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The adult mouse mammary epithelium contains self-sustained cell lineages that form the inner luminal and outer basal cell layers, with stem and progenitor cells contributing to its proliferative and regenerative potential. A key issue in breast cancer biology is the effect of genomic lesions in specific mammary cell lineages on tumour heterogeneity and progression. The impact of transforming events on fate conversion in cancer cells of origin and thus their contribution to tumour heterogeneity remains largely elusive. Using in situ genetic lineage tracing and limiting dilution transplantation, we have unravelled the potential of PIK3CAH1047R, one of the most frequent mutations occurring in human breast cancer, to induce multipotency during tumorigenesis in the mammary gland. Here we show that expression of PIK3CAH1047R in lineage-committed basal Lgr5-positive and luminal keratin-8-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multi-lineage mammary tumours. Moreover, we show that the tumour cell of origin influences the frequency of malignant mammary tumours. Our results define a key effect of PIK3CAH1047R on mammary cell fate in the pre-neoplastic mammary gland and show that the cell of origin of PIK3CAH1047R tumours dictates their malignancy, thus revealing a mechanism underlying tumour heterogeneity and aggressiveness. [ABSTRACT FROM AUTHOR]

Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes. PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers. The cellular origin and the mechanisms leading to PIK3CA-induced tumour heterogeneity remain unknown. Here we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and the impact of mutations in this gene on tumour heterogeneity. Surprisingly, oncogenic Pik3caH1047R mutant expression at physiological levels in basal cells using keratin (K)5-CreERT2 mice induced the formation of luminal oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive tumours, while its expression in luminal cells using K8-CReERT2 mice gave rise to luminal ER+PR+ tumours or basal-like ER−PR− tumours. Concomitant deletion of p53 and expression of Pik3caH1047R accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3caH1047R in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that underwent cell fate transition upon Pik3caH1047R expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3caH1047R expression in basal and luminal cells, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3caH1047R activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation. [ABSTRACT FROM AUTHOR]

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer. [ABSTRACT FROM AUTHOR]

Cancer genome sequencing has revealed considerable variation in somatic mutation rates across the human genome, with mutation rates elevated in heterochromatic late replicating regions and reduced in early replicating euchromatin. Multiple mechanisms have been suggested to underlie this, but the actual cause is unknown. Here we identify variable DNA mismatch repair (MMR) as the basis of this variation. Analysing ∼17 million single-nucleotide variants from the genomes of 652 tumours, we show that regional autosomal mutation rates at megabase resolution are largely stable across cancer types, with differences related to changes in replication timing and gene expression. However, mutations arising after the inactivation of MMR are no longer enriched in late replicating heterochromatin relative to early replicating euchromatin. Thus, differential DNA repair and not differential mutation supply is the primary cause of the large-scale regional mutation rate variation across the human genome. [ABSTRACT FROM AUTHOR]

Crypt stem cells represent the cells of origin for intestinal neoplasia. Both mouse and human intestinal stem cells can be cultured in medium containing the stem-cell-niche factors WNT, R-spondin, epidermal growth factor (EGF) and noggin over long time periods as epithelial organoids that remain genetically and phenotypically stable. Here we utilize CRISPR/Cas9 technology for targeted gene modification of four of the most commonly mutated colorectal cancer genes (APC, P53 (also known as TP53), KRAS and SMAD4) in cultured human intestinal stem cells. Mutant organoids can be selected by removing individual growth factors from the culture medium. Quadruple mutants grow independently of all stem-cell-niche factors and tolerate the presence of the P53 stabilizer nutlin-3. Upon xenotransplantation into mice, quadruple mutants grow as tumours with features of invasive carcinoma. Finally, combined loss of APC and P53 is sufficient for the appearance of extensive aneuploidy, a hallmark of tumour progression. [ABSTRACT FROM AUTHOR]

Whereas cancers grow within host tissues and evade host immunity through immune-editing and immunosuppression, tumours are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumours are reliably rejected by host T cells, even when the tumour and host share the same major histocompatibility complex alleles, the most potent determinants of transplant rejection. How such tumour-eradicating immunity is initiated remains unknown, although elucidating this process could provide the basis for inducing similar responses against naturally arising tumours. Here we find that allogeneic tumour rejection is initiated in mice by naturally occurring tumour-binding IgG antibodies, which enable dendritic cells (DCs) to internalize tumour antigens and subsequently activate tumour-reactive T cells. We exploited this mechanism to treat autologous and autochthonous tumours successfully. Either systemic administration of DCs loaded with allogeneic-IgG-coated tumour cells or intratumoral injection of allogeneic IgG in combination with DC stimuli induced potent T-cell-mediated antitumour immune responses, resulting in tumour eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumours and metastases, as well as the injected primary tumours. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumour antigens after culture with allogeneic-IgG-loaded DCs, recapitulating our findings in mice. These results reveal that tumour-binding allogeneic IgG can induce powerful antitumour immunity that can be exploited for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Large-scale genomic studies have shown that half of epithelial ovarian cancers (EOCs) have alterations in genes regulating homologous recombination (HR) repair. Loss of HR accounts for the genomic instability of EOCs and for their cellular hyper-dependence on alternative poly-ADP ribose polymerase (PARP)-mediated DNA repair mechanisms. Previous studies have implicated the DNA polymerase θ (Polθ also known as POLQ, encoded by POLQ) in a pathway required for the repair of DNA double-strand breaks, referred to as the error-prone microhomology-mediated end-joining (MMEJ) pathway. Whether Polθ interacts with canonical DNA repair pathways to prevent genomic instability remains unknown. Here we report an inverse correlation between HR activity and Polθ expression in EOCs. Knockdown of Polθ in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, while knockdown of Polθ in HR-deficient EOCs enhances cell death. Consistent with these results, genetic inactivation of an HR gene (Fancd2) and Polq in mice results in embryonic lethality. Moreover, Polθ contains RAD51 binding motifs and it blocks RAD51-mediated recombination. Our results reveal a synthetic lethal relationship between the HR pathway and Polθ-mediated repair in EOCs, and identify Polθ as a novel druggable target for cancer therapy. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is characterized by elevated glycogen levels and fat deposition. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs) secondary to von Hippel-Lindau (VHL) mutations that occur in over 90% of ccRCC tumours. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo-1, SET domain containing 2 and BRCA1-associated protein-1, among others), indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin, thereby inhibiting a potential Warburg effect. Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours. [ABSTRACT FROM AUTHOR]

KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. Conversely, potent inhibition of active, phosphorylated MEK is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in superior efficacy in this genotype with GDC-0973 (also known as cobimetinib), a MEK inhibitor currently in phase III clinical trials. Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK. These inhibitors are currently being evaluated in clinical trials to determine whether improvements in therapeutic index within KRAS versus BRAF preclinical models translate to improved clinical responses in patients. [ABSTRACT FROM AUTHOR]

Genomic analysis provides insights into the role of copy number variation in disease, but most methods are not designed to resolve mixed populations of cells. In tumours, where genetic heterogeneity is common, very important information may be lost that would be useful for reconstructing evolutionary history. Here we show that with flow-sorted nuclei, whole genome amplification and next generation sequencing we can accurately quantify genomic copy number within an individual nucleus. We apply single-nucleus sequencing to investigate tumour population structure and evolution in two human breast cancer cases. Analysis of 100 single cells from a polygenomic tumour revealed three distinct clonal subpopulations that probably represent sequential clonal expansions. Additional analysis of 100 single cells from a monogenomic primary tumour and its liver metastasis indicated that a single clonal expansion formed the primary tumour and seeded the metastasis. In both primary tumours, we also identified an unexpectedly abundant subpopulation of genetically diverse 'pseudodiploid' cells that do not travel to the metastatic site. In contrast to gradual models of tumour progression, our data indicate that tumours grow by punctuated clonal expansions with few persistent intermediates. [ABSTRACT FROM AUTHOR]

Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms. [ABSTRACT FROM AUTHOR]

Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in several solid tumour types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to target of rapamycin (TOR) signalling. Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR (also known as FRAP1) signalling in human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus, genomic and genetic, biological, functional and biochemical data in yeast and humans establishes GOLPH3 as a new oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to rapamycin, a cancer drug in clinical use. [ABSTRACT FROM AUTHOR]

Dietary restriction delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction remain unknown. Here we show that certain human cancer cell lines, when grown as tumour xenografts in mice, are highly sensitive to the anti-growth effects of dietary restriction, whereas others are resistant. Cancer cells that form dietary-restriction-resistant tumours carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway and in culture proliferate in the absence of insulin or insulin-like growth factor 1. Substitution of an activated mutant allele of PI3K with wild-type PI3K in otherwise isogenic cancer cells, or the restoration of PTEN expression in a PTEN-null cancer cell line, is sufficient to convert a dietary-restriction-resistant tumour into one that is dietary-restriction-sensitive. Dietary restriction does not affect a PTEN-null mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling. Thus, the PI3K pathway is an important determinant of the sensitivity of tumours to dietary restriction, and activating mutations in the pathway may influence the response of cancers to dietary restriction-mimetic therapies. [ABSTRACT FROM AUTHOR]

The ubiquitin system is a network of proteins dedicated to the ubiquitylation of cellular targets and the subsequent control of numerous cellular functions. The deregulation of components of this elaborate network leads to human pathogenesis, including the development of many types of tumour. Alterations in the ubiquitin system that occur during the initiation and progression of cancer are now being uncovered, and this knowledge is starting to be exploited for both molecular diagnostics and the development of novel strategies to combat cancer. [ABSTRACT FROM AUTHOR]

Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the neoplastic transformation process. Here we engineered lymphoma-prone mice with chromosomal instability to assess the usefulness of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Along with targeted re-sequencing, our comparative oncogenomic studies identified FBXW7 and PTEN to be commonly deleted both in murine lymphomas and in human T-cell acute lymphoblastic leukaemia/lymphoma (T-ALL). The murine cancers acquire widespread recurrent amplifications and deletions targeting loci syntenic to those not only in human T-ALL but also in diverse human haematopoietic, mesenchymal and epithelial tumours. These results indicate that murine and human tumours experience common biological processes driven by orthologous genetic events in their malignant evolution. The highly concordant nature of genomic events encourages the use of genomically unstable murine cancer models in the discovery of biological driver events in the human oncogenome. [ABSTRACT FROM AUTHOR]

Details a study which examined the structural basis for the relationship between protein of the von Hippel-Lindau tumor (pVHL) suppressor gene and hypoxia-inducible factor-1 (HIF-1) transcriptional complex. Physiological significance of pVHL and HIF-1; Mechanism of action of pVHL and HIF-1; Methodology and results.

Describes the genetic factors which increase the predisposition of mice to tumorigenesis. Description of the generation and characterization of specific genes that retain normal function; Contrast to mouse embryo fibroblasts.

Demonstrates that mice do not show a significant predisposition to spontaneous melanoma tumor formation after the loss of a genetic factor. Proliferation of embryo fibroblast; Mild phenotype implying the loss of genetic material.

Examines the role of common genetic variation in determining the range of individual's cancer susceptibility within the population using information from the Human Genome Project. Factors that can influence the evolution of a cancer; Development in the concept of genetic role in tumor formation; Examples of genetic events outside the cancer pathway; Probability of cancer based on family history.

Investigates K-ras gene mutations in human tumor using a gene targeting procedure to create a mouse strains carrying oncogenic alleles of K-ras. Effects of K-ras gene mutations; Evolution of lung tumors; Evidence for recombination of the latent allele in tumors.

Shows that the deacetylation of the tumor suppressor and transcriptional factor p53 is mediated by a histone deacetylase-1 (HDAC1)-containing complex. Purification of a p53 target protein which has been identified as a component of the NuRD complex; Results, which show that deacetylation and functional interactions by the PID/MTA2-associated NuRD complex may represent an important pathway to regulate p53 function.

Presents a study in which a mouse embryonic stem cell system is used to examine the role of DNA damage on the formation of translocations, which are associated with numerous tumors. Finding that shows that two chromosomal double-strand breaks (DSB) on different chromosomes are sufficient to promote frequent reciprocal translocations; Contrast with interchromosomal repair of a single DSB in an analogous system in which translocations are not recovered; How the presence of two DSBs can alter the spectrum of repair products recovered.

Examines the molecular heterogeneity in the tumors of diffuse large B-cell lymphoma (DLBCL) patients. How researchers conducted a systematic characterization of gene expression in B-cell malignancies; Identification of two molecularly distinct forms of DLBCL; Observation that patients with germinal center B-like DLBCL had better survival rates than patients with activated B-like DLBCL; Conclusions.

The article discusses treatment for patients affected with advanced melanoma. Topics discussed include approval for the treatments by the U.S. Food and Drug Administration, targeted therapies for the patients, and treatment for BRAF-Mutant melanoma. Also discussed are mutations of the tumour cells and targeted immunotherapy.

Presents research which found that the proto-oncogene product PML induces expression of several proteins in an MHC-class I-negative, recurrent tumor. Role of the major histocompatibility complex (MHC) in immune responses; Expression of genes contained in the MHC; Repression of genes in virus-transformed cell lines and tumors; PML regulating MHC expression in fibroblasts; Impact of PML malfunction on immune reaction.

Presents research which showed that both p27 nullizygous and p27 heterozygous mice are predisposed to tumors in multiple tissues. Why p27Kip is a candidate human tumor-suppressor protein; Meaning of low levels of the p27 protein; Molecular analyses of mice tumors; p27 being a multiple-tissue tumor suppressor in mice; p27 being haplo-insufficient for tumor suppression.

Presents research which reported that the loss of E-cadherin expression coincides with the transition from adenoma to invasive carcinoma in a transgenic mouse model of pancreatic beta-cell carcinogenesis. How malignant tumors develop; What E-cadherin is; E-cadherin's role in carcinogenesis; Effects of reestablishing functional cadherin complex in tumor cell lines; Effects of loss of E-cadherin-mediated cell adhesion.

The article examines how the basic questions about drug resistance, tumour spread, and the role of normal tissue continue to be unanswered despite the improvement of cancer therapies. Topics covered include how researchers are studying the cancer genome to come up with new methods for designing anti-cancer drugs and how a better understanding of the genetic diversity of tumour cells could help researchers to work out how to deal with drug resistance.

The article the need for genomic data related to breast cancer generated by technological innovations to be used to inform patient care. Particular attention is given to the collection and analysis of big data on tumors and patterns of mutations as the author examines how this knowledge is transferred to clinical purposes.

The article discusses how the huge amount of data from cancer research and treatment are providing new insights on the disease in 2015. Topics covered include how the genome of a tumour can be sequenced to determine its likelihood of responding to a specific drug and the development of the Bionimbus cloud-based, open source platform for sharing and analysing genomic data from the Cancer Genome Atlas.

The article focuses on a study by Charles Swanton at Cancer Research UK's London Research Institute and colleagues which analyses the diversity of a single tumour with distinct genetic mutations by reconstructing the four kidney cancers evolution that provide implications for cancer-genome studies.

The article discusses a study which examines the association of tumour stem cells on the emergence of endothelial cells which contribute to blood vessels in glioblastoma. Findings of the study reveal that the occurrence of endothelial cells is triggered by the tumour stem cells. It indicates that these endothelial cells carry genetic abnormalities which are found in the tumour cells themselves.

The article discusses cancer-genome screening projects like the International Cancer Genome Consortium (ICGC) that want to simplify management of human gene-sequencing data that are available in massive amounts. The ICGC will sequence full genomes of numerous tumor samples, but is focusing first on sequencing the exome and its exons that code for proteins within genomes.

The article discusses personalized genetic medicine for cancer patients. Cancer centers including one at Massachusetts General Hospital in Boston, are making preparations to screen all patients for genetic mutations associated with disease and scientists are using the genomes of patient's tumors to decide on the most beneficial treatment option. Topics include studies showing the shortcomings of single gene approaches due to the complexity of mutations and their genetic pathways, the sequencing of an entire genome of a tumor from lung a cancer patient by Marco Marra and colleagues at the British Columbia Cancer Agency's genome center, and its impact on the patient's treatment and recovery.

The article discusses research that identified the protein PHD2 as a key regulator of oxygen supply to tumours and posits that it could be involved in the way blood-vessel networks are shaped. This enables the understanding of tumour maintenance, which depends on a supply of oxygen and on removal of metabolic waste by the blood. When this can't be supplied by the blood-vessels, tumour cells invade surrounding tissue and begin to metastasize. The researchers genetically engineered mice lacking one copy of the gene and evaluated the resultant vascular morphology of implanted tumours.

A correction is offered to the article "Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment," by several authors, including E. M. Alexandrova, A. R. Yallowitz, D. Li, in volume 523 during 2015.

TheRb gene is known to put brakes on cell division, controlling cell numbers and thereby helping to prevent tumours from forming. Mutations that inactivate this 'tumour suppressor' gene are often seen in human cancers. One way in which researchers try to learn more about how the inactivation of particular genes contributes to cancer development is to mutate them in mice, and see what happens. But a problem with such mouse models is that they generally involve mutating the gene of interest in the germline, the tissue that produces eggs and sperm. Compensation could occur directly, if the back-up genes are simply upregulated or downregulated as appropriate as a direct result of Rb loss. Indirect mechanisms come into play abundantly during development of tumors, a distinct chromatin configuration is often fixed during development in a cell-type-specific fashion, and thereby imposed on all daughter cells.

An interview with oncologist Victor Velculescu is presented. When asked what circulating tumor DNA (ctDNA) was and how it could help in cancer therapeutics, he said ctDNA was fragments of DNA that escaped from tumors into the bloodstream which provides genetic clues to detect and analyse the cancer. He commented on how ctDNA could help in early detection of disease recurrence and how it is complementary in the analysis of circulating tumor cells.

Discusses research which showed that control mechanisms that ensure proper separation of chromosomes during cell division can be defective in colorectal cancer cells. Complex development of cancer tumors; Mutations and tumor cell proliferation; Research by Cahill et al in this issue; Impact of mutation rate; Role of tumor cell mutability; Aneuploidy; Role of proteins; Aneuploid colorectal tumor cell lines; Future research.

Reports on the role of the retinoblastoma tumor-suppressor protein Rb in regulating the cell cycle and the genesis of a wide variety of human tumors. Previous belief that Rb restrained cell proliferation in vertebrate cells by inhibiting factors needed for the transcription of specific genes involved in promoting DNA replication; Rb's repression of genes transcribed by Pol III.

The article reports on the findings of the study by researchers led by Mikala Egeblad which show that the response of tumour to chemotherapy is shaped through the interactions between the tumour and microenvironment.

The article cites a study which found a link between a mutation in a protein and a development of a type of tumour. A team led by Jared Rutter determined the function of SDH5, a structural protein of the enzyme succinate dehydrogenase (SDH). It is noted that the neuroendocrine tumour called paraganglioma is attributed to human mutations that inhibit SDH activity, thus signifying a metabolic cause of the tumour.

The article discusses genetic studies of human tumors that suggest solid cancers have different genetic mutations, though scientists have been unable to work out which mutations trigger disease. Topics include an overview of research by Largaespada and colleagues who engineered mice that contain a jumping gene called a transposon which can be switched on or off in specific tissues. The team used the approach to identify potential genes involved in human colorectal cancer.

Arising from: Tomlins et al. 448, 595–599 (2007); Tomlins et al. replyThe first recurrent translocation event in prostate cancer has been recently described; it results in the translocation of an ETS (E26 transformation specific) transcription factor (ERG or ETV1) to the TMPRSS2 promoter region, which contains androgen responsive elements. The TMPRSS2:ERG genetic rearrangement has been reported to occur in approximately 40% of primary prostate tumours (ETV1 genetic rearrangements occur at a much lower frequency), and it results in the aberrant androgen-regulated expression of ERG. Tomlins et al. concluded that ETS genetic rearrangements are sufficient to initiate prostate neoplasia. However, here we show that ETS genetic rearrangements may in fact represent progression events rather than initiation events in prostate tumorigenesis. To this end, we demonstrate that the prostate-specific overexpression of ERG does not initiate prostate tumorigenesis. [ABSTRACT FROM AUTHOR]

The article offers information on the study conducted to determine the possible therapeutic role of Down syndrome in cancer prevention. Geneticists at the Johns Hopkins University School of Medicine in Baltimore, Maryland conducted an epidemiological study to prove the claim that person with Down syndrome are less likely to develop solid tumours. The result of the study showed that high proportion of intestinal cancers reduced tumour formation by half. The study is important in developing pharmacological approaches to help people with Down syndrome to live even fuller.

This article focuses on the role oncogenes and tumor-suppressor genes play in tumor formation and tumor suppression. Viewing cancer as a disease of cell differentiation rather than multiplication, allows a redefinition of the role of onco genes and tumour-suppressor genes. It is often said that the growth of tumours is determined by the balance between the activity of oncogenes and that of tumour-suppressor genes. But the nature of this "balance" is not at all clear. It is really being proposed that the cell in some way titrates the cumulative effect of one set of genes against the cumulative effect of another. In this apparently simple notion of "balance" there is ample room for complexity. But, however complex the ultimate phenotype of a malignant cell might be, it would reduce confusion if it could be agreed that cancer, in the first instance, is not a disease of cell multiplication, but a disease of differentiation.

Discusses the field of tumor virology and its history. Excitement caused by the field early in the 20th century; Its fall into disrepute; Its renaissance in the 1950s; Discussion of class I & class II RNA tumor viruses; Oncogene concept of tumor virology; Outlook for tumor virology.

Discusses the article in the February 1995 issue of `Nature Medicine' periodical on the possible dynamic process of the dormancy of metases associated with primary tumors.