Search

Glioma is the most common malignant primary brain tumors with poor prognosis. Genome wide association studies (GWAS) of glioma in populations with Western European ancestry were completed in the US and UK. However, our previous results strongly suggest the genetic heterogeneity could be important in glioma risk. To systematically investigate glioma risk–associated variants in Chinese population, we performed a multistage GWAS of glioma in the Han Chinese population, with a total of 3,097 glioma cases and 4,362 controls. In addition to confirming two associations reported in other ancestry groups, this study identified one new risk‐associated locus for glioma on chromosome 12p11.23 (rs10842893, pmeta = 2.33x10‐12, STK38L) as well as a promising association at 15q15‐21.1 (rs4774756, pmeta = 6.12x10‐8, RAB27A) in 3,097 glioma cases and 4,362 controls. Our findings demonstrate two novel association between the glioma risk region marked by variant rs10842893 and rs4774756) and glioma risk. These findings may advance the understanding of genetic susceptibility to glioma. What's new? While very few brain tumors are attributed to familial risk factors, the previous identification of inherited genetic variants linked to glioma has raised new questions about the impact of genetics on brain tumor risk. In this genome‐wide association study in a Han Chinese population, two independent genetic variants, one on chromosome 12p11.23 and the second on 15q15‐21.1, were found to be significantly associated with glioma risk. In addition, two risk‐associated variants previously reported in other ancestry groups were also associated with glioma risk in Han Chinese patients. The findings may help advance understanding of genetic susceptibility to glioma. [ABSTRACT FROM AUTHOR]

Epidemiological and twin studies have consistently demonstrated a strong genetic component to prostate cancer (PCa) susceptibility. To date, numerous linkage studies have been performed to identify chromosomal regions containing PCa susceptibility genes. Unfortunately, results from these studies have failed to form any obvious consensus regarding which regions are most likely to contain genes that may contribute to PCa predisposition. One plausible explanation for the difficulty in mapping susceptibility loci is the existence of considerable heterogeneity in the phenotype of PCa, with significant variation in clinical stage and grade of disease even among family members. To address this issue, we performed a genome-wide linkage scan on 71 informative families with two or more men with aggressive PCa. When only men with aggressive PCa were coded as affected, statistically significant evidence for linkage at chromosome 15q12 was detected (LOD=3.49; genome-wide p=0.005). Furthermore, the evidence for linkage increased when analyses were restricted to Caucasian–American pedigrees ( n=65; LOD=4.05) and pedigrees with two confirmed aggressive cases ( n=42, LOD=4.76). Interestingly, a 1-LOD support interval about our peak at 15q12 overlaps a region of suggestive linkage, 15q11, identified by a recent linkage study on 1,233 PCa families by the International Consortium for Prostate Cancer Genetics. Using a more rigid definition of PCa in linkage studies will result in a severe reduction in sample sizes available for study, but may ultimately prove to increase statistical power to detect susceptibility genes for this multigenic trait. [ABSTRACT FROM AUTHOR]

Three prostate cancer susceptibility genes have been reported to be linked to different regions on chromosome 1: HPC1 at 1q24–25, PCAP at 1q42–43, and CAPB at 1p36. Replication studies analyzing each of these regions have yielded inconsistent results. To evaluate linkage across this chromosome systematically, we performed multipoint linkage analyses with 50 microsatellite markers spanning chromosome 1 in 159 hereditary prostate cancer families (HPC), including 79 families analyzed in the original report describing HPC1 linkage. The highest lod scores for the complete dataset of 159 families were observed at 1q24–25 at which the parametric lod score assuming heterogeneity (hlod) was 2.54 (P=0.0006) with an allele sharing lod of 2.34 (P=0.001) at marker D1S413, although only weak evidence was observed in the 80 families not previously analyzed for this region (hlod=0.44, P=0.14, and allele sharing lod=0.67, P=0.08). In the complete data set, the evidence for linkage across this region was very broad, with allele sharing lod scores greater than 0.5 extending approximately 100 cM from 1p13 to 1q32, possibly indicating the presence of multiple susceptibility genes. Elsewhere on chromosome 1, some evidence of linkage was observed at 1q42–43, with a peak allele sharing lod of 0.56 (P=0.11) and hlod of 0.24 (P=0.25) at D1S235. For analysis of the CAPB locus at 1p36, we focused on six HPC families in our collection with a history of primary brain cancer; four of these families had positive linkage results at 1p36, with a peak allele sharing lod of 0.61 (P=0.09) and hlod of 0.39 (P=0.16) at D1S407 in all six families. These results are consistent with the heterogeneous nature of hereditary prostate cancer, and the existence of multiple loci on chromosome 1 for this disease. [ABSTRACT FROM AUTHOR]

Autosomal recessive ataxias represent genetic and clinical heterogeneity. Unsteady gait is often accompanied by poor coordination of limbs, speech, and eye movements. To date, seven genes have been identified. In addition, five chromosomal loci have been localized in non-related families. Here, we report homozygosity mapping of a novel locus to a 19.5-cM region on chromosome 20q11–q13 in a large inbred Norwegian family with infantile non-progressive ataxia. [ABSTRACT FROM AUTHOR]

Genetic linkage studies indicate that germline variations in a gene or genes on chromosome Xq27-28 are implicated in prostate carcinogenesis. The linkage peak of prostate cancer overlies a region of ∼750 kb containing five SPANX genes (SPANX-A1, -A2, -B, -C, and -D) encoding sperm proteins associated with the nucleus; their expression was also detected in a variety of cancers. SPANX genes are >95% identical and reside within large segmental duplications (SDs) with a high level of similarity, which confounds mutational analysis of this gene family by routine PCR methods. In this work, we applied transformation-associated recombination cloning (TAR) in yeast to characterize individual SPANX genes from prostate cancer patients showing linkage to Xq27-28 and unaffected controls. Analysis of genomic TAR clones revealed a dynamic nature of the replicated region of linkage. Both frequent gene deletion/duplication and homology-based sequence transfer events were identified within the region and were presumably caused by recombinational interactions between SDs harboring the SPANX genes. These interactions contribute to diversity of the SPANX coding regions in humans. We speculate that the predisposition to prostate cancer in X-linked families is an example of a genomic disease caused by a specific architecture of the SPANX gene cluster. [ABSTRACT FROM AUTHOR]

Here we report the identification of a novel transcript containing SNF2, PHD-finger, RING-finger, helicase, and linker histone domains mapping to the q24 band region of human chromosome 6. These domains are characteristic of several DNA repair proteins, transcription factors, and helicases. We have cloned both human and mouse homologs of this novel gene using interexon PCR and RACE technologies. The human cDNA, termed SHPRH, is 6018 bp and codes for a putative protein of 1683 amino acids. The mouse cDNA, termed Shprh, is 7225 bp and codes for a putative protein of 1616 amino acids. The deduced amino acid sequences of the two proteins share 86% identity. Both genes are expressed ubiquitously, with a transcript size of ∼7.5 kb. Mapping of this gene to 6q24, a region reported to contain a tumor suppressor locus, prompted us to evaluate SHPRH by mutation analysis in tumor cell lines. We have identified one truncating and three missense mutations, thus suggesting SHPRH as a possible candidate for the tumor suppressor gene. [Copyright &y& Elsevier]

A gene or genes on chromosome 8p22-23 have been implicated in prostate carcinogenesis by the observation of frequent deletions of this region in prostate cancer cells. More recently, two genetic linkage studies in hereditary prostate cancer (HPC) families suggest that germline variation in a gene in this region may influence prostate cancer susceptibility as well. DLC1 (deleted in liver cancer), a gene in this interval, has been proposed as a candidate tumor suppressor gene because of its homology (86% similarity) with rat p122 RhoGAP, which catalyzes the conversion of active GTP-bound rho complex to the inactive GDP-bound form, and thus suppresses Ras-mediated oncogenic transformation. A missense mutation and three intronic insertions/deletions in 126 primary colorectal tumors have been previously identified. However, there are no reports of DLC1 mutation screening in prostate tumors or in germ line DNA of prostate cancer patients. In this study, we report the results of the first mutation screen and association study of DLC1 in genomic DNA samples from hereditary and sporadic prostate cancer patients. The PCR products in the 5′ UTR, all 14 exons, exon–intron junctions, and 3′ UTR were directly sequenced in 159 HPC probands. Eight exonic nucleotide polymorphisms (SNPs) were identified, only one of which resulted in an amino acid change. Twenty-three other SNPs were identified in intronic regions. Seven informative SNPs that spanned the complete DLC1 gene were genotyped in an additional 249 sporadic cases and 222 unaffected controls. No significant difference in the allele and genotype frequencies were observed among HPC probands, sporadic cases, and unaffected controls. These results suggest that DLC1 is unlikely to play an important role in prostate cancer susceptibility. [Copyright &y& Elsevier]

Presents a study which examined pedigrees affected by hereditary prostate cancer using markers on chromosome 8. Methods; Results; Discussion.

Analyzes the linkage at chromosome 1 locus in families with hereditary prostate cancer (PRCA). Determination of the linkage using microsatellite markers; Involvements of multiple susceptibility cells and phenotypic expression; Evidence on the linkage of 1q24-25 chromosome in male-to-male transmission.