Strong impact of TGF-β1 gene polymorphisms on breast cancer risk in Indian women: a case-control and population-based study

Introduction: TGF-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. Methods: 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-β1 gene were analyzed using direct DNA sequencing, and peripheral level of TGF-β1 were measured by ELISA. Results: 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-β1 was significantly elevated in patients in comparison to controls (p<0.001). Conclusion: c.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

SRD5A2 gene polymorphisms affect the risk of breast cancer

Androgens in breast cancer have been studied alone and in correlation with estrogens as estrogen to testosterone ratio. 5-α-reductase is one of the important enzymes participating in androgen metabolism, which affects androgen activity by affecting conversion of testosterone to dihydrotestosterone. We hypothesized that polymorphisms in the SRD5A2 gene (encoding 5-α-reductase) may affect breast cancer risk by affecting total androgen activity. Complete coding region of the SRD5A2 gene was sequenced in a group of 628 patients and 244 control samples from three southern states (Tamil Nadu, Andhra Pradesh and Karnataka) of India. We observed three common polymorphisms in this gene; namely, A49T, V89L and (TA)n repeats. A49T locus was monomorphic in the study population, but V89L showed a strong correlation with breast cancer (P = 0.03, OR = 1.40, CI = 1.02–1.91). (TA)0/(TA)9 and (TA)9/(TA)9 genotypes were at a lower risk of breast cancer (P = 0.01, OR = 0.64, CI = 0.46–0.90). We conclude that SRD5A2 genotypes significantly affect breast cancer risk in the South Indian populations

A mitochondrial DNA variant 10398G>A in breast cancer among south Indians: an original study with meta-analysis

The m.10398G > A polymorphism in the MT-ND3 gene has been linked to the manifestation of several neurodegenerative disorders and cancers. Several research groups have analyzed the association between m.10398G > A polymorphism and breast cancer; however, the results do not follow a consensus. We have studied this polymorphism in three Dravidian populations from South India. Analysis on 716 cases and 724 controls found no association between m.10398G > A polymorphism and breast cancer [OR = 0.916 (0.743–1.128); P = 0.409]. Menopausal stratification also revealed no significant association in either pre-menopausal or post-menopausal breast cancer groups. In addition, we undertook a meta-analysis on 16 study groups, comprising a total of 7202 cases and 7490 controls. The pooled odds ratio suggested no significant association of m.10398G > A substitution with breast cancer [OR = 1.016 (0.85–1.22); P = 0.86]. In conclusion, there is no evidence of association between m.10398G > A polymorphism and breast cancer risk among South Indian women. Meta-analysis suggested no overall correlation between this polymorphism and breast cancer risk

Distribution of the two polymorphisms in Indian populations.

<p>Distribution of the two polymorphisms in Indian populations.</p

Comparison of +29 C>T genotype data between case groups as per menopause and the controls.

<p>Allele and genotype frequency is followed by percent values in parenthesis.</p>*<p>Indicates statistical significant value at 95% level of confidence.</p

Age dependent associations of genotypes with confounding covariates in north Indian population by Cox regression analysis.

<p>The odds are of BMI “>23 kg/m², Diet “Non vegetarian”, Religion “Hindu”, Family history “Yes”, Personal habits “Yes”, Age at menarche “>14 yrs), Age at 1^st full term pregnancy “>19 yrs” and Menopausal status “Yes” against BMI “≤23 kg/m², Diet “Vegetarian”, Religion “Muslim”, Family history “No”, Personal habits “No”, Age at menarche “≤14 yrs), Age at 1^st full term pregnancy “≤19 yrs” and Menopausal status “No”.</p>*<p>Statistically significant (p<0.001).</p

Comparison of +74 G>C genotype data between cases and controls.

<p>Allele and genotype frequency is followed by percent values in parenthesis.</p>*<p>Indicates statistical significant value at 95% level of confidence.</p

Participant characteristics.

<p>Participant characteristics.</p

Pooled data comparison for all cases versus controls.

<p>Allele and genotype frequency is followed by percent values in parenthesis.</p>*<p>Indicates statistical significant value at 95% level of confidence.</p