Breast Cancer Susceptibility In Population Research Articles

A systematic analysis of the association studies between CASP8 D302H polymorphisms and breast cancer risk.

Caspase 8 (CASP8) is a regulator of apoptosis, whose genetic variation has been reported to be associated with the risk of various cancers. Especially, the single-nucleotide polymorphism (SNP) rs1045485, which generates the substitution D302H in CASP8, is likely to be associated with breast cancer. Several previous studies have reported the association of CASP8 D302H polymorphism with breast cancer; however, the results are inconsistent. To validate the association between CASP8 D302H polymorphism and breast cancer risk, we performed an updated meta-analysis of 18 studies including 27,807 cases and 32,332 controls. We tested the overall association between this SNP and breast cancer susceptibility and stratified subgroups based on countries where cases are from. We confirmed a significant correlation between CASP8 D302H polymorphism and the reduced breast cancer susceptibility in population from UK, Germany and Poland, but no significant association was observed in other countries, such as Finland or USA. Our findings indicate the relationship of SNP CASP8 D302H and breast cancer would not be universal but only be sensitive in some particular European countries. The genetic difference for diverse countries may be useful in individual and precision medicine or health.

A two-stage association study identifies methyl-CpG-binding domain protein 2 gene polymorphisms as candidates for breast cancer susceptibility

Genome-wide association studies for breast cancer have identified over 40 single-nucleotide polymorphisms (SNPs), a subset of which remains statistically significant after genome-wide correction. Improved strategies for mining of genome-wide association data have been suggested to address heritable component of genetic risk in breast cancer. In this study, we attempted a two-stage association design using markers from a genome-wide study (stage 1, Affymetrix Human SNP 6.0 array, cases=302, controls=321). We restricted our analysis to DNA repair/modifications/metabolism pathway related gene polymorphisms for their obvious role in carcinogenesis in general and for their known protein–protein interactions vis-à-vis, potential epistatic effects. We selected 22 SNPs based on linkage disequilibrium patterns and high statistical significance. Genotyping assays in an independent replication study of 1178 cases and 1314 controls were attempted using Sequenom iPLEX Gold platform (stage 2). Six SNPs (rs8094493, rs4041245, rs7614, rs13250873, rs1556459 and rs2297381) showed consistent and statistically significant associations with breast cancer risk in both stages, with allelic odds ratios (and P-values) of 0.85 (0.0021), 0.86 (0.0026), 0.86 (0.0041), 1.17 (0.0043), 1.20 (0.0103) and 1.13 (0.0154), respectively, in combined analysis (N=3115). Of these, three polymorphisms were located in methyl-CpG-binding domain protein 2 gene regions and were in strong linkage disequilibrium. The remaining three SNPs were in proximity to RAD21 homolog (S. pombe), O-6-methylguanine-DNA methyltransferase and RNA polymerase II-associated protein 1. The identified markers may be relevant to breast cancer susceptibility in populations if these findings are confirmed in independent cohorts.

Detection of the CHEK2 1100delC mutation by MLPA BRCA1/2 analysis: a worthwhile strategy for its clinical applicability in 1100delC low-frequency populations?

Dear Editor, We would like to add some information and thoughts in relation to the letter of Martinez-Bouzas et al. [1] published in your journal, dealing with the presence of the CHEK2 1100delC mutation in Spanish families. Germ-line mutations in the CHEK2 gene (OMIM 604373) have been identified in breast cancer (BC) families negative for BRCA1/2 mutations. The 1100delC variant was initially identified as a susceptibility allele to BC from a study in 718 Western-European and North-American BRCA1/2 negative families. The variant was found in 5.1% of these families and in 1.1% of healthy individuals [2]. The authors estimated that the variant results in a 2-fold increase of BC risk in women, accounting for about 1% of all female BC. This estimate has been confirmed in another population-based study from Denmark [3]. Additionally, having a personal or familial history of bilateral BC increased the probability of finding the 1100delC mutation [4]. Recent data suggest that premenopausal carriers of this variant have a 2-fold increased risk of developing a second BC (mostly contralateral) and a worse 10-year recurrencefree survival [5]. It has also been suggested a 10-fold increased risk for male BC for 1100delC carriers and that this mutation accounts for as much as 9% of all male BC in the population [2]. Although increased risk of prostate cancer has not been confirmed, some data suggest that risks of colon and lung cancer might be higher in female carriers between ages 20 and 50 years than non carriers [6]. Overall, these reports suggest that CHEK2 acts as a lowpenetrance tumour suppressor gene, and that it makes a significant contribution to familial clustering of BC, including families with only two affected relatives. In some populations, the variant has been identified in approximately 3–4% of young BC patients unselected for family history, and between 3% and 6% of non-BRCA1/2 BC families [2, 4, 7, 8]. Nevertheless, a wide variation in the frequency of 1100delC mutation in CHEK2 has been observed in different populations. The 1100delC mutation accounts for a part of BC susceptibility in populations from Northern Europe (Netherlands, Denmark, Finland, UK, Poland), and North America. But it does not seem to play a role in Ashkenazi Jewish families, and in some other countries, such as Australia, Italy and Spain, this association is not so clear [reviewed in 9]. Osorio et al. [10] did not find this mutation in 400 non-BRCA1/2 Spanish BC families, 56 patients with BC diagnosed before 40 years of age without family history, and 400 healthy individuals. The authors stated that its low penetrance and low frequency make this variant irrelevant for the clinical practice in our population. These results were confirmed by two other studies [11, 12]. Bellosillo et al. [11] studied the CHEK2 gene in 28 highrisk and 53 moderate-risk Spanish BC cases negative for BRCA1/2 mutations, and in none of them could the 1100delC mutation nor other variants previously described be detected. Sanchez de Abajo et al. [12] analysed 148 Hereditary non-Polyposis Colorectal Cancer (HNPCC) and 32 Hereditary Breast and Colon Cancer (HBCC) Spanish families and found that this variant was of no clinical relevance in this population. S. Gutierrez-Enriquez M. Baiget O. Diez (&) Servei de Genetica, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, Barcelona 08025, Spain e-mail: odiez@santpau.es