PMID: 20393566
Title: Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.
Journal: Nature 2010
Authors: Rajnish A Gupta Nilay Shah Kevin C Wang Jeewon Kim Hugo M Horlings David J Wong Miao-Chih Tsai Tiffany Hung Pedram Argani John L Rinn Yulei Wang Pius Brzoska Benjamin Kong Rui Li Robert B West Marc J van de Vijver Saraswati Sukumar Howard Y Chang
ALL_TEXT: Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.

PMID: 21633166
Title: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.
Journal: The Journal of clinical investigation 2011
Authors: Brian D Lehmann Joshua A Bauer Xi Chen Melinda E Sanders A Bapsi Chakravarthy Yu Shyr Jennifer A Pietenpol
ALL_TEXT: Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted "driver" signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.

PMID: 22522925
Title: The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.
Journal: Nature 2012
Authors: Christina Curtis Sohrab P Shah Suet-Feung Chin Gulisa Turashvili Oscar M Rueda Mark J Dunning Doug Speed Andy G Lynch Shamith Samarajiwa Yinyin Yuan Stefan Gräf Gavin Ha Gholamreza Haffari Ali Bashashati Roslin Russell Steven McKinney Anita Langerød Andrew Green Elena Provenzano Gordon Wishart Sarah Pinder Peter Watson Florian Markowetz Leigh Murphy Ian Ellis Arnie Purushotham Anne-Lise Børresen-Dale James D Brenton Simon Tavaré Carlos Caldas Samuel Aparicio
ALL_TEXT: The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA-RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the 'CNA-devoid' subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.

PMID: 22658128
Title: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
Journal: The New England journal of medicine 2012
Authors: Julie R Brahmer Scott S Tykodi Laura Q M Chow Wen-Jen Hwu Suzanne L Topalian Patrick Hwu Charles G Drake Luis H Camacho John Kauh Kunle Odunsi Henry C Pitot Omid Hamid Shailender Bhatia Renato Martins Keith Eaton Shuming Chen Theresa M Salay Suresh Alaparthy Joseph F Grosso Alan J Korman Susan M Parker Shruti Agrawal Stacie M Goldberg Drew M Pardoll Ashok Gupta Jon M Wigginton
BACKGROUND: Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models.
METHODS: In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression.
RESULTS: As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up.
CONCLUSIONS: Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).

PMID: 22818936
Title: Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy.
Journal: Lancet (London, England) 2012
Authors: I-Min Lee Eric J Shiroma Felipe Lobelo Pekka Puska Steven N Blair Peter T Katzmarzyk
BACKGROUND: Strong evidence shows that physical inactivity increases the risk of many adverse health conditions, including major non-communicable diseases such as coronary heart disease, type 2 diabetes, and breast and colon cancers, and shortens life expectancy. Because much of the world's population is inactive, this link presents a major public health issue. We aimed to quantify the eff ect of physical inactivity on these major non-communicable diseases by estimating how much disease could be averted if inactive people were to become active and to estimate gain in life expectancy at the population level.
METHODS: For our analysis of burden of disease, we calculated population attributable fractions (PAFs) associated with physical inactivity using conservative assumptions for each of the major non-communicable diseases, by country, to estimate how much disease could be averted if physical inactivity were eliminated. We used life-table analysis to estimate gains in life expectancy of the population.
FINDINGS: Worldwide, we estimate that physical inactivity causes 6% (ranging from 3*2% in southeast Asia to 7*8% in the eastern Mediterranean region) of the burden of disease from coronary heart disease, 7% (3*9-9*6) of type 2 diabetes, 10% (5*6-14*1) of breast cancer, and 10% (5*7-13*8) of colon cancer. Inactivity causes 9% (range 5*1-12*5) of premature mortality, or more than 5*3 million of the 57 million deaths that occurred worldwide in 2008. If inactivity were not eliminated, but decreased instead by 10% or 25%, more than 533 000 and more than 1*3 million deaths, respectively, could be averted every year. We estimated that elimination of physical inactivity would increase the life expectancy of the world's population by 0*68 (range 0*41-0*95) years.
INTERPRETATION: Physical inactivity has a major health eff ect worldwide. Decrease in or removal of this unhealthy behaviour could improve health substantially.
FUNDING: None.

PMID: 23000897
Title: Comprehensive molecular portraits of human breast tumours.
Journal: Nature 2012
Authors:
ALL_TEXT: We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.

PMID: 23485231
Title: Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012.
Journal: European journal of cancer (Oxford, England : 1990) 2013
Authors: J Ferlay E Steliarova-Foucher J Lortet-Tieulent S Rosso J W W Coebergh H Comber D Forman F Bray
INTRODUCTION: Cancer incidence and mortality estimates for 25 cancers are presented for the 40 countries in the four United Nations-defined areas of Europe and for the European Union (EU-27) for 2012.
METHODS: We used statistical models to estimate national incidence and mortality rates in 2012 from recently-published data, predicting incidence and mortality rates for the year 2012 from recent trends, wherever possible. The estimated rates in 2012 were applied to the corresponding population estimates to obtain the estimated numbers of new cancer cases and deaths in Europe in 2012.
RESULTS: There were an estimated 3.45 million new cases of cancer (excluding non-melanoma skin cancer) and 1.75 million deaths from cancer in Europe in 2012. The most common cancer sites were cancers of the female breast (464,000 cases), followed by colorectal (447,000), prostate (417,000) and lung (410,000). These four cancers represent half of the overall burden of cancer in Europe. The most common causes of death from cancer were cancers of the lung (353,000 deaths), colorectal (215,000), breast (131,000) and stomach (107,000). In the European Union, the estimated numbers of new cases of cancer were approximately 1.4 million in males and 1.2 million in females, and around 707,000 men and 555,000 women died from cancer in the same year.
CONCLUSION: These up-to-date estimates of the cancer burden in Europe alongside the description of the varying distribution of common cancers at both the regional and country level provide a basis for establishing priorities to cancer control actions in Europe. The important role of cancer registries in disease surveillance and in planning and evaluating national cancer plans is becoming increasingly recognised, but needs to be further advocated. The estimates and software tools for further analysis (EUCAN 2012) are available online as part of the European Cancer Observatory (ECO) (http://eco.iarc.fr).

PMID: 24336805
Title: Causal analysis approaches in Ingenuity Pathway Analysis.
Journal: Bioinformatics (Oxford, England) 2014
Authors: Andreas Krämer Jeff Green Jack Pollard Stuart Tugendreich
MOTIVATION: Prior biological knowledge greatly facilitates the meaningful interpretation of gene-expression data. Causal networks constructed from individual relationships curated from the literature are particularly suited for this task, since they create mechanistic hypotheses that explain the expression changes observed in datasets.
RESULTS: We present and discuss a suite of algorithms and tools for inferring and scoring regulator networks upstream of gene-expression data based on a large-scale causal network derived from the Ingenuity Knowledge Base. We extend the method to predict downstream effects on biological functions and diseases and demonstrate the validity of our approach by applying it to example datasets.
AVAILABILITY: The causal analytics tools 'Upstream Regulator Analysis', 'Mechanistic Networks', 'Causal Network Analysis' and 'Downstream Effects Analysis' are implemented and available within Ingenuity Pathway Analysis (IPA, http://www.ingenuity.com).
SUPPLEMENTARY INFORMATION: Supplementary material is available at Bioinformatics online.

PMID: 25651787
Title: Global cancer statistics, 2012.
Journal: CA: a cancer journal for clinicians 2015
Authors: Lindsey A Torre Freddie Bray Rebecca L Siegel Jacques Ferlay Joannie Lortet-Tieulent Ahmedin Jemal
ALL_TEXT: Cancer constitutes an enormous burden on society in more and less economically developed countries alike. The occurrence of cancer is increasing because of the growth and aging of the population, as well as an increasing prevalence of established risk factors such as smoking, overweight, physical inactivity, and changing reproductive patterns associated with urbanization and economic development. Based on GLOBOCAN estimates, about 14.1 million new cancer cases and 8.2 million deaths occurred in 2012 worldwide. Over the years, the burden has shifted to less developed countries, which currently account for about 57% of cases and 65% of cancer deaths worldwide. Lung cancer is the leading cause of cancer death among males in both more and less developed countries, and has surpassed breast cancer as the leading cause of cancer death among females in more developed countries; breast cancer remains the leading cause of cancer death among females in less developed countries. Other leading causes of cancer death in more developed countries include colorectal cancer among males and females and prostate cancer among males. In less developed countries, liver and stomach cancer among males and cervical cancer among females are also leading causes of cancer death. Although incidence rates for all cancers combined are nearly twice as high in more developed than in less developed countries in both males and females, mortality rates are only 8% to 15% higher in more developed countries. This disparity reflects regional differences in the mix of cancers, which is affected by risk factors and detection practices, and/or the availability of treatment. Risk factors associated with the leading causes of cancer death include tobacco use (lung, colorectal, stomach, and liver cancer), overweight/obesity and physical inactivity (breast and colorectal cancer), and infection (liver, stomach, and cervical cancer). A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests.

PMID: 27253694
Title: Cancer treatment and survivorship statistics, 2016.
Journal: CA: a cancer journal for clinicians 2016
Authors: Kimberly D Miller Rebecca L Siegel Chun Chieh Lin Angela B Mariotto Joan L Kramer Julia H Rowland Kevin D Stein Rick Alteri Ahmedin Jemal
ALL_TEXT: The number of cancer survivors continues to increase because of both advances in early detection and treatment and the aging and growth of the population. For the public health community to better serve these survivors, the American Cancer Society and the National Cancer Institute collaborate to estimate the number of current and future cancer survivors using data from the Surveillance, Epidemiology, and End Results cancer registries. In addition, current treatment patterns for the most prevalent cancer types are presented based on information in the National Cancer Data Base and treatment-related side effects are briefly described. More than 15.5 million Americans with a history of cancer were alive on January 1, 2016, and this number is projected to reach more than 20 million by January 1, 2026. The 3 most prevalent cancers are prostate (3,306,760), colon and rectum (724,690), and melanoma (614,460) among males and breast (3,560,570), uterine corpus (757,190), and colon and rectum (727,350) among females. More than one-half (56%) of survivors were diagnosed within the past 10 years, and almost one-half (47%) are aged 70 years or older. People with a history of cancer have unique medical and psychosocial needs that require proactive assessment and management by primary care providers. Although there are a growing number of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based resources are needed to optimize care. CA Cancer J Clin 2016;66:271-289. (c) 2016 American Cancer Society.