Asta Försti

Vascular endothelial growth factor polymorphisms in relation to breast cancer development and prognosis.

Purpose: Angiogenesis is a necessary step in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a major mediator of breast cancer angiogenesis. Therefore, we investigated the association of polymorphisms in the VEGF gene with breast cancer risk and prognostic characteristics of the tumors in a large case-control study. Experimental Design: We examined three polymorphisms in the VEGF gene (−2578C/A, −1154G/A, and +936C/T) in 571 familial breast cancer cases from Poland and Germany and −2578C/A, −634G/C, and +936C/T polymorphisms in 974 unselected breast cancer cases from Sweden together with ethnically and geographically selected controls. Results: None of the polymorphisms or any haplotype was significantly associated with either familial or unselected breast cancers. Our study suggests that the +936C/T polymorphism is unlikely to be associated with breast cancer. We also analyzed the unselected cases for genotypes or haplotypes that associated with tumor characteristics. The −634CC genotype and the −2578/−634 CC haplotype were significantly associated with high tumor aggressiveness (large tumor size and high histologic grade, P < 0.01) and the −2578AA genotype and the −2578/−634 AG haplotype with low histologic grade tumors (P = 0.04). The genotypes and haplotypes were not related with other tumor characteristics such as regional or distant metastasis, stage at diagnosis, or estrogen or progesterone receptor status. Conclusions: Although none of the polymorphisms studied in the VEGF gene was found to influence susceptibility to breast cancer significantly, some of the VEGF genotypes and haplotypes may influence tumor growth through an altered expression of VEGF and tumor angiogenesis.

The balance between heritable and environmental aetiology of human disease.

The Human Genome Project and the ensuing International HapMap Project were largely motivated by human health issues. But the distance from a DNA sequence variation to a novel disease gene is considerable; for complex diseases, closing this gap hinges on the premise that they arise mainly from heritable causes. Using cancer as an example of complex disease, we examine the scientific evidence for the hypothesis that human diseases result from interactions between genetic variants and the environment.

A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 ( REL ), 8q24.21 and 10p14 ( GATA3 )

To identify susceptibility loci for classical Hodgkins lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10−8), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10−13) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10−8). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10−50). These data provide new insight into the pathogenesis of cHL.

Chromosome 7p11.2 (EGFR) variation influences glioma risk

While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two case-control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population-corrected statistics, P(c) = 7.72 × 10(-8) and 2.09 × 10(-8), respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk.

Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk

To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 × 10−9) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 × 10−15). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 × 10−7). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights.

Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk

To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10−14), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 × 10−11), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 × 10−9) and 22q13.1 (rs877529, CBX7, P = 7.63 × 10−16). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition.

Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor α (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case∶control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2×10−3), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9×10−4) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9×10−7), was without significant heterogeneity between ancestries (Phet = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.

Polymorphisms and haplotype structures in genes for transforming growth factor β1 and its receptors in familial and unselected breast cancers

Alterations in TGF‐β signaling appear to be associated with an altered risk of developing cancer, including breast cancer. We carried out a case‐control study on 8 polymorphisms, including 5 in the TGF‐β1 gene (G‐800A, C‐509T, Leu10→Pro, Arg25→Pro and Thr263→Ile), a polyalanine polymorphism (9A→6A) in the TGF‐βRI gene and 2 (G‐875A and A‐364G) in the TGF‐βRII gene, using samples from 2 different populations, Polish familial and Finnish unselected breast cancer cases, together with ethnically and geographically matched controls. Additionally, familial breast cancer cases with respective controls from Sweden and Germany were studied in the Leu10→Pro polymorphism, making the total number of familial cases 659. Allele, genotype and haplotype analysis on the TGF‐β1 gene as well as an analysis of the combinations of genotypes of the TGF‐β1 and its receptor genes in each individual were performed. Population differences in the allele and genotype distributions were found from 5 of the polymorphisms and 3 common haplotypes from the TGF‐β1 gene between the Finnish and other populations. However, no statistically significant difference between the breast cancer and healthy control groups was found for any of the 8 polymorphisms nor did the haplotype or genotype combination analysis reach statistical significance. Thus, none of the studied polymorphisms from the TGF‐β1 and its receptor genes was found to influence significantly susceptibility to breast cancer. The possible contribution of 6A/6A homozygosity in the TGF‐βRI gene to breast cancer needs to be confirmed in an independent study.

Association Between TAS2R38 Gene Polymorphisms and Colorectal Cancer Risk: A Case-Control Study in Two Independent Populations of Caucasian Origin

Molecular sensing in the lingual mucosa and in the gastro-intestinal tract play a role in the detection of ingested harmful drugs and toxins. Therefore, genetic polymorphisms affecting the capability of initiating these responses may be critical for the subsequent efficiency of avoiding and/or eliminating possible threats to the organism. By using a tagging approach in the region of Taste Receptor 2R38 (TAS2R38) gene, we investigated all the common genetic variation of this gene region in relation to colorectal cancer risk with a case-control study in a German population (709 controls and 602 cases) and in a Czech population (623 controls and 601 cases). We found that there were no significant associations between individual SNPs of the TAS2R38 gene and colorectal cancer in the Czech or in the German population, nor in the joint analysis. However, when we analyzed the diplotypes and the phenotypes we found that the non-taster group had an increased risk of colorectal cancer in comparison to the taster group. This association was borderline significant in the Czech population, (OR = 1.28, 95% CI 0.99–1.67; Pvalue = 0.058) and statistically significant in the German population (OR = 1.36, 95% CI 1.06–1.75; Pvalue = 0.016) and in the joint analysis (OR = 1.34, 95% CI 1.12–1.61; Pvalue = 0.001). In conclusion, we found a suggestive association between the human bitter tasting phenotype and the risk of CRC in two different populations of Caucasian origin.

Single nucleotide polymorphisms in the XPG gene: Determination of role in DNA repair and breast cancer risk

In this study we determined the effect of single nucleotide polymorphisms in the XPG gene on DNA repair and breast cancer susceptibility. Ninety individuals, with previously studied DNA repair rate at 24 hr of 2 types of UV‐specific cyclobutane pyrimidines dimers (CPDs) in skin were genotyped for XPG polymorphism at codon 1104 (exon 15 G>C; Asp > His). The repair rate of TT=C dimer was similar in both wild‐type GG homozygotes and GC heterozygotes, whereas, for TT=T, dimer repair was non‐significantly (Students t‐test, p = 0.34) lower in GC heterozygotes than wild‐type GG homozygotes. Genotyping of 220 breast cancer cases and 308 controls for the same single nucleotide polymorphism in exon 15 of the XPG gene exhibited marginally significant increased frequency of the variant allele (χ2 3.84, p = 0.05; OR 1.33, 95% CI 1.0–1.8) in cases (C‐allele 0.29) compared to controls (C‐allele 0.24). Combined heterozygote and variant homozygote genotype frequency was also higher in cases than controls (χ2 4.79, p = 0.03; OR 1.50, 95%CI 1.04–2.16).