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.
"Signalling elicited by activated cell surface receptors and transduced through RAS proteins to the RAF/MEK/ERK and PI3K/AKT cascades is central to cell proliferation, survival, differentiation and metabolism (1,2). Owing to this nodal role, enhanced traffic through RAS proteins and their downstream effectors has been established to have a major impact on oncogenesis (3,4). This signalling network also controls early and late developmental processes (e.g. "
[Show abstract][Hide abstract] ABSTRACT: RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive
deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly
through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects
among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common
RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic
disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing
to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant
homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2S2G mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted
role of enhanced RRAS function in human disease.
Human Molecular Genetics 04/2014; 23(16). DOI:10.1093/hmg/ddu148 · 6.39 Impact Factor
"In addition, PDGF and its receptor are overproduced in a subset of glioblastomas, although the underlying mechanisms are unclear . KRAS and BRAF mutations occur frequently in multiple tumor types and are prevalent in melanoma, pancreatic adenocarcinoma, colorectal carcinoma, and lung adenocarcinoma  . Activating mutations in PIK3CA, encoding a catalytic subunit of PI(3)K, occur frequently in breast, ovarian, and colorectal cancer, and loss of heterozygosity of PTEN is one of the most common genetic alterations observed in multiple tumor types  . "
[Show abstract][Hide abstract] ABSTRACT: Oncogenic mutations disrupt the regulatory circuits that govern cell function, enabling tumor cells to undergo de-regulated mitogenesis, to resist pro-apoptotic insults, and to invade through tissue boundaries. Cancer cell biology has played a crucial role in elucidating the signaling mechanisms by which oncogenic mutations sustain these malignant behaviors and thereby in identifying rational targets for cancer drugs. The efficacy of such targeted therapies illustrate the power of a reductionist approach to the study of cancer.
"These results from uncertainties may indicate a mixed or transitory state between previous and following stages supporting the fact that tumors are heterogeneous within stages and even within individuals . This is also consistent with in-situ studies showing that markers are commonly present only in a fraction of samples of the same tumor grade . Other studies have shown that 12 and 9 genes on average were mutated in individual breast and colorectal cancers from a total of 122 and 69 genes respectively that were mutated in 11 tumors  and reviews of further studies show that between 33 to 66 genes are mutated in several common cancers . "
[Show abstract][Hide abstract] ABSTRACT: Background
Cancer is a complex disease commonly characterized by the disrupted activity of several cancer-related genes such as oncogenes and tumor-suppressor genes. Previous studies suggest that the process of tumor progression to malignancy is dynamic and can be traced by changes in gene expression. Despite the enormous efforts made for differential expression detection and biomarker discovery, few methods have been designed to model the gene expression level to tumor stage during malignancy progression. Such models could help us understand the dynamics and simplify or reveal the complexity of tumor progression.
We have modeled an on-off state of gene activation per sample then per stage to select gene expression profiles associated to tumor progression. The selection is guided by statistical significance of profiles based on random permutated datasets.
We show that our method identifies expected profiles corresponding to oncogenes and tumor suppressor genes in a prostate tumor progression dataset. Comparisons with other methods support our findings and indicate that a considerable proportion of significant profiles is not found by other statistical tests commonly used to detect differential expression between tumor stages nor found by other tailored methods. Ontology and pathway analysis concurred with these findings.
Results suggest that our methodology may be a valuable tool to study tumor malignancy progression, which might reveal novel cancer therapies.
Theoretical Biology and Medical Modelling 05/2013; 10(1):37. DOI:10.1186/1742-4682-10-37 · 0.95 Impact Factor
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