Cancer biology and genomics: translating discoveries, transforming pathology

Advances in our understanding of cancer biology and discoveries emerging from cancer genomics are being translated into real clinical benefits for patients with cancer. The 2011 Journal of Pathology Annual Review Issue provides a snapshot of recent rapid progress on multiple fronts in the war on cancer or, more precisely, the wars on cancers. Indeed, perhaps the most notable recent shift is reflected by the sharp increase in understanding the biology of multiple specific cancers and using these new insights to inform rationally targeted therapies, with often striking successes. These recent developments, as reviewed in this issue, show how the long-term investments in basic cancer research are finally beginning to bear fruit. Copyright. (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.MTG

Kidney: t(6;11)(p21;q12) in renal cell carcinoma

Review on Kidney: t(6;11)(p21;q12) in renal cell carcinoma, with data on clinics, and the genes involved

CLTC (clathrin heavy polypeptide)

Review on CLTC (clathrin heavy polypeptide), with data on DNA, on the protein encoded, and where the gene is implicated

Kidney: t(X;17)(p11.2;q23) in renal cell carcinoma

Review on Kidney: t(X;17)(p11.2;q23) in renal cell carcinoma, with data on clinics, and the genes involved

Kidney: inv(X)(p11.2;q12) in renal cell carcinoma

Review on Kidney: inv(X)(p11.2;q12) in renal cell carcinoma, with data on clinics, and the genes involved

An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors.

To address the biological heterogeneity of lung cancer, we studied 199 lung adenocarcinomas by integrating genome-wide data on copy number alterations and gene expression with full annotation for major known somatic mutations in this cancer. This showed non-random patterns of copy number alterations significantly linked to EGFR and KRAS mutation status and to distinct clinical outcomes, and led to the discovery of a striking association of EGFR mutations with underexpression of DUSP4, a gene within a broad region of frequent single-copy loss on 8p. DUSP4 is involved in negative feedback control of EGFR signaling, and we provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. DUSP4 loss also associates with p16/CDKN2A deletion and defines a distinct clinical subset of lung cancer patients. Another novel observation is that of a reciprocal relationship between EGFR and LKB1 mutations. These results highlight the power of integrated genomics to identify candidate driver genes within recurrent broad regions of copy number alteration and to delineate distinct oncogenetic pathways in genetically complex common epithelial cancers

Layer Analysis of the Structure of Water Confined in Vycor Glass

A Molecular Dynamics simulation of the microscopic structure of water confined in a silica pore is presented. A single cavity in the silica glass has been modeled as to reproduce the main features of the pores of real Vycor glass. A layer analysis of the site-site radial distribution functions evidence the presence in the pore of two subsets of water molecules with different microscopic structure. Molecules which reside in the inner layer, close to the center of the pore, have the same structure as bulk water but at a temperature of 30 K higher. On the contrary the structure of the water molecules in the outer layer, close to the substrate, is strongly influenced by the water-substrate hydrophilic interaction and sensible distortions of the H-bond network and of the orientational correlations between neighboring molecules show up. Lowering the hydration has little effect on the structure of water in the outer layer. The consequences on experimental determinations of the structural properties of water in confinement are discussed.Comment: 6 pages, 8 figures included in the text, one figure added, changes in the tex

Clinical Characteristics of Patients with Malignant Pleural Mesothelioma Harboring Somatic BAP1 Mutations

IntroductionGenomic studies of malignant pleural mesothelioma (MPM) have recently identified frequent mutations in the BRCA-associated protein 1(BAP1) gene. In uveal melanoma and clear cell renal cell carcinoma, BAP1 mutations are associated with poor outcomes but their clinical significance in MPM is unknown. We therefore undertook this study to define the characteristics of patients whose MPM tumors harbor somatic BAP1 mutation and to examine the relationship between BAP1 mutation and survival.MethodsWe reviewed the charts of 121 patients with MPM tumors diagnosed between 1991 and 2009 tested for BAP1 mutation, and extracted the following information: age at diagnosis, sex, histology, stage, smoking status, asbestos exposure, family or personal history of malignancy, and treatment including surgery, chemotherapy, and radiation as well as survival status.ResultsTwenty-four of the 121 tumors (20%) harbored somatic BAP1 mutations. The percentage of current or former smokers among cases with BAP1 mutations was significantly higher than in BAP1 wild-type cases, (75% versus 42%; p = 0.006). However, the types of nucleotide substitutions in BAP1 did not suggest that this association was because of a causative role of smoking in BAP1 mutations. No other clinical feature was significantly different among those with and without BAP1 mutations in their MPM. There was also no difference in survival according to somatic BAP1 mutation status.ConclusionThere is no apparent distinct clinical phenotype for MPM with somatic BAP1 mutation. The significance of the more frequent history of smoking among patients with BAP1-mutated MPM warrants further study

ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research

Abstract Background NTRK1, NTRK2 and NTRK3 fusions are present in a plethora of malignancies across different histologies. These fusions represent the most frequent mechanism of oncogenic activation of these receptor tyrosine kinases, and biomarkers for the use of TRK small molecule inhibitors. Given the varying frequency of NTRK1/2/3 fusions, crucial to the administration of NTRK inhibitors is the development of optimal approaches for the detection of human cancers harbouring activating NTRK1/2/3 fusion genes. Materials and methods Experts from several Institutions were recruited by the European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) to review the available methods for the detection of NTRK gene fusions, their potential applications, and strategies for the implementation of a rational approach for the detection of NTRK1/2/3 fusion genes in human malignancies. A consensus on the most reasonable strategy to adopt when screening for NTRK fusions in oncologic patients was sought, and further reviewed and approved by the ESMO TR and PM WG and the ESMO leadership. Results The main techniques employed for NTRK fusion gene detection include immunohistochemistry, fluorescence in situ hybridization (FISH), RT-PCR, and both RNA-based and DNA-based next generation sequencing (NGS). Each technique has advantages and limitations, and the choice of assays for screening and final diagnosis should also take into account the resources and clinical context. Conclusion In tumours where NTRK fusions are highly recurrent, FISH, RT-PCR or RNA-based sequencing panels can be used as confirmatory techniques, whereas in the scenario of testing an unselected population where NTRK1/2/3 fusions are uncommon, either front-line sequencing (preferentially RNA-sequencing) or screening by immunohistochemistry followed by sequencing of positive cases should be pursued

DOK2 inhibits EGFR-mutated lung adenocarcinoma

Somatic mutations in the EGFR proto-oncogene occur in ~15% of human lung adenocarcinomas and the importance of EGFR mutations for the initiation and maintenance of lung cancer is well established from mouse models and cancer therapy trials in human lung cancer patients. Recently, we identified DOK2 as a lung adenocarcinoma tumor suppressor gene. Here we show that genomic loss of DOK2 is associated with EGFR mutations in human lung adenocarcinoma, and we hypothesized that loss of DOK2 might therefore cooperate with EGFR mutations to promote lung tumorigenesis. We tested this hypothesis using genetically engineered mouse models and find that loss of Dok2 in the mouse accelerates lung tumorigenesis initiated by oncogenic EGFR, but not that initiated by mutated Kras. Moreover, we find that DOK2 participates in a negative feedback loop that opposes mutated EGFR; EGFR mutation leads to recruitment of DOK2 to EGFR and DOK2-mediated inhibition of downstream activation of RAS. These data identify DOK2 as a tumor suppressor in EGFR-mutant lung adenocarcinoma