The molecular pathology of cancer.
ABSTRACT Rapid technical advances in DNA sequencing and genome-wide association studies are driving the discovery of the germline and somatic mutations that are present in different cancers. Mutations in genes involved in cellular signaling are common, and often shared by tumors that arise in distinct anatomical locations. Here we review the most important molecular changes in different cancers from the perspective of what should be analyzed on a routine basis in the clinic. The paradigms are EGFR mutations in adenocarcinoma of the lung that can be treated with gefitinib, KRAS mutations in colon cancer with respect to treatment with EGFR antibodies, and the use of gene-expression analysis for ER-positive, node-negative breast cancer patients with respect to chemotherapy options. Several other examples in both solid and hematological cancers are also provided. We focus on how disease subtypes can influence therapy and discuss the implications of the impending molecular diagnostic revolution from the point of view of the patients, clinicians, and the diagnostic and pharmaceutical companies. This paradigm shift is occurring first in cancer patient management and is likely to promote the application of these technologies to other diseases.
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ABSTRACT: Dyskeratosis congenita (DC) encompasses a large spectrum of diseases and clinical manifestations generally related to premature aging, including bone marrow failure and cancer predisposition. The major risk factor for DC is to carry germline telomere-related mutations-in telomerase or telomere shelterin genes-which results in premature telomere dysfunction, thus increasing the risk of premature aging impairments. Despite the advances that have been accomplished in DC research, the molecular aspects underlying the phenotypic variability of the disease remain poorly understood. Here different aspects of telomere biology, concerning adult stem cells senescence, tumor suppression and cancer are considered in the context of DC, resulting in two translational models: late onset of DC symptoms in telomere-related mutations carriers is a potential indicator of increased cancer risk and differences in tumor suppression capacities among the genetic subgroups are (at least partial) causes of different clinical manifestations of the disease. The limitations of both models are presented, and further experiments for their validation, as well as clinical implications, are discussed.Ageing research reviews 03/2013; DOI:10.1016/j.arr.2013.03.003 · 7.63 Impact Factor
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ABSTRACT: G protein-coupled receptor 30/G protein estrogen receptor-1 (GPR30/GPER-1) is a novel membrane receptor for estrogen whose mRNA is expressed at high levels in estrogen-dependent cells such as breast cancer cell lines. However, mutations in GRP30 related to diseases remain unreported. To detect unknown mutations in the GPR30 open reading frame (ORF) quickly, the experimental conditions for high-resolution melting (HRM) analysis were examined for PCR primers, Taq polymerases, saturation DNA binding dyes, Mg(2+) concentration, and normalized temperatures. Nine known SNPs and 13 artificial point mutations within the GPR30 ORF, as well as single nucleotide variants in DNA extracted from subjects with breast cancers were tested under the optimal experimental conditions. The combination of Expand High Fidelity(PLUS) and SYTO9 in the presence of 2.0 mM MgCl(2) produced the best separation in melting curves of mutations in all regions of the GPR30 ORF. Under these experimental conditions, the mutations were clearly detected in both heterozygotes and homozygotes. HRM analysis of GPR30 using genomic DNA from subjects with breast cancers showed a novel single nucleotide variant, 111C>T in GPR30 and 4 known SNPs. The experimental conditions determined in this study for HRM analysis are useful for high throughput assays to detect unknown mutations within the GPR30 ORF.Gene 04/2012; 501(2):118-26. DOI:10.1016/j.gene.2012.04.029 · 2.08 Impact Factor
- Genome Research 02/2012; 22(2):177-82. DOI:10.1101/gr.136044.111 · 13.85 Impact Factor