Abstract
The potential association of G870A SNP (rs603965) of cyclin D1 gene (CCND1) with susceptibility to breast cancer in the north Indian population was investigated. The study included 230 subjects comprising 115 breast cancer cases and an even number of controls. PCR-RFLP employed for genotyping revealed that the females carrying AA genotype have 2.66- fold increased risk for development of breast cancer in the total cohort (OR 2.66, 95% CI 1.25– 5.67; P= 0.017) compared to GG genotype. Further, a significantly higher risk was also observed in premenopausal women (OR 3.35, 95% CI 1.22– 9.18; P= 0.0310). However, GG and GA genotype are not found associated significantly with breast cancer risk. The results suggest that CCND1 G870A polymorphism influences the genetic susceptibility to breast cancer. Larger studies conducted in diverse populations are needed to ascertain the contribution of these risk alleles to breast cancer risk.
Highlights
Cyclin D1 gene encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein and promotes progression through the G1-S phase of the cell cycle (Malumbres and Barbacid 2001; Sherr 1996)
The relative abundance of the cyclin D1b isoform is affected by G/A single nucleotide polymorphism at the last base of exon 4, which is the –1 position of the intron 4 splice donor consensus (Knudsen et al, 2006)
Several molecular epidemiological studies have been conducted to examine the association between CCND1 G870A polymorphism and breast cancer risk (Ceschi et al, 2005; Forsti et al, 2004; Grieu et al, 2003; Krippl et al, 2003; Onay et al, 2008; Shu et al, 2005; Yu et al, 2008), but the results remain inconsistent
Summary
Cyclin D1 (or CCND1) gene encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein and promotes progression through the G1-S phase of the cell cycle (Malumbres and Barbacid 2001; Sherr 1996). Cyclin D1 exerts as a CDK-dependent as well as CDK-independent regulator of the cell cycle (Radu et al, 2003). Cyclin D1 in association with CDK4 regulates the G1/S phase progression by phosphorylating and inactivating the RB protein in turn releasing the transcription factor E2F from RB protein and an eventual DNA synthesis (Radu et al, 2003). Cyclin D1 overexpression may lead to the early phosphorylation of RB protein, uncontrolled cell growth and tumorigenesis (Huynh et al, 2004). Five exons of CCND1 encode two major isoforms, cyclin D1a and D1b after alternative splicing. The majority of cyclin D1a isoform mRNA, 4.5 kilobases (kb) in length, with a coding region of only 882 bp, consists of 3'UTR sequences and harbors mRNA destabilizing elements
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