Prognostic impact of polymorphisms in the MYBL2 interacting genes in breast cancer

MYBL2 is a transcription factor, which regulates the expression of genes involved in cancer progression. In this study, we investigated whether putative functional variants in genes regulating MYBL2 (E2F1, E2F3 and E2F4) or in genes, which are regulated by MYBL2 (BCL2, BIRC5, COL1A1, COL1A2, COL5A2, ERBB2, CLU, LIN9 and TOP2A) affect breast cancer (BC) susceptibility and clinical outcome. Twenty-eight SNPs were genotyped in a population-based series of 782 Swedish BC cases and 1,559 matched controls. BC-specific survival analysis of BIRC5 suggested that carriers of the minor allele of rs8073069 and rs1042489 have a worse survival compared with the major homozygotes (HR 2.46, 95% CI 1.39-4.36 and HR 1.81, 95% CI 1.01-3.25, respectively). The poor survival was observed especially in women with aggressive tumours. Multivariate analysis supported the role of rs8073069 as an independent prognostic marker. For BCL2, minor allele carriers of rs1564483 were more likely to have hormone receptor-positive tumours than the major homozygotes. Another SNP in BCL2, rs4987852, was associated with tumour stages II-IV and histologic grade 3. In CLU, the minor allele carriers of rs9331888 were more likely to have tumours with regional lymph node metastasis and stages II-IV than the major homozygotes. In conclusion, our study suggests a role of genetic variation in BIRC5, BCL2 and CLU as progression and prognostic markers for BC, supporting previous studies based on the expression of the genes

Functional germline variants in driver genes of breast cancer

Purpose: Germline mutations in tumour suppressor genes cause various cancers. These genes are also somatically mutated in sporadic tumours. We hypothesized that there may also be cancer-related germline variants in the genes commonly mutated in sporadic breast tumours. Methods: After excluding the well-characterized breast cancer (BC) genes, we screened 15 novel genes consistently classified as BC driver genes in next-generation sequencing approaches for single nucleotide polymorphisms (SNPs). Altogether 40 SNPs located in the core promoter, 5′- and 3′-UTR or which were nonsynonymous SNPs were genotyped in 782 Swedish incident BC cases and 1,559 matched controls. After statistical analyses, further evaluations related to functional prediction and signatures of selection were performed. Results: TBX3 was associated with BC risk (rs2242442: OR = 0.76, 95% CI 0.64–0.92, dominant model) and with less aggressive tumour characteristics. An association with BC survival and aggressive tumour characteristics was detected for the genes ATR (rs2227928: HR = 1.63; 95% CI 1.00–2.64, dominant model), RUNX1 (rs17227210: HR = 3.50, 95% CI 1.42–8.61, recessive model) and TTN (rs2303838: HR = 2.36; 95% CI 1.04–5.39; rs2042996: HR = 2.28; 95% CI 1.19–4.37, recessive model). According to the experimental ENCODE data all these SNPs themselves or SNPs in high linkage disequilibrium with them (r2 ≥ 0.80) were located in regulatory regions. RUNX1 and TTN showed also several signatures of positive selection. Conclusion: The study gave evidence that germline variants in BC driver genes may have impact on BC risk and/or survival. Future studies could discover further germline variants in known or so far unknown driver genes which contribute to cancer development

Genetic variation in ALCAM and other chromosomal instability genes in breast cancer survival

Chromosomal instability is a hallmark of many cancers and it has a potential to predict clinical outcome of a cancer patient. We hypothesized that genes whose expression status differs between chromosomal stable and unstable breast tumors represent target genes for the identification of genetic variants predicting breast cancer (BC) risk, disease progression, and survival. We used a published list of 38 genes associated with chromosomal instability as a basis for searching potentially functional and informative tagging single nucleotide polymorphisms (SNPs). As a result, 33 SNPs in 16 genes were genotyped in a population-based series of 783 Swedish BC cases. Two SNPs in the ALCAM gene associated with BC-specific survival. For rs1044243, the HR was 4.35 (95% CI 1.34-14.18), and for rs1157, the HR was 3.42 (95% CI 1.32-8.83) for the homozygous carriers of the minor alleles. For the minor allele carriers of CCL18 SNP rs14304, we observed a significant association with aggressive tumor characteristics: large tumor size (OR 1.53, 95% CI 1.10-2.14), positive lymph node metastasis (OR 1.75, 95% CI 1.02-3.00), and high stage (OR 1.37, 95% CI 1.02-1.85). In a Polish population consisting of 506 familial/early onset BC cases, no association with event-free survival for the ALCAM SNPs nor any association with tumor characteristics for the CCL18 SNP were observed, suggesting either a chance finding in the Swedish population or population-based or etiological differences between sporadic and familial/early onset BC

Systematic Pathway Enrichment Analysis of a Genome-Wide Association Study on Breast Cancer Survival Reveals an Influence of Genes Involved in Cell Adhesion and Calcium Signaling on the Patients' Clinical Outcome

Genome-wide association studies (GWASs) may help to understand the effects of genetic polymorphisms on breast cancer (BC) progression and survival. However, they give only a focused view, which cannot capture the tremendous complexity of this disease. Therefore, we investigated data from a previously conducted GWAS on BC survival for enriched pathways by different enrichment analysis tools using the two main annotation databases Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The goal was to identify the functional categories (GO terms and KEGG pathways) that are consistently overrepresented in a statistically significant way in the list of genes generated from the single nucleotide polymorphism (SNP) data. The SNPs with allelic p-value cut-offs 0.005 and 0.01 were annotated to the genes by excluding or including a 20 kb up-and down-stream sequence of the genes and analyzed by six different tools. We identified eleven consistently enriched categories, the most significant ones relating to cell adhesion and calcium ion binding. Moreover, we investigated the similarity between our GWAS and the enrichment analyses of twelve published gene expression signatures for breast cancer prognosis. Five of them were commonly used and commercially available, five were based on different aspects of metastasis formation and two were developed from meta-analyses of published prognostic signatures. This comparison revealed similarities between our GWAS data and the general and the specific brain metastasis gene signatures as well as the Oncotype DX signature. As metastasis formation is a strong indicator of a patient's prognosis, this result reflects the survival aspect of the conducted GWAS and supports cell adhesion and calcium signaling as important pathways in cancer progression

Inbreeding and homozygosity in breast cancer survival

Genome-wide association studies (GWASs) help to understand the effects of single nucleotide polymorphisms (SNPs) on breast cancer (BC) progression and survival. We performed multiple analyses on data from a previously conducted GWAS for the influence of individual SNPs, runs of homozygosity (ROHs) and inbreeding on BC survival. (I.) The association of individual SNPs indicated no differences in the proportions of homozygous individuals among short-time survivors (STSs) and long-time survivors (LTSs). (II.) The analysis revealed differences among the populations for the number of ROHs per person and the total and average length of ROHs per person and among LTSs and STSs for the number of ROHs per person. (III.) Common ROHs at particular genomic positions were nominally more frequent among LTSs than in STSs. Common ROHs showed significant evidence for natural selection (iHS, Tajima's D, Fay-Wu's H). Most regions could be linked to genes related to BC progression or treatment. (IV.) Results were supported by a higher level of inbreeding among LTSs. Our results showed that an increased level of homozygosity may result in a preference of individuals during BC treatment. Although common ROHs were short, variants within ROHs might favor survival of BC and may function in a recessive manner

Inbreeding and homozygosity in breast cancer survival

Genome-wide association studies (GWASs) help to understand the effects of single nucleotide polymorphisms (SNPs) on breast cancer (BC) progression and survival. We performed multiple analyses on data from a previously conducted GWAS for the influence of individual SNPs, runs of homozygosity (ROHs) and inbreeding on BC survival. (I.) The association of individual SNPs indicated no differences in the proportions of homozygous individuals among short-time survivors (STSs) and long-time survivors (LTSs). (II.) The analysis revealed differences among the populations for the number of ROHs per person and the total and average length of ROHs per person and among LTSs and STSs for the number of ROHs per person. (III.) Common ROHs at particular genomic positions were nominally more frequent among LTSs than in STSs. Common ROHs showed significant evidence for natural selection (iHS, Tajima's D, Fay-Wu's H). Most regions could be linked to genes related to BC progression or treatment. (IV.) Results were supported by a higher level of inbreeding among LTSs. Our results showed that an increased level of homozygosity may result in a preference of individuals during BC treatment. Although common ROHs were short, variants within ROHs might favor survival of BC and may function in a recessive manner

Flow chart of the pathway enrichment analysis of the GWAS on BC survival.

<p>Flow chart of the pathway enrichment analysis of the GWAS on BC survival.</p

Consistently enriched categories of the GWAS on BC survival.

<p>Only categories enriched in all four gene lists and by more than one tool were considered consistently enriched. * Genes present in the 0.01 gene list (allelic SNP <i>p</i>-value cut-off 0.01).</p

Distribution of the seven generic terms among the 50 top pathways in the enrichment analyses of the 13 gene lists.

<p>Distribution of the seven generic terms among the 50 top pathways in the enrichment analyses of the 13 gene lists.</p

Top 25 GeneGO pathways enriched simultaneously by the 0.01 gene list and general metastasis signature; red numbers = significant at FDR of 0.05; green box = pathway significantly enriched by both gene lists; Pathway “Airway smooth muscle contraction in asthma” was placed at rank 7, pathway “Cytoskeleton remodeling_Cytoskeleton remodeling” was placed at rank 9.

<p>Top 25 GeneGO pathways enriched simultaneously by the 0.01 gene list and general metastasis signature; red numbers = significant at FDR of 0.05; green box = pathway significantly enriched by both gene lists; Pathway “Airway smooth muscle contraction in asthma” was placed at rank 7, pathway “Cytoskeleton remodeling_Cytoskeleton remodeling” was placed at rank 9.</p