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Enriched variations in TEKT4 and breast cancer resistance to paclitaxel
Paclitaxel is effective in the treatment of breast cancer but predicting which patients might respond to this drug is of clinical importance. Here, Jiang et al. show that germline mutations in TEKT4, a protein that associates with microtubules, are associated with resistance to paclitaxel therapy.
- Yi-Zhou Jiang
- , Ke-Da Yu
- & Zhi-Ming Shao
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Massive gene amplification drives paediatric hepatocellular carcinoma caused by bile salt export pump deficiency
Hepatocellular carcinoma (HCC) is associated with chronic inflammation, but the genetic basis of the disease remains unclear. Here, the authors report that defects in hepatocyte biliary transporters and subsequent liver inflammation induce genomic alterations that promote HCC in human and mouse.
- Fabio Iannelli
- , Agnese Collino
- & Francesca D. Ciccarelli
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| Open AccessWhole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden
Bladder cancer is a complex genetic disease and a common cause of death due to malignancy. Here, the authors carry out whole-genome sequencing of 14 bladder cancers to characterize the genomic landscape of the disease and show that mutational burden is associated with tumour progression in these samples.
- J. -B. Cazier
- , S. R. Rao
- & F. C. Hamdy
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Targeted genomic rearrangements using CRISPR/Cas technology
Genomic rearrangements have important functional consequences for cancer. Here, Choi and Meyerson use CRISPR/Cas technology to generate translocations and inversions that are known drivers of lung cancer, and demonstrate the utility of this technology for studying the role of genomic rearrangements in disease.
- Peter S. Choi
- & Matthew Meyerson
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| Open AccessProcessed pseudogenes acquired somatically during cancer development
Germline pseudogenes have an important role in human evolution. Here, the authors analyse sequencing data from 660 cancer samples and find evidence for the formation of somatically acquired pseudogenes, a new class of mutation, which may contribute to cancer development.
- Susanna L. Cooke
- , Adam Shlien
- & Gerrit K.J. Hooijer
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Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids
Pulmonary carcinoids account for about 2% of pulmonary neoplasms. Here, the authors carry out gene copy number analysis, genome/exome, and transcriptome sequencing of pulmonary carcinoids and identify frequent mutations in chromatin-remodelling genes that can drive tumorigenesis in these tumours.
- Lynnette Fernandez-Cuesta
- , Martin Peifer
- & Roman K. Thomas
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MTSS1 is a metastasis driver in a subset of human melanomas
Complex genomic alterations segregate melanoma into different molecular subsets, but for most subsets it is unclear whether they drive a distinct clinical behaviour. Here, the authors use gene-expression data from melanoma patients to search for outlier genes that correlate with survival and identify that MTSS1 is associated with metastasis.
- Kirsten D. Mertz
- , Gaurav Pathria
- & Stephan N. Wagner
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Telomerase reverse transcriptase promoter mutations in primary cutaneous melanoma
Cutaneous melanoma is an aggressive form of skin cancer. Here, the authors show that mutations in the TERT promoter of 287 primary melanomas are associated with age, Breslow thickness and tumour ulceration and frequently occur at sun-exposed sites.
- Barbara Heidenreich
- , Eduardo Nagore
- & Rajiv Kumar
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Integrated analysis of germline and somatic variants in ovarian cancer
Ovarian cancer is one of the most common cancers in women and has an average 5-year survival of only 43%. Here, Kanchi et al.describe the germline and somatic mutation spectrum in ovarian cancer patients and identify potential risk variants associated with the disease.
- Krishna L. Kanchi
- , Kimberly J. Johnson
- & Li Ding
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Kinase fusions are frequent in Spitz tumours and spitzoid melanomas
Spitzoid neoplasms constitute a spectrum of melanocytic tumours, characterized by distinct clinical, pathological and genetic features. Here, Wiesner et al. show that kinase fusions represent the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanoma.
- Thomas Wiesner
- , Jie He
- & Boris C. Bastian
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Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1
Insulinomas develop from pancreatic β-cells and secrete insulin, but the underlying genetic defects are largely unknown. In this study, Cao et al. identify recurrent T372R mutations in the transcription factor YY1, and validate this hotspot mutation in 30% of insulinomas.
- Yanan Cao
- , Zhibo Gao
- & Guang Ning
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| Open AccessMutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups
Gingivo-buccal oral squamous cell carcinoma (OSCC-GB) is the leading cancer among males in India. Here, the authors carry out exome sequencing and recurrence testing in patients with OSCC-GB and highlight genes and biological pathways associated with the disease.
- Arindam Maitra
- , Nidhan K. Biswas
- & D. Sutradhar
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A common variant at 8q24.21 is associated with renal cell cancer
Renal cell carcinoma (RCC) accounts for 80–90% of all kidney cancers, but to date, only five genome-wide significant RCC risk loci have been identified. Here, Gudmundsson et al.identify a new RCC susceptibility locus and provide insight into the genetic basis of the disease.
- Julius Gudmundsson
- , Patrick Sulem
- & Kari Stefansson
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| Open AccessHeterozygous mutations in PALB2 cause DNA replication and damage response defects
PALB2 is a BRCA1-/BRCA2-interacting protein and heterozygous mutations in PALB2 are associated with hereditary breast cancer predisposition. Here the authors show that human lymphoblastoid cells from heterozygous PALB2mutation carriers display abnormal DNA replication dynamics and DNA damage response.
- Jenni Nikkilä
- , Ann Christin Parplys
- & Robert Winqvist
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Rb1 family mutation is sufficient for sarcoma initiation
Loss of the tumour suppressor Rb1 alone is thought to be insufficient for tumorigenesis. In this study, Liu et al. demonstrate that cells in which all three Rb1 family members are inactivated can initiate tumour formation, but only if cell survival is ensured by the retention of cell–cell contacts.
- Yongqing Liu
- , Ester Sánchez-Tilló
- & Douglas C. Dean
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Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin’s lymphoma
Hodgkin’s lymphoma has a genetic component that is poorly understood. In this study, Frampton et al. perform a genome-wide association study in German patients and combine the results with a previously published UK genome-wide association study to identify susceptibility loci at 3p24.1 and 6q23.3.
- Matthew Frampton
- , Miguel Inacio da Silva Filho
- & Richard S. Houlston
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| Open AccessMaster regulators of FGFR2 signalling and breast cancer risk
FGFR2 gene variation is associated with breast cancer risk but the molecular mechanism is unknown. Fletcher et al. provide a link between FGFR2 signalling and breast cancer susceptibility by demonstrating that FGFR2 signalling activates the ERa transcriptional network, which drives transcription of risk genes.
- Michael N. C. Fletcher
- , Mauro A. A. Castro
- & Kerstin B. Meyer
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| Open AccessHigh frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions
Telomerase reverse-trancriptase promoter mutations have been recently found in human melanomas. Here, Nault et al.identify telomerase reverse-trancriptase promoter mutations as the most frequent somatic genetic alterations in hepatocellular carcinomas and as the first mutation identified in cirrhotic preneoplastic lesions.
- Jean Charles Nault
- , Maxime Mallet
- & Jessica Zucman-Rossi
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Frequency of TERT promoter mutations in human cancers
Reactivation of telomerase has been implicated in human tumorigenesis. Here, somatic mutations in the TERT promoter are reported in cancers of the central nervous system, bladder, follicular cell-derived thyroid and melanoma, thus demonstrating that TERTpromoter mutations are a frequent event in human cancer.
- João Vinagre
- , Ana Almeida
- & Paula Soares
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| Open AccessMeta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2
Cancer-associated mutations in isocitrate dehydrogenase are proposed to impair TET2-dependent DNA demethylation. By comparing the methylomes of IDH-mutant cancers, the authors identify the transcription factor EBF1 as a partner of TET2, suggesting a possible means for targeting TET2 to specific DNA sequences.
- Paul Guilhamon
- , Malihe Eskandarpour
- & Stephan Beck
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| Open AccessIdentification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31
Most confirmed susceptibility variants for epithelial ovarian cancer lie in non-protein-coding sequences. Here Permuth-Wey and colleagues investigate variants in 3′ untranslated regions (UTRs) and uncover a new susceptibility locus.
- Jennifer Permuth-Wey
- , Kate Lawrenson
- & Simon A. Gayther
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Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells
The TMPRSS2/ERG gene fusion is frequently expressed in prostate cancers, however, its clinical significance is unclear. Polsen et al. show that this gene fusion is expressed monoallelically in prostate cancer stem cells, and may influence their self-renewal and maintenance.
- Euan S. Polson
- , John L. Lewis
- & Norman J. Maitland
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| Open AccessEpigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer
HNF1B is overexpressed in the clear cell subtype and epigenetically silenced in the serous subtype of ovarian cancer. Pearce and colleagues now show that genetic variants in HNF1B are differentially associated with risks of developing these two cancer subtypes, possibly through an epigenetic mechanism.
- Hui Shen
- , Brooke L. Fridley
- & Celeste Leigh Pearce
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DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes
Human cancer genomes often contain large amounts of single-nucleotide substitutions (SNS). Liu et al. catalogued SNS signatures across various cancer and normal genomes, demonstrating coordinative effects between replication timing and nuclear architecture on SNS patterns in cancer genomes.
- Lin Liu
- , Subhajyoti De
- & Franziska Michor
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Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer
Diabetes and obesity pose an increased risk for breast cancer; however, the reasons for this link remain unclear. Di et al.provide evidence that CtBP, a metabolically regulated transcriptional repressor, regulates a gene network that is selectively downregulated in more aggressive forms of breast cancer.
- Li-Jun Di
- , Jung S. Byun
- & Kevin Gardner
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Detection and differential diagnosis of colon cancer by a cumulative analysis of promoter methylation
Changes in the methylation pattern of gene promoters are hallmarks of certain cancers, such as colon cancer. Here Yang et al.identify and validate a set of genes and measure the cumulative methylation of promoters, which allows them to distinguish between two stages of colon cancer.
- Qiong Yang
- , Ying Dong
- & Shu Wang
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DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes
Cancer cells form by somatic mutations and natural selection, but how these factors affect tumorigenesis is not clear. Here, somatic mutations are characterized in human cancer genomes, revealing that DNA replication timing influences the frequency of single-nucleotide variants in different genomic regions.
- Yong H Woo
- & Wen-Hsiung Li
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Polyploid cells rewire DNA damage response networks to overcome replication stress-induced barriers for tumour progression
Tumour cells are subject to replication stress but how cells overcome damage without inducing senescence and apoptotic pathways is unclear. Here, the authors study polyploidy in cancer cells and show that this blocks apoptotic and senescent pathways, resulting in the induction of proteins involved in DNA repair.
- Li Zheng
- , Huifang Dai
- & Binghui Shen
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Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance
B-RAF is mutated in a large proportion of melanomas, and the first small molecule inhibitor has recently been approved for melanoma treatment. Here, by exome sequencing melanoma samples, Shi and colleagues show that B-RAF is amplified in tumours that have acquired resistance to the B-RAF inhibitor vemurafenib.
- Hubing Shi
- , Gatien Moriceau
- & Roger S. Lo
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miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia
HOX9AandMEIS1are key oncogenes in MLL-rearranged leukaemia. miRNA-196b is shown here to directly suppress their expression and delay MLL-fusion-mediated leukaemia, but to also cause an aggressive leukaemia phenotype when expressed ectopically, suggesting that it targets tumour suppressors as well.
- Zejuan Li
- , Hao Huang
- & Jianjun Chen
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Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer
Ageing associated diseases are the subject of intense study. In this article Serrano and colleagues demonstrate that Sirt1 over-expression in mice prevents both ageing associated diseases and liver cancer.
- Daniel Herranz
- , Maribel Muñoz-Martin
- & Manuel Serrano