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Predisposing Genes (predisposing + gene)
Selected AbstractsA Novel Renal Carcinoma Predisposing Gene of the Nihon Rat Maps on Chromosome 10CANCER SCIENCE, Issue 11 2001Okio Hino A novel rat model of hereditary renal cell carcinoma (RC) was found in a rat colony of the Spra-gue-Dawley (SD) strain in Japan, and named the "Nihon" rat in 2000. This study was designed to map the RC susceptibility gene in the Nihon rat using 113 backcross annuals. Our present data clearly show that the Nihon gene is genetically linked to interleukin-3 (IL3) gene (,2=93.6, Lod score=25.16), lethal (2) giant larvae (LLGL1) locus (,2=109.0, Lod score=31.56) and myosin heavy chain, embryonic skeletal muscle (MYHSE) gene (,2=90.6, Lod score=23.87), which are located on the distal part of rat chromosome 10. The order of the genes is the Eker (Tsc2) gene (located on the proximal part of rat chromosome 10; human chromosome 16p 13.3),21.3 cM,IL3 gene (human 5q23-31),4.4 cM,Nihon gene,0.9 cM,LLGL1 locus (human 17p11.2)-4.4 cM,MYHSE gene (human 17pl3.1). We also detected loss of the wild-type allele at the MYHSE locus, fitting Knudson's "two hit" model. Thus, the Nihon rat should have a mutation of a novel tumor suppressor gene related to renal carcinogenesis. [source] Localization of a putative low-penetrance ependymoma susceptibility locus to 22q11 using a chromosome 22 tiling-path genomic microarrayGENES, CHROMOSOMES AND CANCER, Issue 4 2005Anneke C. J. Ammerlaan Ependymomas frequently display allelic loss of chromosome 22 in the absence of mutations in the known tumor-suppressor genes on chromosome 22, suggesting the role of an alternative predisposing gene or genes from this chromosome. In an effort to localize these genes, 37 ependymomas derived from 33 patients were analyzed for the presence of copy number changes by use of a high-resolution chromosome 22 genomic microarray. Eighteen ependymomas (49%) displayed an array-CGH profile consistent with monosomy of chromosome 22. However, in 10 of these tumors, the fluorescence ratios for 22q clones scored as deleted were different from those at the single gene copy level. This suggests either analysis of mixed populations of tumor and normal stromal cells or analysis of mixed tumor cell populations with different genetic profiles. Four ependymomas derived from two patients showed overlapping interstitial deletions of 2.2 Mb and ,510 kb. Further analyses revealed that these deletions were present in the constitutional DNA of these two patients as well as in some of their unaffected relatives. Detailed microsatellite analysis of these families refined the commonly deleted segment to a region of 320 kb between markers RH13801 and D22S419. Our results provide additional evidence for the involvement of genes on chromosome 22 in the development of ependymoma and suggest the presence of a low-penetrance ependymoma susceptibility locus at 22q11. © 2005 Wiley-Liss, Inc. [source] Multipoint Linkage Disequilibrium Mapping Using Multilocus Allele Frequency DataANNALS OF HUMAN GENETICS, Issue 4 2005T. Johnson Summary This paper describes a likelihood based fine scale linkage disequilibrium mapping method for estimating the position of a disease predisposing gene relative to a battery of typed marker loci. The method uses multilocus allele frequency data from a sample of unrelated diseased individuals and from a sample of unrelated control individuals, that is, a case and control type design. This type of data could be obtained by typing DNA pools, which is less expensive than typing individuals separately. The method described uses a nonparametric model that makes it robust to the shape of the genealogy at the disease locus. It can be implemented efficiently, making a multipoint analysis of a data set of a thousand markers feasible. An example power analysis uses simulations to estimate the amount of information that can be extracted from fully resolved haplotype data, relative to multilocus allele frequency data. For the assumed parameter values and a battery of 10 markers, roughly three times narrower region estimates can be derived from haplotype data than from allele frequency data only. Depending on how we choose to measure information, allele frequency data at an additional ,18 or ,33 markers is needed to compensate for this loss of information. [source] BRCA2 gene mutations in Greek patients with familial breast cancer ,,HUMAN MUTATION, Issue 1 2002Athanasios Armakolas Abstract Family history is a well-recognized risk factor for the development of breast cancer. The isolation of BRCA1 and BRCA2 genes, the two major predisposing genes in familial and to early onset breast and ovarian cancer, has resulted to the identification of a large number of families with mutations in these two genes. Despite the large number of distinct mutations detected in both genes, several mutations have been found to recur in unrelated families of diverse geographical origin. We have analyzed 27 Greek patients with familial breast cancer the majority of those having one first and one second degree relatives affected and 28 patients with sporadic breast cancer for BRCA2 germline mutations. The techniques used were single-strand conformation polymorphism analysis (SSCP) followed by sequencing. Furthermore, the clinical presentation and prognosis of BRCA2 associated breast cancer cases was compared to 20 adequately matched for age and date of diagnosis (within one year) sporadic breast cancer patients. We identified three novel BRCA2 mutations (3058delA, 6024delTA, and 4147delG) in the ovarian cancer cluster region (OCCR) and one already known (2024del5) germline BRCA2 gene mutation in five different breast cancer families. The 4147delG mutation was detected in two unrelated patients. BRCA2 germline mutations were correlated with early-onset breast cancer RR=4.77 (95% CI: 0.666-34.463). Although patients with BRCA2 germline mutations did not have a distinct histological phenotype they had an improved overall survival (100% vs 65%). Our findings suggest that there is a cluster of novel mutations in exons 10 and 11 in Greek patients with familial breast cancer. These mutations appear to have a milder clinical phenotype when compared to the rest of the study group. © 2001 Wiley-Liss, Inc. [source] Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2PATHOLOGY INTERNATIONAL, Issue 8 2001Hiroshi Maruyama Tuberous sclerosis (TSC) is a rare, genetically determined disorder / familial tumor syndrome, currently diagnosed using specific clinical criteria proposed by Gomez, including the presence of multiorgan hamartomas. Pulmonary involvement in TSC is well known as pulmonary lymphangioleiomyomatosis (LAM), which has an incidence of 1,2.3% in TSC patients. LAM has immunohistochemical expression of both smooth-muscle actin and a monoclonal antibody specific for human melanoma, HMB-45. It has recently been reported that multifocal micronodular pneumocyte hyperplasia (MMPH) associated with TSC should be considered as a distinct type of lung lesion, whether it occurs with or without LAM. Two predisposing genes have been found in families affected by TSC; approximately half of the families show linkage to TSC1 at 9q34.3, and the other half show linkage to TSC2 at 16p13.3. TSC genes are considered to be tumor suppressor genes, and mutations in them may lead to abnormal differentiation and proliferation of cells. Tuberin, the TSC2 gene product, has recently been found to be expressed in LAM and MMPH. In this article we discuss the histogenesis and genetic abnormalities of neoplastic lesions associated with TSC, and we review the current understanding of the pathogenesis of pulmonary hamartomatous lesions such as LAM and MMPH in TSC. [source] Impact of BRCA mutations on female fertility and offspring sex ratio,AMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 2 2010Roxana Moslehi Positive selection for inherited mutations in breast and ovarian cancer predisposing genes, BRCA1 and BRCA2, may contribute to the high frequency of BRCA mutations among the Ashkenazi Jewish population. Impact of BRCA mutations on fertility has not been generally explored in epidemiologic studies. There are reports of distorted sex ratios in BRCA carrier families but these findings have been attributed to bias. We investigated the effect of BRCA mutations on female fertility and offspring sex ratio in a study of 260 Ashkenazi Jewish women with ovarian cancer and 331 controls, unselected for age or family history of the disease. Pregnancy success was similar for 96 mutation carrier (0.84) and 164 noncarrier cases (0.87) and controls (0.83). After adjusting for covariates, there were no significant differences between BRCA carrier and noncarrier cases and controls with regards to fertility, despite lower pregnancy rates among all cases compared to controls (P = 0.0049). Male/female sex ratios were significantly lower among offspring of carriers (0.71) than offspring of noncarriers (0.95) or those of the controls (0.99). Comparisons among the three groups yielded statistically significant distortion against males among the offspring of known and obligate BRCA carriers compared to noncarriers (OR = 0.74, 95% CI:0.55,0.99) and controls (OR = 0.71, 95% CI:0.54,0.94). In conclusion, we did not find evidence for an effect of BRCA mutations on female fertility. We found a significant excess of females among the offspring of female carriers of BRCA1 and BRCA2 mutations. Potential contribution of observed sex ratio distortions to positive selection for BRCA mutations may warrant further investigation. Am. J. Hum. Biol., 2010. © 2009 Wiley-Liss, Inc. [source] MicroRNAs in the pathogeny of chronic lymphocytic leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2007Milena S. Nicoloso Summary MicroRNAs (miRNAs) have been linked to the initiation and progression of chronic lymphocytic leukaemia (CLL). The main molecular alterations are represented by variations in gene expression, usually mild and with consequences for a vast number of target protein-coding genes. Recent studies have shown that miRNAs are the main candidates for the elusive class of CLL predisposing genes. These discoveries could be exploited for the development of useful markers for diagnosis and prognosis, as well as for the development of new RNA-based cancer therapies. [source] | |||||||||||||