Unsupervised class discovery is a highly useful technique in cancer research, where intrinsic groups sharing biological characteristics may exist but are unknown. The consensus clustering (CC) method ...provides quantitative and visual stability evidence for estimating the number of unsupervised classes in a dataset. ConsensusClusterPlus implements the CC method in R and extends it with new functionality and visualizations including item tracking, item-consensus and cluster-consensus plots. These new features provide users with detailed information that enable more specific decisions in unsupervised class discovery. Availability: ConsensusClusterPlus is open source software, written in R, under GPL-2, and available through the Bioconductor project (http://www.bioconductor.org/). Contact: mwilkers@med.unc.edu Supplementary Information: Supplementary data are available at Bioinformatics online.
Head and neck cancer is the fifth most common cancer worldwide. It is often amenable to curative intent therapy when localized to the head and neck region, but it carries a poor prognosis when it is ...recurrent or metastatic. Therefore, initial treatment decisions are critical to improve patient survival. However, multimodality therapy used with curative intent is toxic. The balance between offering intensive versus tolerable and function-preserving therapy has been thrown into sharp relief with the recently described epidemic of human papillomavirus-associated head and neck squamous cell carcinomas characterized by improved clinical outcomes compared with smoking-associated head and neck tumors. Model systems and clinical trials have been slow to address the clinical questions that face the field to date. With this as a background, a host of translational studies have recently reported the somatic alterations in head and neck cancer and have highlighted the distinct genetic and biologic differences between viral and tobacco-associated tumors. This review seeks to summarize the main findings of studies, including The Cancer Genome Atlas, for the clinician scientist, with a goal of leveraging this new knowledge toward the betterment of patients with head and neck cancer.
The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor ...(EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition.
We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non-cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape.
To evaluate the incidence of oral cavity squamous cell carcinoma (OCSCC) and oral tongue squamous cell carcinoma (OTSCC) in young white women, age 18 to 44 years.
We analyzed incidence and survival ...data from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute from 1975 to 2007 for OCSCC and OTSCC. Three cohorts were examined: all ages, age 18 to 44 years (ie, "young"), and age > 44 years. Individuals were stratified by sex and/or race. Percentage change (PC) and annual percentage change (APC) were calculated. Joinpoint regression analyses were performed to examine trend differences.
Overall, incidence of OCSCC was decreasing for all ages. However, incidence was increasing for young white women (PC, 34.8; APC, 2.2; P < .05). Incidence of OTSCC was decreasing for all ages except in the age 18 to 44 years group (PC, 28.8; APC, 1.8; P < .05). Young white individuals had increasing incidence trends of OTSCC (white women: PC, 111.3; APC, 4; P < .05; young white men: PC, 43.7; APC, 1.6; P < .05). The APC of OTSCC was significantly greater in young white women compared with that in young white men (P = .007). Furthermore, incidence of SCC in all other subsites of the oral cavity was decreasing. Nonwhites had a decreasing incidence of OCSCC and OTSCC. Cause-specific survival was similar among whites age 18 to 44 and individuals older than age 44 years.
OTSCC is increasing among young white individuals age 18 to 44 years, particularly among white women. Young white women may be a new, emerging head and neck cancer patient population.
Variant detection from next-generation sequencing (NGS) data is an increasingly vital aspect of disease diagnosis, treatment and research. Commonly used NGS-variant analysis tools generally rely on ...accurately mapped short reads to identify somatic variants and germ-line genotypes. Existing NGS read mappers have difficulty accurately mapping short reads containing complex variation (i.e. more than a single base change), thus making identification of such variants difficult or impossible. Insertions and deletions (indels) in particular have been an area of great difficulty. Indels are frequent and can have substantial impact on function, which makes their detection all the more imperative.
We present ABRA, an assembly-based realigner, which uses an efficient and flexible localized de novo assembly followed by global realignment to more accurately remap reads. This results in enhanced performance for indel detection as well as improved accuracy in variant allele frequency estimation.
ABRA is implemented in a combination of Java and C/C++ and is freely available for download at https://github.com/mozack/abra.
Molecular subtyping of lung adenocarcinoma (AD) and lung squamous cell carcinoma (SCC) reveal biologically diverse tumors that vary in their genomic and clinical attributes.
Published immune cell ...signatures and several lung AD and SCC gene expression data sets, including The Cancer Genome Atlas, were used to examine immune response in relation to AD and SCC expression subtypes. Expression of immune cell populations and other immune related genes, including CD274 molecule gene (CD274) (programmed death ligand 1), was investigated in the tumor microenvironment relative to the expression subtypes of the AD (terminal respiratory unit, proximal proliferative, and proximal inflammatory) and SCC (primitive, classical, secretory, and basal) subtypes.
Lung AD and SCC expression subtypes demonstrated significant differences in tumor immune landscape. The proximal proliferative subtype of AD demonstrated low immune cell expression among ADs whereas the secretory subtype showed elevated immune cell expression among SCCs. Tumor expression subtype was a better predictor of immune cell expression than CD274 (programmed death ligand 1) in SCC tumors but was a comparable predictor in AD tumors. Nonsilent mutation burden was not correlated with immune cell expression across subtypes; however, major histocompatibility complex class II gene expression was highly correlated with immune cell expression. Increased immune and major histocompatibility complex II gene expression was associated with improved survival in the terminal respiratory unit and proximal inflammatory subtypes of AD and in the primitive subtype of SCC.
Molecular expression subtypes of lung AD and SCC demonstrate key and reproducible differences in immune host response. Evaluation of tumor expression subtypes as potential biomarkers for immunotherapy should be investigated.
Uterine carcinosarcoma is an aggressive variant of endometrial carcinoma characterized by unusual histologic features including discrete malignant epithelial and mesenchymal components (carcinoma and ...sarcoma). Recent studies have confirmed a monoclonal origin, and comprehensive genomic characterizations have identified mutations such as Tp53 and Pten. However, the biological origins and specific combination of driver events underpinning uterine carcinosarcoma have remained mysterious. Here, we explored the role of the tumor suppressor Fbxw7 in endometrial cancer through defined genetic model systems. Inactivation of Fbxw7 and Pten resulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas. Surprisingly, all adenocarcinomas eventually developed into definitive uterine carcinosarcomas with carcinomatous and sarcomatous elements including heterologous differentiation, yielding a faithful genetically engineered model of this cancer type. Genomic analysis showed that most tumors spontaneously acquired Trp53 mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type. Lineage tracing provided formal genetic proof that the uterine carcinosarcoma cell of origin is an endometrial epithelial cell that subsequently undergoes a prominent epithelial–mesenchymal transition underlying the attainment of a highly invasive phenotype specifically driven by Fbxw7.
Lung squamous cell carcinoma (LSCC) currently lacks effective targeted therapies. Previous studies reported overexpression of Hedgehog (HH)-GLI signaling components in LSCC. However, they addressed ...neither the tumor heterogeneity nor the requirement for HH-GLI signaling. Here, we investigated the role of HH-GLI signaling in LSCC, and studied the therapeutic potential of HH-GLI suppression.
Gene expression datasets of two independent LSCC patient cohorts were analyzed to study the activation of HH-GLI signaling. Four human LSCC cell lines were examined for HH-GLI signaling components. Cell proliferation and apoptosis were assayed in these cells after blocking the HH-GLI pathway by lentiviral-shRNA knockdown or small-molecule inhibitors. Xenografts in immunodeficient mice were used to determine the in vivo efficacy of GLI inhibitor GANT61.
In both cohorts, activation of HH-GLI signaling was significantly associated with the classical subtype of LSCC. In cell lines, genetic knockdown of Smoothened (SMO) produced minor effects on cell survival, whereas GLI2 knockdown significantly reduced proliferation and induced extensive apoptosis. Consistently, the SMO inhibitor GDC-0449 resulted in limited cytotoxicity in LSCC cells, whereas the GLI inhibitor GANT61 was very effective. Importantly, GANT61 demonstrated specific in vivo antitumor activity in xenograft models of GLI(+) cell lines.
Our studies demonstrate an important role for GLI2 in LSCC, and suggest GLI inhibition as a novel and potent strategy to treat a subset of patients with LSCC.
Large and comprehensive genomic surveys of head and neck squamous cell carcinomas (HNSCC) are now greatly increasing our understanding of the diversity of this disease and the key genomic changes ...that drive these tumors. The results from these studies are beginning to inform the introduction of novel therapies for patients with HNSCCs. Here, we review some of the key findings from recent genomic studies of head and neck cancers, including the most comprehensive study to date from The Cancer Genome Atlas Network.
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