Strong Impact of TGF-[beta]1 Gene Polymorphisms on Breast Cancer Risk in Indian Women: A Case-Control and Population-Based Study

• Published in: PloS one 2013-10, Vol.8 (10), p.e75979
• Main Authors: Pooja, Singh, Francis, Amirtharaj, Rajender, Singh, Tamang, Rakesh, Rajkumar, Raja, Saini, Karan Singh, Megu, Kaling, Goel, Madhu Mati, Surekha, Daminani, Rao, Digumarthi Raghunatha, Rao, Lakshmi, Ramachandra, Lingadakai, Kumar, Sandeep, Kumar, Surender, Vishnupriya, Satti, Satyamoorthy, Kapaettu, Negi, Mahendra Pal Singh, Thangaraj, Kumarasamy, Konwar, Rituraj
• Format: Article
• Language: English
• Subjects: Bone morphogenetic proteins; Breast cancer; Cancer genetics; Cancer prevention; Cancer research; Cytokines; Development and progression; DNA sequencing; Epidemiology; Genes; Genetic aspects; Genetic polymorphisms; Risk factors; Transforming growth factors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0075979

TGF-[beta]1 is a multi-functional cytokine that plays an important role in breast carcinogenesis. Critical role of TGF-[beta]1 signaling in breast cancer progression is well documented. Some TGF-[beta]1 polymorphisms influence its expression; however, their impact on breast cancer risk is not clear. We 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-[beta]1 gene were analyzed using direct DNA sequencing, and peripheral level of TGF-[beta]1 were measured by ELISA. c.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-[beta]1 was significantly elevated in patients in comparison to controls (pT and c.74G>C polymorphisms in the TGF-[beta]1 gene significantly affect breast cancer risk, which correlates with elevated TGF-[beta]1 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.