Single nucleotide polymorphisms in the 20q13 amplicon genes in relation to breast cancer risk and clinical outcome

Abstract

The 20q13 region is frequently amplified/overexpressed in breast tumours. However, the nature of this amplification/overexpression is unknown. Here, we investigated genetic variation in five 20q13 amplicon genes (MYBL2, AURKA, ZNF217, STK4 and PTPN1) and its impact on breast cancer (BC) susceptibility and clinical outcome. As a novel finding, four polymorphisms in STK4 (rs6017452, rs7271519) and AURKA (rs2273535, rs8173) associated with steroid hormone receptor status both in a Swedish population-based cohort of 783 BC cases and in a Polish familial/early onset cohort of 506 BC cases. In the joint analysis, the minor allele carriers of rs6017452 had more often hormone receptor positive tumours (OR 0.57, 95% CI 0.40-0.81), while homozygotes for the minor allele of rs7271519, rs2273535 and rs8173 had more often hormone receptor negative tumours (2.26, 1.30-3.39; 2.39, 1.14-5.01; 2.39, 1.19-4.80, respectively) than homozygotes for the common allele. BC-specific survival analysis of AURKA suggested that the Swedish carriers of the minor allele of rs16979877, rs2273535 and rs8173 might have a worse survival compared with the major homozygotes. The survival probabilities associated with the AURKA genotypes depended on the tumour phenotype. In the Swedish case-control study, associations with BC susceptibility were observed in a dominant model for three MYBL2 promoter polymorphisms (rs619289, P = 0.02; rs826943, P = 0.03 and rs826944, P = 0.02), two AURKA promoter polymorphisms (rs6064389, P = 0.04 and rs16979877, P = 0.02) and one 3'UTR polymorphism in ZNF217 (rs1056948, P = 0.01). In conclusion, our data confirmed the impact of the previously identified susceptibility locus and provided preliminary evidence for novel susceptibility variants in BC. We provided evidence for the first time that genetic variants at 20q13 may affect hormone receptor status in breast tumours and influence tumour aggressiveness and survival of the patients. Future studies are needed to confirm the prognostic value of our findings in the clinic.

B-Myb Induces APOBEC3B Expression Leading to Somatic Mutation in Multiple Cancers

“…To our knowledge, it is unclear which factors can directly bind the region near rs619289, and no adjacent linkage disequilibrium variant could enable us to clarify how rs619289 might regulate MYBL2 . Nonetheless, our present data and previous results conclusively show that individuals who carry the T allele of rs619289 have significantly greater MYBL2 expression and, consequently, elevated breast cancer risk and poorer outcome26.…”

“…If overexpression of MYBL2 , as well as A3B , is associated with breast cancer progression, polymorphisms in the expression quantitative trait loci (eQTL) that are associated with MYBL2 mRNA expression would be expected to be significantly associated with disease outcome. Based on a literature survey, a single nucleotide polymorphism (SNP), rs619289, which is located in upstream of MYBL2 , was investigated26. To verify the role of this SNP in cancer risk, we performed genotype and expression correlation analysis by retrieving the genotype of rs619289 and MYBL2 expression from the GTEx portal27.…”

Association between genetic polymorphisms in AURKA (rs2273535 and rs1047972) and breast cancer risk: a meta-analysis involving 37,221 subjects

“…The characteristics of the included studies are listed in Tables 1. Among the eligible thirteen studies, seven studies were performed in Caucasians from Sweden, Germany, Iceland, UK and USA [14,15,17–20,24]. Four were based on Asian background and were carried out in China [13,22,23,25].…”

The AURKA Gene rs2273535 Polymorphism Contributes to Breast Carcinoma Risk - Meta-analysis of Eleven Studies

“…Eleven studies satisfied all of the criteria and were included in this report (Dai et al, 2004;Egan et al, 2004;Sun et al, 2004;Lo et al, 2005;Cox et al, 2006;Fletcher et al, 2006;Tchatchou et al, 2007;Vidarsdottir et al, 2007;2010;Ruan et al, 2011;Shi et al, 2011). There were seven studies of Caucasians, and four Asians.…”