Evaluating new candidate SNPs as low penetrance risk factors in sporadic breast cancer: A two-stage Spanish case–control study
Introduction
Little is known about the complex aetiology of breast cancer. BRCA1 and BRCA2 are the most common high penetrance genes described but only account for around 25% of families with hereditary breast cancer and a negligible number of sporadic breast cancers [1]. This fact, together with the failure of linkage studies to identify further high susceptibility genes, points to a polygenic model. According to this model [2] susceptibility to breast cancer is conferred by a large number of alleles, each contributing a small effect. Interest in population-based studies is continuously growing as a consequence of the accessibility to genomic databases, with many million SNPs identified. The HapMap International SNP genotyping project, conceptually based on the ‘common variant-common disease' hypothesis [3], has substantially favored the strategy known as the ‘indirect' approach; according to this method, prior knowledge of the SNP functionality is not necessary, since it is possible to test for association by exploring SNP markers in linkage disequilibrium (LD) with potential causal variants.
During the last decade, the analysis of one or a few polymorphisms in some isolated breast cancer candidate genes has been quite popular [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. On the other hand, high-throughput genotyping studies and genome-wide scans have begun to emerge, identifying various potential low penetrance loci involved in sporadic breast cancer [18], [19], [20], [21], [22], [23], [24], [25].
Here we aim to contribute to the knowledge of the complex genetic aetiology of sporadic breast cancer by performing a two-stage, large-scale genotyping study that covers 91 breast cancer candidate genes.
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Study subjects
Cases in the Spanish mainland series were 450 women with breast cancer and the mean age at diagnosis was 58 years (range 25 to 85 years), recruited between 2000 and 2003. All cases were collected from consecutive series recruited via three public Spanish hospitals: Hospital La Paz (∼ 15%), Fundación Jiménez Díaz (∼ 48%) and Hospital Monte Naranco (37%). Controls in the Spanish mainland series were 448 Spanish women free of breast cancer at ages ranging from 24 to 85 years (mean = 52 years), and
SNP characteristics
A total of 640 SNPs belonging to 91 genes were genotyped in the Spanish mainland series. Allele frequencies in controls were highly consistent with those reported for CEPH individuals of the HapMap project as reported in Ribas et al. [37]. About 68% of the SNPs were located in introns, 5% in coding regions, 6% 5′-upstream, 9% 3′-downstream, 11% 3′-utr, and 1% 5′-utr. Fourteen SNPs were monomorphic (see Table S1) and were therefore excluded from all analyses. All the SNP were in Hardy–Weinberg
Discussion
In our two-stage case–control study, we first aimed to test for potential cryptic population structure in stage 1 in order to rule it out as a potential cause of some spurious associations. No evidence of strong population stratification was observed in the mainland Spanish series, though we are aware that the use of 28 unlinked loci may not completely exclude the existence of a more subtle level of population substructure. In the first stage study, we detected nominal P-values below 0.05 for
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
Thanks to Pilar Zaragoza and José Ignacio Arias for providing part of the samples. This work was supported by grants from the Xunta de Galicia, PGIDIT06PXIB208079PR and PGIDIT06BTF910101PR, given to AS and AV respectively, two grants from the Fundación de Investigación Médica Mutua Madrileña awarded to AS and AV, and two grants from the Spanish Ministerio de Sanidad y Consumo, PI052275 and PI061712, given to AV. and AG. respectively. Genoma España also supported the present study.
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Contributed equally to this work