Large-Scale Association Study Identifies ICAM Gene Region as Breast and Prostate Cancer Susceptibility Locus

Abstract

We conducted a large-scale association study to identify genes that influence nonfamilial breast cancer risk using a collection of German cases and matched controls and >25,000 single nucleotide polymorphisms located within 16,000 genes. One of the candidate loci identified was located on chromosome 19p13.2 [odds ratio (OR) ‫؍‬ 1.5, P ‫؍‬ 0.001]. The effect was substantially stronger in the subset of cases with reported family history of breast cancer (OR ‫؍‬ 3.4, P ‫؍‬ 0.001). The finding was subsequently replicated in two independent collections (combined OR ‫؍‬ 1.4, P < 0.001) and was also associated with predisposition to prostate cancer in an independent sample set of prostate cancer cases and matched controls (OR ‫؍‬ 1.4, P ‫؍‬ 0.002). High-density single nucleotide polymorphism mapping showed that the extent of association spans 20 kb and includes the intercellular adhesion molecule genes ICAM1, ICAM4, and ICAM5. Although genetic variants in ICAM5 showed the strongest association with disease status, ICAM1 is expressed at highest levels in normal and tumor breast tissue. A variant in ICAM5 was also associated with disease progression and prognosis. Because ICAMs are suitable targets for antibodies and small molecules, these findings may not only provide diagnostic and prognostic markers but also new therapeutic opportunities in breast and prostate cancer.

Association between a variation in LRCH1 and knee osteoarthritis: A genome‐wide single‐nucleotide polymorphism association study using DNA pooling

“…The basic design was a 2-group study of subjects with and without OA of the knee. To facilitate the screening of such a large number of SNPs, we utilized a high-throughput approach using DNA pools, chip-based mass spectrometry (24)(25)(26), and a 3-step SNP selection strategy (27). In the first step, we performed a single PCR and primer extension reaction for each SNP on 2 DNA pools consisting of equimolar amounts of DNA from each subject in each study group (knee OA and control).…”

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

“…To facilitate the screening of such a large number of SNPs, we employed a high-throughput approach that used DNA pools, chip-based mass spectrometry [32][33][34] and a three-step SNP selection process that had been successfully used previously. [13][14][15] In the first step, we performed a single PCR and primer extension reaction for each SNP on two DNA pools consisting of schizophrenia cases and controls, respectively. Relative allele frequencies obtained from four mass spectrometry measurements of each extension product were compared between pools.…”

“…Genome-wide association studies using large numbers of single-nucleotide polymorphisms (SNPs) have been proposed and successfully applied to find genetic variations associated with myocardial infarction, 12 bone mineral density 13 and breast cancer. 14,15 In an effort to identify genes and variants that influence the risk of schizophrenia, we carried out a large-scale SNP association study using a multi-center collection of schizophrenia cases and controls. We identified a gene on chromosome 1q32, plexin A2 (PLXNA2), as a candidate gene for schizophrenia.…”

Use of pairwise marker combination and recursive partitioning in a pharmacogenetic genome-wide scan

“…Similar approaches have been adopted in other large-scale genetic association studies. [21][22][23] We believe that the replication of initial findings in a second independent data set is crucial to the validation of association findings. [24][25][26][27] This is especially important for marker combination analyses as the number of false-positive findings would increase exponentially with the number of markers considered.…”