Molecular Approaches Towards the Isolation of Pediatric Cancer Predisposition Genes
John T. Kemshead in Pediatric Tumors: Immunological and Molecular Markers, 2020
Beckwith-Wiedemann syndrome is a condition involving somatic overgrowth.100,101 In a few cases, it is also associated with a chromosome abnormality involving the distal tip of chromosome 11.102,103 One of the features of this condition is that individuals often develop specific rare pediatric tumors, most frequently Wilms’ tumors, but also hepatoblastomas, rhabdomyosarcomas, adrenal adenocarcinomas, and non-Burkitt’s lymphoma. In some patients, combinations of these tumors have been reported, suggesting a common etiological event arising as a result of a mutation at the same locus. Koufos et al.104 analyzed three hepatoblastomas and showed that in two, homozygosity for chromosome 11 markers developed, while in a third tumor, heterozygosity was retained. There were similar findings in two rhabdomyosarcomas. Markers from other chromosomes were the same in tumor and normal tissues showing that loss of alleles was restricted to chromosome 11. Recently Haas et al.102 reported a patient with BWS who developed nephroblastoma and carried a constitutional chromosome deletion of region 11p11.1-p11.2. These studies suggest a common pathogenicity mechanism by these clinically associated tumor types. It is not clear whether the locus involved is the same or constitutes a complex of several genes in the same region of the chromosome. It does appear, however, that these genes contribute to the normal differentiation of the tissues involved.
Pathogenesis of cancer
Peter Hoskin, Peter Ostler in Clinical Oncology, 2020
The best known example of a tumour-suppressor gene is the P53 gene, which has been called ‘the guardian of the genome’ and is found to be mutated in the majority of sporadic cancers. It is also mutated in Li–Fraumeni syndrome, characterized by cancers of the breast, adrenal glands, leukaemia, gliomas and soft-tissue sarcomas. This gene induces cell cycle arrest, which allows cells with DNA damage to repair these mutations before entering mitosis. The mutation of P53 therefore makes the cell susceptible to carcinogenic mutations. Other examples include the retinoblastoma gene which is located on chromosome 13, breast cancer susceptibility genes BRCA1 (chromosome 17) and BRCA2 (chromosome 13), the Wilms’ tumour gene on chromosome 11, and the familial polyposis coli gene on chromosome 5.
Oncogene and Tumor Suppressor Gene Involvement in Human Lung Carcinogenesis
George E. Milo, Bruce C. Casto, Charles F. Shuler in Transformation of Human Epithelial Cells: Molecular and Oncogenetic Mechanisms, 2017
We have studied chromosome 11 extensively for loss of alleles because it has been speculated to have at least one, if not more, tumor suppressor gene. Six different loci on this chromosome have been studied. LOH was observed in 45% of the squamous cell carcinomas and adenocarcinomas studied.72 LOH was most frequently observed at the HBG2, insulin, and cHa-ras loci in both types of cancers. From these data, it was possible to establish two commonly deleted regions in lung cancer for this chromsome, namely, 11pter-p15.5 and 11p13-11q13 (see Figure 2). These findings are consistent with observations that describe two separate regions on chromosome 11 that may harbor tumor suppressor genes that correspond to 11p13 in Wilms’ tumor and 11pter-11p15.5 in rhabdomyosarcoma.58,79
Nonclonal Chromosomal Aberrations in Childhood Leukemia Survivors
Published in Fetal and Pediatric Pathology, 2018
Tong Foh Chin, Kamariah Ibrahim, Tharshanadevasheri Thirunavakarasu, Mohamad Shafiq Azanan, Lixian Oh, Su Han Lum, Tsiao Yi Yap, Hany Ariffin
Monosomy of chromosome 8 and chromosome 11, as found in two of our subjects, are of particular interest. Using interphase FISH on formalin-fixed paraffin embedded breast cancer tissue, Garcia et al. [23] demonstrated that loss of chromosome 8 was more frequent in intraductal proliferative lesions (49%) and invasive ductal carcinoma (27%) compared to controls (6%). Abnormalities in chromosome 11, especially rearrangements of 11q23, have long been implicated in tumorigenesis, particularly leukemia [24]. It is notable that both chromosome 8 and chromosome 11 harbor important tumor supressor genes such as N-myc downstream-regulated gene-1 (Ndrg-1) and DNA repair-associated ataxia-telangiectasia mutated (ATM) serine/threonine kinase gene, respectively [25–27], further adding credence to the possibility that aberrations in these chromosomes may lead to cancer development.
Clinical and genetic predictors of diabetes drug’s response
Published in Drug Metabolism Reviews, 2019
Adriana Fodor, Angela Cozma, Ramona Suharoschi, Adela Sitar-Taut, Gabriela Roman
Ataxia-telangiectasia mutated gene (ATM) Zhou et al. described for the first time how GWAS could be applied to the glycemic response to metformin (Zhou et al. 2011). In the Scottish participants from GoDARTS and UK patients from UKPDS a genome-wide association ‘signal’ on chromosome 11 has been reported in a locus containing seven genes. The minor C-allele of the most strongly associated SNP, rs11212617 increased the ability of metformin to achieve HbA1c below 7% with OR of 1.35 for each minor C-allele (allele frequency of 44%) and OR of 3.3 for two alleles (19% of the patients), compared with those without any variant. The authors suggested that the most likely candidate is the ATM gene, and the researchers have shown in vitro that ATM is involved in AMPK’s activation by metformin. The data have been replicated in a meta-analysis (van Leeuwen et al. 2012) and in a study on Chinese diabetic patients (Zhou et al. 2014). However, the association between rs11212617 variant and the incidence of diabetes might be confined to populations of European descent, as no association was observed in people of American ancestry, enrolled in DPP study (Florez et al. 2012). Moreover, it is a matter of debate if the ATM gene is the causal gene at this region, as the ATM inhibitor used in the in vitro studies, it has since been shown to inhibit OCT1 transport and prevent metformin uptake into hepatic cells (Woods et al. 2012).
Further Characterization of Hb Bronovo [α103(G10)His→Leu; HBA2: c.311A>T] and First Report of the Homozygous State
Published in Hemoglobin, 2020
Nikita Mehta, J. Martin Johnston, Molly Hein, Benjamin R. Kipp, Lea Coon, Michelle E. Savedra, James D. Hoyer, Rong He, Aruna Rangan, Min Shi, Jennifer L. Oliveira
Uniparental disomy (UPD) analysis of chromosomes 11 and 16 were also performed for the proband and his parents. Uniparental disomy studies were performed by a previously described technique [7,8]. In brief, samples were genotyped using PCR of chromosome-specific microsatellite markers (dinucleotide repeats). The markers used for chromosome 16 were D16S521, D16S418, D16S500, D16S3041, D16S3100, D16S3034, D16S3057, D16S503, D16S515, D16S516, D16S505 and D16S520; the markers used for chromosome 11 were D11S1363, D11S4046, D11S4146, D11S1760, D11S1338, D11S4116, D11S935, D11S987, D11S1314, D11S937, D11S901, D11S898, D11S4151, D11S1320 and D11S968. Diagnosis of UPD required that the proband carries at least two informative markers representing uniparental inheritance of chromosome 16, in addition to all informative markers for chromosome 11 showing biparental inheritance [9].
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