The pattern of clinical breast cancer metastasis correlates with a single nucleotide polymorphism in the C1qA component of complement

Abstract

Complement is one of primary defense mechanisms against intravascular microorganisms and could play a role in the immune response to malignancy and hence its clinical behavior. We evaluated if the sole coding polymorphism of C1qA associates with outcome in patients with breast carcinoma. Genotyping for C1qA[276A/G] was performed in 63 breast cancer subjects with localized tumor and compared with that in 38 breast cancer subjects with metastasis. Established risk factors for clinical outcome were considered and evaluated in multivariable analysis. Breast cancer subjects with heterozygous or homozygous C1qA[276G] genotype had a higher rate of metastasis than subjects with the homozygous C1qA[276A] genotype [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.1-4.1]. This association was stronger when only metastatic sites associated with hematogenous spread, i.e., to the bone, liver, and brain, were considered (HR 3.5, 95% CI 1.4-5.6) and remained statistically significant after adjustment for the number of positive lymph nodes, estrogen receptor status, and progesterone receptor status. There was no statistical difference in the C1qA[276A/G] allelic distribution between all subjects with breast cancer and controls. These results suggest there could be an association of a single nucleotide polymorphism at position 276 of the C1qA component of complement with breast cancer metastasis to sites linked to hematogenous spread of disease. The C1qA polymorphism associated with decreased distant metastasis has also been correlated with an increased incidence of subcutaneous systemic lupus and C1q deficiencies, suggesting that an altered immune response may play a role in the observed association.

Common germ-line polymorphism of C1QA and breast cancer survival

“…Recently, we showed that overexpression of C1QA in ER-negative basal-like breast cancer patients, which have the poorest prognosis (Sorlie et al, 2001), is associated with better outcome (Teschendorff et al, 2006Teschendorff and Caldas, 2008). The A allele of C1QA polymorphism rs172378 has been associated with decreased complement activity, resulting in reduced metastasis associated with breast cancer (Petry and Loos, 2005;Racila et al, 2006). The decrease in complement activity is suggested to result in less clearance of apoptotic tumour cells (Racila et al, 2003), and in a more effective antibody response against the tumour.…”

“…On the basis of previous results by Racila et al (2006), a G dominant HR (AG/GG), relative to the common homozygote (AA), was also estimated. Statistical significance was assessed using a trend test (1 degree of freedom).…”

“…There are seven single nucleotide polymorphisms (SNPs) catalogued for C1QA on the NCBI database, of which there is only one common SNP (minor allele frequency 45%) located in an exon rs172378 is a synonymous SNP characterised by a G for A substitution at position 361 (A361G). This SNP has been previously reported as being associated with breast cancer metastasis to sites linked to hematogenous spread of disease (Racila et al, 2006) and with drug response in follicular lymphoma (Racila et al, 2008). In a set of 63 patients with localised breast tumours and 38 patients with metastasis, Racila et al (2006) reported a decreased time to metastasis for G homozygote or heterozygote individuals compared with the common AA homozygote (hazard ratio, 95% CI: 2.4, 1.1 -4.1), even after adjustment for positive lymph nodes, oestrogen and progesterone receptors status.…”

“…This SNP has been previously reported as being associated with breast cancer metastasis to sites linked to hematogenous spread of disease (Racila et al, 2006) and with drug response in follicular lymphoma (Racila et al, 2008). In a set of 63 patients with localised breast tumours and 38 patients with metastasis, Racila et al (2006) reported a decreased time to metastasis for G homozygote or heterozygote individuals compared with the common AA homozygote (hazard ratio, 95% CI: 2.4, 1.1 -4.1), even after adjustment for positive lymph nodes, oestrogen and progesterone receptors status. Racila et al (2006) have also reported that rs172378 correlates with decreased complement activity, which then reduces the instance of metastasis associated with breast cancer, perhaps by resulting in an inefficient clearance of apoptotic tumour cancer cells, which consequently results in the development of a more effective antibody response against the tumour.…”

“…In a set of 63 patients with localised breast tumours and 38 patients with metastasis, Racila et al (2006) reported a decreased time to metastasis for G homozygote or heterozygote individuals compared with the common AA homozygote (hazard ratio, 95% CI: 2.4, 1.1 -4.1), even after adjustment for positive lymph nodes, oestrogen and progesterone receptors status. Racila et al (2006) have also reported that rs172378 correlates with decreased complement activity, which then reduces the instance of metastasis associated with breast cancer, perhaps by resulting in an inefficient clearance of apoptotic tumour cancer cells, which consequently results in the development of a more effective antibody response against the tumour. The same group previously identified a correlation between the A allele of rs172378 with lower expression of the C1QA protein (Racila et al, 2003).…”