGF-β1 and the severity of coronary artery disease.…”