The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.

Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal

Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

/pdf/cancer-genome-landscapes-qmge4i5y2h.pdf

Cancer Genome Landscapes

Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.

https://science.sciencemag.org/content/sci/early/2015/03/11/science.aaa1348.full.pdf

Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

Comprehensive molecular portraits of human breast tumours

Immune checkpoint inhibition represents a major recent breakthrough in the treatment of malignant diseases including breast cancer. Blocking the programmed death receptor-1 (PD-1) and its ligand, PD-L1, has shown impressive antitumor activity and may lead to durable long-term disease control, especially in the triple-negative subtypes of breast cancer (TNBC). Although immune checkpoint blockade is generally well tolerated, specific immune-related adverse events (irAEs) may occur. This review summarizes the clinical efficacy, perspectives, and future challenges of using PD-1/PD-L1-directed antibodies in the treatment of breast cancer.

/pdf/pd-1-and-pd-l1-immune-checkpoint-blockade-to-treat-breast-2u575m0pog.pdf

PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer

Human liver alkaline phosphatase [ortho-phosphoric monoester phosphohydrolase (alkaline optimum), EC 3.1.3.1] was purified, and some of its physical and chemical properties were examined and compared to those of human placental alkaline phosphatase. The results indicated a different peptide structure for each, based upon HB2-terminal residue sequence, two-dimensional tryptic peptide maps, and different amino acid compositions. These data are interpreted to indicate that the enzymes are synthesized by different structural genes. Other molecular properties differentiating the two enzymes were a higher apparent molecular weight for the liver enzyme from sodium dodecyl sulfate gel electrophoresis, a higher S20,w value, different carbohydrate content, and a different isoelectric point. The immunochemical specificity of each enzyme was not affected by removal of sialic acid groups. Both enzymes are similar in that they are dimers of equal molecular weight subunits, and are probably homodimers.

Structural evidence that human liver and placental alkaline phosphatase isoenzymes are coded by different genes.

Acetaminophen is frequently administered to infants and children for its antipyretic and analgesic properties. Oral administration is the route of choice in daily practice. In some circumstances this is impractical. Rectal administration of acetaminophen is an alternative route. This study measures plasma concentrations following rectal administration of acetaminophen 20 mg.kg-1 (10% Infants' Tylenol Drops, McNeil Consumer Product Co., diluted with an equal volume of sterile water) in five preterm neonates. Serial arterial blood samples were obtained at 0, 15, 30, 60, 120, and 240 min. Pharmacokinetic parameters were (mean +/- SD): Cmax (maximum plasma concentration) of 8.38 +/- 3.92 micrograms.ml-1 and Tmax (time to reach maximum plasma concentration) of 78.0 +/- 40.2 min. Our results show that 20 mg.kg-1 of acetaminophen rectally results in low plasma levels in preterm neonates.

Plasma concentrations after rectal administration of acetaminophen in preterm neonates

An alkaline phosphatase immunochemically similar to placental alkaline phosphatase (EC 3.1.3.1) was purified from liver metastases of a giant-cell carcinoma of the lung. Some properties of its physical and chemical structure were determined and compared to those of purified placental alkaline phosphatase. The purified tumor phosphatase and the placental phosphatase were similar with regard to the following properties: (1) NH2-terminal sequence, (2) peptide map, (3) subunit molecular weight, and (4) isoelectric point. The physical properties and NH2-terminal sequence of alkaline phosphatase isoenzyme of liver differed from the placental and the tumor enzyme. The data from the present study strongly support the hypothesis that the tumor and the placental alkaline phosphatases are products of the same gene.

Structural Comparison of Ectopic and Normal Placental Alkaline Phosphatase

Iron participates in a range of reactions that are necessary for cell viability and cell proliferation. Iron is an essential component in DNA synthesis and in respiratory and oxidative metabolism. These functions relate to the properties of unremitting proliferation and a more anaerobic metabolism, that may contribute to a selective advantage of neoplastic cells over nonneoplastic cells. Clinical correlations have been made linking cellular iron content to the development of cancer in humans. The clinical entities include disease states in which there is abnormal accumulation of iron as part of the disease process, and cases in which neoplasms have developed as a result of administered iron preparations. The molecular mechanisms regulating cellular iron incorporation and the iron-dependent formation of reactive oxygen intermediates that can cause cell injury have been recently elucidated and provide a basis for better understanding the relationship of these processes to neoplastic development.

Iron in cancer.

Background: A significant number of squamous cell carcinomas of the head and neck (SCCHN) resist radiation treatment, the most common form of adjuvant therapy for this disease. The presence of a mutant form of the tumor suppressor gene p53 has been correlated with disruption of programmed cell death (apoptosis) and reduced cell cycle arrest, resulting in increased radiation resistance and survival. Methods and Results: We introduced by means of an adenoviral vector a functional p53 gene into a radiation-resistant SCCHN cell line that harbors mutant p53 . Replacement of wild-type p53 restored the G 1 block and apoptosis in these cells in vitro. Moreover, introduction of wild-type p53 sensitized SCCHN-induced mouse xenografts to radiotherapy in vivo. Conclusion: The combination of p53 replacement gene therapy with conventional radiotherapy may treat SCCHN more effectively. Arch Otolaryngol Head Neck Surg. 1997;123:507-512

Restoration of the G1 Checkpoint and the Apoptotic Pathway Mediated by Wild-type p53 Sensitizes Squamous Cell Carcinoma of the Head and Neck to Radiotherapy

Howard H. Sussman

Papers

Structural evidence that human liver and placental alkaline phosphatase isoenzymes are coded by different genes.

Plasma concentrations after rectal administration of acetaminophen in preterm neonates

Structural Comparison of Ectopic and Normal Placental Alkaline Phosphatase

Iron in cancer.

Restoration of the G1 Checkpoint and the Apoptotic Pathway Mediated by Wild-type p53 Sensitizes Squamous Cell Carcinoma of the Head and Neck to Radiotherapy