Table of contents : 

Epidemiology Aetiology Pathogenesis Metastases Oncogenomics Morphology  Symptoms & signs Oncological emergencies Laboratory examinations tumor staging tumor grading

Experimental animal models Prevention Therapy  Prognosis Spontaneous tumour regression Specific organ cancers  Web resources Associations  Journals  Centers / Institutes / Organizations  News  Bibliography

• neoplasia : the progressive multiplication of cells under conditions that would not elicit, or would cause cessation of, multiplication of normal cells; the formation of a neoplasm / tumor : any new and abnormal growth; specifically a new growth of tissue in which the growth is uncontrolled and progressive
• Epidemiology
• Aetiology
• Pathogenesis
• Genetic bases (oncogenomics) : new mutations create subclones with selective advantages
• proto-oncogenes (c- : from cellular genome ; v- : from retroviral genome) : mutation in only one allele is enough for carcinogenesis
• growth factors
• p28^{c-simian sarcoma (Sis)} / PDGF-B [Simian sarcoma virus]
• p27^int2 / FGF3
• KGF / HST
• int1 / WNT1
• int3 / NOTCH1
• receptors for growth factors
• p170 HER1 / avian erythroblastosis 1 (ErbB1) / EGFR
• p185 HER2 / ErbB2 / Neu
• p170 c-FMS / CSF-1R
• p150 FLG / c-FMS2 / FGFR1
• K-SAM / p130 BEK / FGFR2
• p140 TRKA/C
• p250 c-ROS1 / v-ros UR2 sarcoma virus oncogene homolog 1 (avian)
• p145 c-KIT / CD117. Gain-of-function mutations in c-Kit have been described in 86% of erythroleukaemia and in 17-46% of other AML subtypes, especially those carrying core binding fusion genes, where they predict a worse outcome^ref. The c-Kit gene contains 21 exons, and 2 alternative splicing sites have been described. One of these alternative splicing sites is located at the 3 end of exon 9 and results in the expression of two isoforms, designated GNNK^- (Kit) and GNNK⁺ (KitA). The 2 isoforms have different biological activities and the GNNK^- isoform is the main transcript in several human malignant tumours^ref. The oncogenic potential of the two c-Kit isoforms is still a matter of debate: Caruana et al.^ref did not observe difference in ligand-binding affinity between the two isoforms. On the other hand, other authors demonstrated a more rapid internalization and a ubiquitin-mediated degradation of the GNNK^- form^ref
• avian myelocytomatous leukemia (MIL)
• p120 RET / MEN2
• p195 c-MET / HGF-R
• MAS1
• EGFRs are frequently upregulated in breast cancers and glioblastomas : although gene amplification is one mechanism by which this might occur, oncongenic mutations in the CDC42 GTPase that cause it to stay in the active GTP-bound form (sequestering c-CBL and preventing it from degrading EGFR) might well constitute another^ref
• PPARb/d activation promotes growth and development of intestinal adenomas by activating anti-apoptotic pathways in intestinal epithelial cells^ref. Agonists in the later stages of development as drugs to treat dyslipidemia syndromes, obesity and atherosclerosis should be administered with caution, as they might increase the risk of cancer in individuals with familial adenomatous poliposis (FAP)
• PPARg signalling promotes the formation of mammary carcinomas in mice, but only in animals that are genetically predisposed to developing these tumours (e.g. mice that express the polyoma virus middle T antigen (PyV-MT))^ref. Activators of this receptor inhibit tumour development in rat models of mammary carcinoma, indicating that stimulating PPARg signalling might be a useful anticancer treatment. The WNT target geenes cyclin D1 and c-Myc are upregulated in mice expressing PyV-MT and constitutively active PPARg compared to mice expressing PyV-MT only. Increased expression wis also seen for b-catenin, a component of the Wnt pathway, and for the Wnt receptor frizzled homologue 4, whereas Wnt5a, a negative regulator of Wnt signalling, was downregulated. However, PPARg activators can suppress proliferation even in cells in which the receptor is not expressed and can cause increased tumour development in mouse models of colon cancer
• sonic hedgehog (SHH) and its receptor PTCH are expressed in 81% of gut-derived tumour cell lines (from esophageal, stomach, biliary, and pancreatic tumours).
• intracellular transductors :
• G-proteins and their regulators :
• monomeric G-proteins :
• rat sarcoma (Ras) :
• 1964 : retroviral isolates were identified (also in 1967, 1974, and 1978)
• 1973 : Ha-MSV and Ki-MSV were found to contain rat cellular sequences
• 1979 : Ha-MSV cloned and p21 v-Ras was found to bind GTP
• 1981 : Ki-MSV was cloned
• 1982 : human oncogenes were found to be related to v-ras oncogenes. The first human transforming gens was cloned. The human HRAS oncogene was found to be activated by point mutation
• 1983 : neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) was identified. p21 RAS was found to be a GTPase. Ras oncogenes were identified in carcinogen-induced animal tumours. RAS was found to co-operate with MYC and E1A to transform primary cells
• 1984 : RAS was found to be activated by mitogenic factors
• 1987 : RAS-GAP was identified. RAS was shown to be frequently mutated in colon tumours. Ras transgenic mice were generated
• 1989 : RAS proteins were shown to be farnesylated
• 1990 : RAS-GEFs were identified
• 1993 : RAS was shown to interact with RAF
• 1994 : PI3K was shown to be a RAS effector
• 1995 : farnesyltransferase inhibitors (FTI) were found to block Ras-induced tumours in mice
During the 1970s, retroviral oncogenes were generically known as v-src. The realization that these oncogenes were distinct molecular entities led to the proposal that each oncogene should be named with a 3-letter acronym. In the case of Harvey and Kirsten strains, the chosen acronym was ras for rat sarcoma. The finding that v-h-ras and v-k-ras were derived from diffefret cellular loci led, for a brief period of time, to the use of the acronyms v-has for the oncongene present in Harvey-MSV, v-bas for the oncogene of BALB-MSV and v-kis for the Kirsten-MSV oncogene. Their cellular homologues c-has and c-bas corresponded to v-h-ras-1 (HRAS1 in humans) and c-kis to v-k-ras-2 (KRAS2 in humans). This nomenclature has not been used since 1984. Rodents and primates have 2 additional loci that are related to v-ras oncogenes, designated as Hras2 and Kras1 (HRAS2 and KRAS1 in humans). These loci represent processed pseudogenes. For simplicity, we will use the terms Hras (HRAS in humans) for Hras1 and Kras (KRAS in humans) for Kras2.
One of the key issues raised by mutational activation of RAS oncogenes in human tumours was whether they have an initiating - or at least causative - role in tumour development, or whether they are merely activated as a consequence of the genetic instability of malignant cells. As early as 1983, mutated Ras oncogenes were identified in experimental tumours of rodents that were exposed to chemical or physical carcinogens^{ref1, ref2, ref3}. Hras mutations were identified in benign papillomas of mice treateed with the 7,12-dimethylbenz[a]anthracene (DMBA) skin carcinogenesis protocol^ref. Evidence that Ras genes can be involved in the initiation of carcinogenesis was obtainedin 1985 when it was shown that Hras oncogenes that were activated in chemically induced mammary carcinomas od rats were activated by the type of mutations that is known to be caused by the initiating carcinogen^ref. Similar results were subsequently obtained using mouse hepatomas induced by various carcinogens of known mutagenic spectra^ref. The generation of tumours in mice harbouring Ras transgenes has leant further proof to the oncogenic properties of these genes in vivo. In 1987, several groups reported the induction of tumours by Ras oncogenes expressed under the control of various tissue-specific promoters.
• transgenic mice :
• MMTV-v-Hras : oncogenic Hras expression under the MMTV promoter) : mammary tumours, hyperplasia of the harderian gland and other malignancies^ref
• elastase-I-Hras (oncogenic Hras expression under the elastase-I-regulating elements) : rapid development (2 days) of neoplasia in the fetal exocrine pancreas^ref
• Tyr (Tet)-ras (oncogenic Hras under the control of the tyrosinase promoter and tetracycline regulatory sequences) : melanoma development; tumour regression after removal of activator^ref
• CCSP (Tet)-Kras G12D (Tet-regulated Kras oncogene drive by the Clara cell-secretory protein promoter) : adenocarcinomas of the lung and apoptotic regression after removal of inductor^ref
• gene-targeted mice
• Kras^-/- (Kras knockout) : embryonic lethality (E12-E14); fetal liver defects and anaemia^{ref1, ref2}
• Nras^-/- (Nras knockout) : viable, defective immune response and T-cell function^{ref1, ref2}
• Hras^-/- (Hras knockout) : no obvious phenotype; decreased tumour formation after carcinogenic treatments^{ref1, ref2}
• Kras^LA (oncogenic Kras G12D after spontaneous recombination) : "spontaneous" lung tumours, thymic lymphomas and skin papillomas^ref
• LSL-Kras G12D (Cre-inducible form of an oncogenic Kras knock-in) : tumours after activation of the ras oncogenic form with Cre recombinase^ref
Direct proof for the requirement of continuous Ras expression for tumour maintenance has been obtained using mice carrying inducible Ras trangenes^{ref1, ref2}. The advent of gene targeting in the embryonic stem cells has allowed the generation of more physiological tumour models in recent years^{ref1, ref2}. For instance, a conditional mutation in the endogenous mouse Kras locus that can be activated by ectopic expression of a Cre recombinase has bee engineered^ref. Infection of these mice with adenoCre vectors results in the efficient induction of lung tumours. Although this model does not completely mimics human tumorigenesis - for example, Kras becomes activated in a large number of cell - it represents a significant improvement in our quest for faithfully reproduce the human disease in a laboratory model.
• v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homolog (KRAS2) [Kirsten murine sarcoma virus]
Ras and Akt cooperate to alter the rate of recruitment to polysomes and synthesis of specific mRNAs : their oncogenic effects could, largely, be through translation, rather than transcription^ref.
N-ras and K-ras are mutated in many cancers, including 45% of multiple myelomas and > 50% of CMML cases. Constitutive activation of ras can mimic chronic stimulation by the corresponding lineage-specific growth factor.
Web resources : The Ras oncogene product by Frank R. Gorga, at Bridgewater State College
• heterotrimeric G-proteins
• Gsp (Gas)
• Gip (Gai2)
• Gep (Ga12)
• cyclins
• cyclin D1 (CCND1) / B-cell lymphoma 1 (BCL1) / Prad1 transcriptional activity is independent from CDK4 function and is mediated through C/EBPb
• cyclin D2 (CCND2)
• cyclin D3 (CCND3)
• antiapoptotic BCL2 family members
• B-cell CLL/lymphoma 2 (BCL2) gene was initially discovered by virtue of its involvement in the t(14; 18) (q32;q21) translocation^{ref1, ref2, ref3}. This chromosomal abnormality, resulting in production of high levels of bcl-2 protein, is observed in the majority of follicular non-Hodgkin’s lymphomas (NHLs) and in about 20% of diffuse large B-cell lymphomas^{ref1, ref2, ref3, ref4}. However, the expression of bcl-2 protein is not restricted to B-cell lymphomas bearing the t( 14; 18) translocation^ref. Indeed, immunohistochemical studies have shown that, beside follicular lymphomas^{ref1, ref2}, a broad spectrum of lymphoid malignancies including chronic lymphocytic leukemia, plasma cell dyscrasia, diffuse large B- and T-cell lymphomas^ref, as well as non-lymphoid tumors of lung^ref, breast (Nathan B, Anbazhagan R, Dyer M: Expression of bcl-2 like immunoreactivity in breast cancer. Breast 2:134, 1993),  prostate^ref or liver origin^ref, also express the bcl-2 protein. Finally, the bcl-2 protein is also detected in a number of normal tissues, including B lymphocytes of the mantle zone and normal T cell^{ref1, ref2}. Bcl-2 can be regarded as a member of a new category of oncogenes that is involved in cell survival, by blocking programmed cell death, also called apoptosis^ref. Deregulated bcl-2 extends the survival of some interleukin-dependent hematopoietic cell lines when deprived of growth factors^ref. In vivo, bcl-2-Ig transgenic mice express constitutively a high level of bcl-2 protein, and thus accumulate an excess of resting IgIWIgD B cells because of extended survival^ref. Thus, constitutive bcl-2 expression might cooperate with the activation of other oncogenes, such as c-myc, in a multistep development of lymphomas^ref. It has been shown that apoptosis occurs in a majority of lymphoid cells when treated by various antineoplastic agents commonly used in the treatment of NHLs^{ref1, ref2}. Recent in vitro studies on murine and human leukemia cell lines have demonstrated that, although not preventing suppression of cell proliferation, high levels of bcl-2 protein could protect the cells from undergoing apoptosis in the presence of glucocorticoids and multiple chemotherapic drugs^{ref1, ref2}. Taken together, these findings suggest that a high level of bcl-2 protein may play an important role both in lymphoma-genesis and in the development of drug resistance, in follicular, as well as in other varieties of lymphomas. This would provide support for the potential clinical value of bcl-2 protein expression in NHLs, as recently suggested in acute myeloid leukemias^ref and lung carcinoma^ref. However, only few studies have focused on the correlation between bcl-2 expression at the protein level and clinical presentation and outcome in follicular^ref or diffuse^{ref1, ref2} lymphomas. This prompted us to analyze the distribution of bcl-2 at the protein level according to histology and phenotype in 290 uniformly treated patients with intermediate or high-grade NHLs enrolled in the LNH87 protocol^ref. To assess its clinical significance and its potential prognostic value, we focused on the correlation between bcl-2 expression, clinical features, and outcome in diffuse large B-cell lymphomas, which is the most frequent and homogeneous immunohistological subgroup of the present series. bcl-2 is expressed by lymphoma cells with a high frequency regardless of histologic subgroups, and that high bcl-2 expression is correlated with B-cell phenotype. Furthermore,clinical correlations performed in the more homogeneous immunohistological group of diffuse large B-cell NHL disclose that high bcl-2 expression is correlated with extended stage of the disease and appears to be associated with a poor prognosis. Indeed, DFS and survival were significantly reduced in patients with high bcl-2 expression, although the independent effect of high bcl-2 expression, at the time of analysis, could be demonstrated only on DFS. To date, most studies of the bcl-2 gene have focused on the presence of the t(14; IS), which have been found in the majority of follicular lymphomas, and in about 20% of diffuse large cell lymphoma^{ref1, ref2, ref3, ref4}. It has been postulated, although not uncontroversially demonstrated, that the presence of a bcl-2 gene rearrangement or of the translocation t( 14; 18) seemed to be associated with shorter DFS andor failure to achieve a complete remission^{ref1, ref2, ref3, ref4}. In contrast, only a few studies have focused on the clinical relevance of bcl-2 expression at the protein level^{ref1, ref2}. In the present study, we further extend to a large group of patients previous reports showing that the bcl-2/124 monoclonal antibody provides accurate staining even on routine paraffin-embedded biopsy material^{ref1, ref2}. Using this antibody, we confirmed that high expression of bcl-2 is found in a large number (45%) of lymphomas with intermediate-or high-grade histology. The apparent discrepancy between the frequency of high expression of the protein and the bcl-2 gene rearrangement is consistent with the findings that bcl-2 protein is expressed in other hematologic malignancies such as acute^ref and chronic myelogeneous leukemia^ref, in a large variety of carcinomas from liver^ref, lung^ref, prostatic gland^ref as well as in normal tissues, independently of the t(14; 18) translocation^ref. These data strongly suggest that, beside the t(14; 18) translocation, other pathological mechanisms may increase the expression of bcl-2. As an example, upregulation of bcl-2 expression has already been reported in vitro as a consequence of Epstein-Barr virus (EBV) infection^ref or IL-10 stimulation (Levy E, Brouet JC: Interleukin-10 presents spontaneous death of germinal center B cells by induction of the bcl-2 protein. J Clin Invest 93:424, 1994). Alternatively, the transformation process may have occurred in subsets of normal B or T lymphocytes in which constitutive high levels of endogenous bcl-2 protein are present^ref. This study further confirms previous observations that most high-grade mucosa-associated lymphoid tissue (MALT) lymphomas are bcl-2 negative^ref, as the latter pattern was shown in 12 of the 14 large B-cell lymphomas of the gastrointestinal tract (data not shown). The absence of detectable bcl-2 protein in a number of intermediate- and highgrade lymphoma, especially in high-grade MALT lymphomas, might reflect a breakdown in bcl-2 gene expression at the transcriptional or the posttranscriptional level^ref. However, whatever the mechanism of deregulation of the bcl-2 gene, the finding of high expression of bcl-2 observed in a large proportion of NHLs raises the question of its clinical value and biological significance, because bcl-2 is now regarded as a member of a new category of oncogenes involved in blocking programmed cell death, thus leading to abnormal accumulation of cells^{ref1, ref2, ref3}. Our analysis, which was performed on fixed paraffin-embedded material, thus preserving morphology, easily identified 3 patterns of bcl-2 protein expression. We chose to individualize the group with virtually all tumor cells bcl-2 positive from the other 2 groups exhibiting either no or intermediate bcl-2 expression, because the labeling in the high bcl-2 expression group was homogeneous and easily distinguishable from the other 2. In addition, several recent in vitro and in vivo studies have pointed out the physiological and clinical importance of high bcl-2 expression^{ref1, ref2, ref3, ref4}. Furthermore, when comparing, in the present study, survival according to the level of bcl-2 expression, no difference was observed for the bcl-2^- and bcl-2 intermediate groups. In the present series, including patients who were all treated with the same induction regimen of the LNH87 protocol containing high doses of anthracyclins and cyclophosphamide^ref, we show that the patients' outcome after chemotherapy was predicted by bcl-2 expression.sion. Indeed, for the whole group, as well as for the more homogeneous subgroup of diffuse large Bcell lymphomas, relapses occurred more frequently and earlier in lymphomas of the high bcl-2 expression category. In addition, in the large B-cell NHL subgroup, survival was significantly reduced in patients with high bcl-2 expression. The prognostic differences between patients whose neoplasms show high bcl-2 expression and those that do not, may reflect different genetic and immunologic pathways for achieving similar histological tumors and clinical presentation rather than a direct effect of bcl-2. However, our finding is consistent with the recent in vitro studies of Myashita and Reed^{ref1, ref2, ref3} who reported that bcl-2 transfected murine and human lymphoid cell lines exhibit higher resistance to several antineoplastic agents, including those used in the present study. Indeed, in bcl-2 transfected cells, chemotherapy induces arrest of proliferation, but unlike in control cells, death by apoptosis is prevented, and drug withdrawal results in reinitiation of cell growth. In the more homogeneous subset of diffuse large B-cell lymphomas, high bcl-2 expression appears, in multivariate analysis, as an independent prognostic factor for DFS together with performance status. Therefore, it is not likely that the association of high bcl-2 expression with a poor clinical outcome is due to its correlation with stage III-IV disease. Moreover, the fact that high bcl-2 expression is not correlated with the level of LDH, suggests that the poor outcome is mainly due to delayed cell death or resistance to treatment, but not to increased cell proliferation. This hypothesis is consistent with the putative role of bcl-2 in lymphomagenesis, as a suppressor of apoptosis without effect on cell proliferation^ref. In contrast, the finding that high bcl-2 protein expression does not appear to affect independently overall survival of patients with diffuse large B-cell lymphomas may be due to an insufficient follow up, and thus should be reevaluated later. In conclusion, in this series of uniformly treated patients with a diffuse large B-cell lymphoma, high bcl-2 protein expression was closely linked to reduced DFS and, at a lesser extent, to shorter survival. Together with the results of recent studies^{ref1, ref2} (Kramer MHH, Hermans J, Krol S, van Groningen K, van Krieken JHJM, de Jong D, Kluin P:Bcl-2 expression in diffuse large cell lymphoma. Blood 84:444a, 1994 (abstr)) performed on a smaller number of patients and/or receiving heterogeneous treatments, it appears that bcl-2 protein expression, as evaluated in routinely paraffin-embedded tissue, may be considered as a new independent biological prognostic parameter. The bcl-2 protein expression, like the Ki67 proliferating index^ref, the presence of the lymphocyte homing receptor (CD44)^ref, or deregulation of the p53 oncogene^ref may aid in the identification of patient risk groups.^ref
• B-cell CLL/lymphoma 6 (BCL6) gene on chromosome 3q27 contains 10 exons and encodes the Bcl-6 protein consisting of 706 amino acids^{ref1, ref2, ref3}. This protein is a transcriptional repressor expressed by GC B cells, and it is necessary for GC formation^{ref1, ref2, ref3}. BCL6 functions by directly binding to specific DNA sequences and suppressing the transcription of target genes. An alternative mechanism by which BCL6 controls the transcription of genes lacking a BCL6 binding site is required for the prevention of tumor suppressor p53-independent cell cycle arrest in germinal center B cells. BCL6 interacted with the transcriptional activator Miz-1 and, via Miz-1, bound to the promoter and suppressed transcription of the cell cycle arrest gene CDKN1A. Through this mechanism, BCL6 may facilitate the proliferative expansion of germinal centers during the normal immune response and, when deregulated, the pathological expansion of B cell lymphomas^ref. Cytogenetic and molecular analyses have demonstrated that alteration of 3q27, BCL6, or both is one of the most common genetic abnormalities in B-cell tumors^{ref1, ref2, ref3}. The BCL6 gene was first identified at the breakpoints on 3q27 involved in t(3;14)(q27; q32) and t(3;22)(q27;q11) translocations in diffuse large B-cell lymphoma^{ref1, ref2, ref3, ref4}. Initial studies suggested that 3q27 translocation or rearrangement of the BCL6 gene were specifically associated with 30-40% of DLBCL^ref, but it is observed in 6.4% up to 14.3% of FL^{ref1, ref2, ref3, ref4}. Although almost all the proto-oncogenes in B-cell NHL such as c-MYC, BCL1, BCL2, BCL3, PAX5 translocate only to the IG loci^ref, the 3q27 translocation is unique in that it fuses the BCL6 gene on 3q27 not only to IG genes but also to multiple non-IG partners on other chromosomes^{ref1,ref2, ref3, ref4}. To date, > 20 partner chromosomal loci have been reported^ref. As the result of the translocation in those cases, the structure of the Bcl-6 protein is not affected^ref, but the promoter region of the BCL6 gene is substituted for that of each partner^ref, respectively, and the rearranged BCL6 gene is presumed to come under the control of the replaced promoter^ref. In addition to chromosomal translocation, the BCL6 gene in B-cell neoplasms is also affected by point mutations^{ref1, ref2}. Furthermore, there is a possibility that the same mechanism is responsible for those 2 processes^{ref1, ref2}, because the target zones within the BCL6 gene for rearrangement and for somatic mutation are overlapping. Somatic mutation of the BCL6 gene was reported to be associated with the morphologic transformation of FL^ref. Some of these mutations were reported to be associated with increased BCL6 mRNA expression; however, increased BCL6 mRNA expression is not uniformly necessary for the transformation^ref. Multiple BCL6 translocation partners in individual cases of primary gastric lymphoma (GL), including MALT lymphoma, diffuse large cell lymphoma with residual MALT lymphoma, and DLBCL^ref. Translocations juxtaposing the BCL6 oncogene next to the IGH locus occur in 20% of nodular lymphocyte predominant Hodgkin’s lymphoma (NLPHL)^ref. The higher sensitivity of 2 PCR-based techniques—long-distance inverse polymerase chain reaction (LDI-PCR) on chromosomal DNA and 5' RACE on mRNA—can detect not only the main lymphoma clone but also the emerging minor subclones with new BCL6 translocations and possibly altered pathogenicity
• CDC91L1 encodes PIG-U, a subunit of a glycosylphosphatidylinositol (GPI) transamidase-complex, which is overexpressed 5-fold in the uroepithelial cells from 30% of patients with bladder cancer (e.g. from t(5;20)(p15;q11), leding to overproduction of several GPI-anchored proteins, including uPAR (which is associated with JAK-STAT signalling), in different cell types, that confer a faster growth rate and increased anchorage-independent growth capability^ref
• murine double minute 2 (MDM2) regulates p53 via an autoregulatory feedback loop in which both proteins mutually control their cellular level. MDM2 protein has multiple options for abrogating p53 function, including blocking access of p53 to basal transcription molecules, preventing its C-terminal acetylation, and inducing p53 ubiquitination

Web resources : MDM2 Database : data on the frequency of MDM2 amplifications in human cancers
• COX-2
• stathmin 1 (STMN1) / oncoprotein 18 prevents assembly and promotes disassembly of microtubules and is phosphorylated by kinase interacting with leukemia-associated gene (stathmin) (KIS)
• kinases
• protein kinases
• serine/threonine kinases
• cyclin-dependent kinase (CDK) family
• CDK4
• CDK6
• p39 c-MOS / v-mos Moloney murine sarcoma viral oncogene homolog [Moloney murine sarcoma virus]
• c-RAF family
• B-RAF initiates downstream signalling by phosphorylating MEK, which, in turn, activates ERK. Most cancer-associated BRAF mutations affect residues in the kinase domain, indicating that increased catalytic activity is responsible for oncogenesis, but even BRAF mutants with decreased kinase activity can have oncogenic effects, through interactions with CRAF, another member of the RAF family. Altered residues in kinase domains might lead to a conformation change which could be transmitted to the CRAF kinase domain, leading to its activation^ref
• AKT / PKB
• PIM-1
• nonreceptor protein tyrosine kinase (PTKs)
• p60 c-SRC [Rous sarcoma virus]
• p145 c-ABL1 [Abelson murine leukemia virus] 9q => BCR in 22p (Ph*) in CML
• p56 LCK
• p62 c-YES
• feline sarcoma oncogene (FES) / V-FES feline sarcoma viral/V-FPS fujinami avian sarcoma viral oncogene homolog [Snyder-Theilen feline sarcoma virus] [Fujinami sarcoma virus]
• c-FGR [Gardner-Rasheed feline sarcoma virus]
• PI3KCA, which encodes the p110a catalytic subunit of PI3K, is mutated in many colon, brain (anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas^ref), gastric cancers, breast^ref and lung cancers^ref
• STK15 : T91A transition causes a Phe residue at position 31 to be replaced with Ile : the Ile³¹ variant cannot bind UBE2N, so the ubiquitin ligase remains in the cytoplasm and cannot localize to the centrosomes to regulate chromosome segregation
• specific transcription factors
• transcriptional activators for other protooncogenes
• AP-1
• p39 c-JUN [Avian sarcoma virus 17]
• c-FOS [FBJ Murine osteosarcoma virus]
• c-MYC [avian myelocytic leukemia virus] is one of the most famous oncoproteins. It contributes to
• invasion
• angiogenesis
• genomic instability by interfering with the repair of DNA DSBs => gene amplification and fusions
• sensitization to apoptotic stimuli.
• up-regulation of genes that are involved in cellular immortalization or escape from cellular senescence, as WRN.
• MYCN
Traslocation from 8q to Ig genes on chromosomes 2, 14q, and 22 causes Burkitt's lymphoma
• RARa in APL
• c-ERBA / T3R [Avian erythroblastosis virus]
• c-MAF / v-maf musculoaponeurotic fibrosarcoma oncogene homolog (avian)
• MAFA
• MAFB
• MAFF
• MAFG
• MAFK
• c-MYB / v-myb myeloblastosis viral oncogene homolog (avian) [Avian myeloblastosis virus]
• MAX
• REL
• B-LYM
• SKI / v-ski sarcoma viral oncogene homolog (avian)
• regulated in glioma (RIG)
• T-cell acute lymphocytic leukemia 1 (TAL1)
• ETS1 / v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) [Avian erythroblastosis virus]
• ETS2 / v-ets erythroblastosis virus E26 oncogene homolog 2 (avian) [Avian erythroblastosis virus]
• ELK-1, member of ETS oncogene family
• ERG-1 / CUB and zona pellucida-like domains 1 (CUZD1)
• ERG-2
• glioma-associated oncogene homolog (GLI)
• Oct-3/4 contributes exclusively  to germ-cell neoplasia from an early stage and is required for tumour maintenance^ref
• transcriptional repressors of tumour suppressor genes
• Pokemon (encoded by the Zbtb7 gene) is a critical factor in oncogenesis. Mouse embryonic fibroblasts lacking Zbtb7 are completely refractory to oncogene-mediated cellular transformation. Conversely, Pokemon overexpression leads to overt oncogenic transformation both in vitro and in vivo in transgenic mice. Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding. Pokemon is aberrantly overexpressed in human cancers and its expression levels predict biological behaviour and clinical outcome. Pokemon's critical role in cellular transformation makes it an attractive target for therapeutic intervention^ref
• E1A
• EMSY (amplified in 13% of breast cancers and 17% of ovarian cancers)
• matriptase / membrane-type serine protease / suppression of tumorigenicity 14 : the first known cell-surface protease that can act as an oncogene^{ref1, ref2}
• nucleophosmin / NPM / B23 / NO38 is a nucleolar protein that specifically associates with the bodies of mRNAs as a result of the process of 3'-end formation. NPM deposition requires polyadenylation but not the 3' cleavage event to occur on the transcript. Furthermore, the protein does not associate with RNAs bearing a preformed poly(A) tail or with mRNAs that have undergone cleavage but not polyadenylation. A region within 10 bases upstream of the AAUAAA element is required for NPM association, but deposition of the protein seems to be sequence independent. NPM association with poly(A)⁺ mRNAs was also demonstrated in vivo. NPM, therefore, represents a mark left on transcripts as a result of 3'-end processing and may have a role in one or more of a variety of post-transcriptional processes influenced by the polyadenylation event^ref. It is directly implicated in cancer pathogenesis, as the NPM1 gene is found mutated and rearranged in a number of haematological disorders : 27.5% of acute myeloid leukemia (AML). Furthermore, the region of chromosome 5 to which NPM1 maps is deleted in a proportion of de novo human myelodysplastic syndromes (MDS), and loss of chromosome 5 is extremely frequent in therapy-related MDS. NPM is a multifunctional protein, and its role in oncogenesis is controversial as NPM has been attributed with both oncogenic and tumour suppressive functions. A hypomorphic Npm1 mutant series (Npm1^+/- < Npm1^hy/hy < Npm1^-/-) was generated in mouse. Npm is essential for embryonic development and the maintenance of genomic stability. Npm1^-/- and Npm1^hy/hy mutants have aberrant organogenesis and die between embryonic day E11.5 and E16.5 owing to severe anaemia resulting from defects in primitive haematopoiesis. Npm1 inactivation leads to unrestricted centrosome duplication and genomic instability. Npm is haploinsufficient in the control of genetic stability and that Npm1 heterozygosity accelerates oncogenesis both in vitro and in vivo. Notably, Npm1^+/- mice develop a haematological syndrome with features of human MDS. Our findings uncover an essential developmental role for Npm and implicate its functional loss in tumorigenesis and MDS pathogenesis^ref
Activation mecahanisms for proto-oncogenes :
• overexpression due to gene amplification of a normal gene
• double minute (DM)
• homogeneously staining regions (HSR) : long unbanded regions on chromosomes created by gene amplification; they are tumor markers indicative of solid neoplasms with poor prognosis.
• extended chromosome regions (ESR)
• macrobands
E.g.
• c-MYC in adenocarcinomas, squamous cell carcinomas, sarcomas, medulloblastomas
• N-MYC
• ErbA
• ErbB1
• ErbB2
• MET
• normal expresion of a mutated gene
• point mutations : e.g.
• HRAS
• KRAS
• NRAS in CML and ALL
• insertions : e.g.
• c-MYC in mammary ductal adenocarcinoma
• reciprocal unbalanced chromosomal translocations :
• with overexpression of one of the normal genes due to position effect : e.g.
• BCL2
• c-MYC in Burkitt lymphoma and ATL
• MOS
• TAL1
• with formation of a fusion protein whose expression level depends on that of source genes : e.g.
• BCR/c-Abl in CML (Ph* chromosome)
• RET
• tumour suppressors : usually they are direct inhibitors of proto-oncogenes; mutation of both alleles is required for carcinogenesis
• caretaker genes : their mutations are more malignant than those of gatekeeper genes as they cause clastogenias
• telomerase comprises 2 subunits, telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC). Telomerase adds telomere repeats to the ends of chromosomes by reverse transcribing the sequence in the template region of TERC from RNA to DNA in six-nucleotide increments. Telomerase can continue elongating telomeres through a ratcheting mechanism, by repeatedly dissociating from the newly synthesized telomere, realigning, and adding another six nucleotides at a time. Telomerase appears to be up-regulated late in tumor development, which may explain why telomeres shorten considerably during tumorigenesis. This telomere shortening can profoundly compromise chromosomal stability and may contribute to the widespread genomic changes seen in cancer in humans.
• mutS homolog 2 (MSH2), colon cancer, nonpolyposis type 1 (HNPCC) in Muir-Torre syndrome
• mutS homolog 3 (E. coli) (MSH3)
• mutS homolog 6 (E. coli) (MSH6) / GTBP
• mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1)
• mutL homolog 3 (E. coli) (MLH3)
• in humans, breast cancer 1 (BRCA1) and BRCA2 encode large, nuclear-localized proteins of 1,863 and 3,418 amino acids, respectively. The sequence of the proteins provides few clues as to their biological roles, because they are devoid of significant similarity to molecules of known function. Importantly, BRCA1 and BRCA2 do not resemble one another, despite the sometimes confusing similarities in nomenclature. For example, the 2 BRCT domains that are found at the carboxyl terminus of BRCA1 are 100-residue structures that mediate protein-protein interactions. They bear no resemblance to the similarly named BRC repeats in BRCA2, which are evolutionarily conserved peptide motifs of 30-40 amino acids each, that recur 8 times in all known vertebrate BRCA2 molecules and are implicated in binding RAD51 / RecA homolog
• BRCA1 : humans and dogs share about 96% of the same coding sequence within the gene, while humans and rodents share only about 65% of the genetic coding. BRCA1 is mutated in 8% of all breast cancer : among the known BRCA-1 mutations, sites within the genetic coding that are likely targets of mutation are the same sites conserved among humans, dogs, rats and mice, and among the conserved amino acids that make up the BRCA-1 protein in the 4 species, the amino acids that are most likely to be mutated are those that are hydrophobic. BRCA1 is a transcriptional repressor of ERa and participates in DNA repair. BRCA1 localizes to both the unpaired X chromosome in the XY body of male pachytene spermatocytes and the inactive X (Xi) chromosome in female somatic cells : susceptibility to breast cancer occurs only in females who inherit a mutation in BRCA1 as mutated BRCA1 inhibits the non-coding XIST RNA localization to the Xi chromosome, reactivating genes that are normally silent on the Xi. Women with BRCA-1 mutation are twice as likely to give birth to girls, thus passing on the vulnerability). BRCA1-IRIS as a 1,399-amino-acid BRCA1 gene product encoded by an uninterrupted open reading frame that extends from codon 1 of the known BRCA1 open reading frame to a termination point 34 triplets into intron 11. Unlike full-length BRCA1 (p220), BRCA1-IRIS is exclusively chromatin-associated, fails to interact with BARD1 in vivo or in vitro and exhibits unique nuclear immunostaining. Unlike BRCA1FL (or p220), BRCA1-IRIS also co-immunoprecipitated with DNA-replication-licensing proteins and with known replication initiation sites. Suppression of BRCA1-IRIS expression hindered the normal departure of geminin from pre-replication complexes, and depressed the rate of cellular DNA replication and possibly initiation-related synthesis. In contrast, BRCA1-IRIS overexpression stimulated DNA replication. These data imply that endogenous BRCA1-IRIS positively influences the DNA replication initiation machinery^ref.
• BRCA2 (deleted in 2% of breast cancer) : wild-type BRCA2 ...
• binds to RAD51 / RecA homolog through 6 of its 8 so-called BRC repeats (BRC1-8), controlling RAD51 oligomerization. Although it is not part of the normal replication machinery, BRCA2 localizes in the nuclear foci that are formed when replication is inhibited. BRCA2 is required to  prevent the breakdown of stalled replication forks and disruption of this function leads to the chromosomal rearrangements that occur spontaneously in dividing BRCA2-mutant cells^ref.
• enhances the transcriptional activity of AR by 10-fold by synergizing with GRIP1
The mutant form of BRCA2 ...
• cannot bind RAD51, preventing repair of damaged DNA
• cannot enhance AR activity
Families with only the BRCA-2 gene have roughly equal proportions to give birth to boys and girls. Biallelic germline mutations in BRCA2 are associated with the very rare complementation group of Fanconi anaemia. The clinical features of FA-D1 patients - who develop Wilms' tumour, breast cancer and medulloblastoma, differ from typical FA cases. BRCA and FA proteins work in a network of connected biological processes, and not in a linear sequence of evens that constitutes a single "pathway".
BRCA2 carriers are at increased risk for cancers of the prostate (RR = 2.5) and pancreas (RR = 5.9), and possibly bone (RR = 14.4) and pharynx (RR = 7.3)^ref
• BRCA3
• ataxia telangiectasia mutated (ATM : includes complementation groups A, C and D) in ataxia teleangiectasia (AT). The related kinases ATM and ataxia-telangiectasia and Rad3-related (ATR) phosphorylate a limited number of downstream protein targets in response to DNA damage. ATM kinase signals the DNA damage response by targeting the transcriptional cofactor serine/threonine kinase receptor associated protein (STRAP). ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex. Strap activity enhances p53acetylation, and augments the response to DNA damage. Strap remains localized in the cytoplasm in cells derived from ataxia telangiectasia individuals with defective ATM, as well as in cells expressing a Strap mutant that cannot be phosphorylated by ATM. Targeting Strap to the nucleus reinstates protein stabilization and activates the DNA damage response. These results indicate that the nuclear accumulation of Strap is a critical regulator in the damage response, and argue that this function can be assigned to ATM through the DNA damage-dependent phosphorylation of Strap^ref.
• PMS1 postmeiotic segregation increased 1 (S. cerevisiae)
• PMS2 postmeiotic segregation increased 2 (S. cerevisiae)
• fragile histidine triad (FHIT) gene
• Bloom syndrome (BLM)
• Werner syndrome (WRN)
• Fanconi anemia, complementation group A (FACA / FANCA)
• Fanconi anemia, complementation group C (FACC / FANCC)
• MRE11
• MRE11 meiotic recombination 11 homolog A (MRE11A) (S. cerevisiae)
• MRE11 meiotic recombination 11 homolog B (MRE11B) (S. cerevisiae)
• p95 Nijmegen breakage syndrome 1 (nibrin)
• xeroderma pigmentosum, complementation group A (XPA)
• xeroderma pigmentosum, complementation group C (XPC)
• gatekeeper genes
• negative growth factors
• TGF-b loss of signalling in stromal fibroblasts leads to oncogenic changes in adjacent epithelial cells by upregulating HGF / SF and c-Met / HGF-Rexpression, whose signalling upregulates c-Myc and downregulates Waf1 and Kip1 expression^ref

Web resources : The TGF-b system : TGF-b family, their receptors, and SMAD transcription factors, by Joan Massagué
• TNF-a
• IFN-g
• IL-24
• receptors for negative growth factors
• intracellular transductors
• pNF1 / neurofibromin (Ras-GAP) in type 1 neurofibromatosis or von Recklinghausen's disease
• deleted in pancreatic cancer (DPC4) / MAD homologue 4 (Drosophila) (SMAD4) encodes a central mediator of TGF-b signalling. Germline mutations in SMAD4 are found in > 50% of patients with familial juvenile polyposis, an autosomal dominant disorder characterized by predisposition to hamartomatous polyps and gastrointestinal cancer. Dense inflammatory cell infiltrates underlay grossly normal appearing, non-polypoid colonic and gastric mucosa of patients with familial juvenile polyposis. This prominent stromal component suggests that loss of SMAD4-dependent signalling in cells within the epithelial microenvironment has an important role in the evolution of intestinal tumorigenesis in this syndrome. Selective loss of Smad4-dependent signalling in T cells leads to spontaneous epithelial cancers throughout the gastrointestinal tract in mice, whereas epithelial-specific deletion of the Smad4 gene does not. Tumours arising within the colon, rectum, duodenum, stomach and oral cavity are stroma-rich with dense plasma cell infiltrates. Smad4^-/- T cells produce abundant T_h2-type cytokines including IL-5, IL-6 and IL-13, known mediators of plasma cell and stromal expansion. The results support the concept that cancer, as an outcome, reflects the loss of the normal communication between the cellular constituents of a given organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbours^ref
• FBXW7/hCDC4 is a haploinsufficient p53-dependent tumour suppressor gene that encodes a ubiquitin ligase implicated in the control of chromosome stability. Its loss leads to genetic instability by mechanisms that might involve the activation of Aurora-A, providing a rationale for the early occurrence of these mutations in human cancers.

^ref
• cyclin-dependent kinase inhibitors (CKIs / CDIs)
• CDKN1A / p21^Cip1/Waf1
• CDKN2Aencodes the tumour suppressors :
• INK4A
• ARF
• CDKN1B / p27^Kip1
• proapoptotic BCL2 family members
• adenomatous polyposis coli (APC) : mutations cause  familial adenomatous poliposis (FAP)


APC encodes a 2843-amino-acid protein with 6 major domains: an oligomerization region (O), armadillo repeats (ARM), 15-amino-acid repeats (15 AA), 20-amino-acid repeats (20 AA), a basic region, and a domain involved in binding EB1 and the Drosophila discs large homologue (E/D). Shown are the positions within the APC gene of a total of 650 somatic and 826 germline mutations. The vast majority of these mutations result in the truncation of the APC protein. Germline mutations are found to be relatively evenly distributed up to codon 1600 except for 2 mutation hotspots at amino acids 1061 and 1309, which together account for one-third of the mutations found in familial adenomatous polyposis (FAP) families. Somatic APC mutations in colon tumors cluster in an area of the gene known as the mutation cluster region (MCR). The location of the MCR suggests that the 20-amino-acid domain plays a crucial role in tumor suppression. Note that loss of the second functional APC allele in tumors from FAP families often occurs through loss of heterozygosity.
Web resources : Thierry Soussi's lab on p53 and APC at Institute Curie
• deleted in colorectal carcinoma (DCC)
• ARC1 / uvomorulin / E-cadherin. The phenotypic changes of increased motility and invasiveness of cancer cells are reminiscent of the epithelial–mesenchymal transition (EMT) that occurs during embryonic development. Snail, a highly unstable zinc-finger transcription factor with a short half-life about 25 min, triggers this process by repressing E-cadherin expression. GSK-3b binds to and phosphorylates Snail at 2 consensus motifs to dually regulate the function of this protein. Phosphorylation of the first motif regulates its b-Trcp-mediated ubiquitination, whereas phosphorylation of the second motif controls its subcellular localization. A variant of Snail (Snail-6SA), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce EMT. Furthermore, inhibition of GSK-3b results in the upregulation of Snail and downregulation of E-cadherin in vivo. Thus, Snail and GSK-3b together function as a molecular switch for many signalling pathways that lead to EMT^ref.
• pNF2 / neurofibromin 2 in type 2 neurofibromatosis
• DUBs : TRE2 / USP6
• CDC4 / FBXW7 is an E3 ubiquitin ligase that targets cyclin E (which regulates G1-S transition and chromosome stability) for degradation^ref
• kinases
• protein kinases in STPs from negative growth factor
• phosphatases
• protein phosphatases
• PP2R1B (b isozyme of A subunit of PP2A)
• PTP
• PTEN phosphatase has long been known to have tumour-suppressive activity through its ability to antagonize te PI3K-AKT signalling pathway. The C2 domain of PTEN inhibits cell motility independently of the PI3K-AKT pathway : the C2 domain is inactive when it is phosphorylated and activation by dephosphroylation of Thr³⁸³ enables PTEN to interfere with migration^ref
• specific negative transcription factors
• tumour protein of 53 kDa (TP53) is a sequence-specific DNA-binding nuclear protein that acts to induce gene expression. Overall, the program of p53-activated genes is associated with suppression of cell growth, consistent with our understanding of the action of anti-oncogenes. Mutations of p53 may not only inactivate its growth-suppression function, but can actually generate a genetically dominant, functional oncogene. Human tumors associated with p53 mutations include those of hematopoietic tissues (e.g., 20% of multiple myelomas), bladder, liver, brain, breast, lung, and colon. It is likely the most frequently mutated gene in human cancer. P53 has both pro-apoptotic functions and prevents genome instability - possibly by inducing cell-cycle arrest : the latter is preserved even in Trp53^515C/515C mutant, which corresponds to an arginine to proline amino-acid substituion at residue 172^ref. Loss of p53 characteristically results in highly aneuploid cells as control over centrosome duplication is removed, but this is not the case in the Trp53^515C/515C cells. Inherited loss of functions results in Li-Fraumeni syndrome. p53-regulated angiogenic molecules :
• genes upregulated by p53
• thrombospondin-1 (TSP1) is an endogenous angiogenesis inhibitor^{ref1, ref2}
• brain-specific angiogenesis inhibitor 1 (BAI1)^ref
• MMP2 promotes endogenous antiangiogenic peptide formation from basement membrane proteins^ref
• Eph receptor A2 (EphA2) induces apoptosis; soluble EphA2 receptors are anti-angiogenic^{ref1, ref2, ref3}
• genes downregulated by p53
• MMP1 promotes angiogenesis in bone and activates latent MMP2^{ref1, ref2}
• COX-2 promotes angiogenesis^ref
• VEGF-A is a potent pro-angiogenic and permeability factor^ref
• HIF-1a induces angiogenesis by activation of VEGFA transcription under hypoxic conditions^ref
Using a mouse model in which p53 status can be reversibly switched in vivo between functional and inactive states, it has been shown that the p53-mediated pathological response to whole-body irradiation, a prototypical genotoxic carcinogen, is irrelevant for suppression of radiation-induced lymphoma. In contrast, delaying the restoration of p53 function until the acute radiation response has subsided abrogates all of the radiation-induced pathology yet preserves much of the protection from lymphoma. Such protection is absolutely dependent on p19ARF—a tumour suppressor induced not by DNA damage, but by oncogenic disruption of the cell cycle^ref.
Web resources :
• Thierry Soussi's lab on p53 and APC at Institute Curie
• TP53 mutation database by the International Agency for Research on Cancer (IARC)
• p110 retinoblastoma 1 (RB1) : the prototypical tumor suppressor gene Rb behaves in a genetically recessive fashion. Elimination or inactivation of both Rb gene copies is required for manifestation of the tumorigenic phenotype, first recognized in children with retinoblastoma. Such children inherit only a single functional copy; subsequent mutagenic inactivation of the remaining allele results in tumor susceptibility. Rb acts to sequester a group of transcription factors, termed E2F, which regulate genes critical for DNA synthesis. Alterations of Rb alleles are found in approximately 30% of human acute leukemias. RB1 binds to RBP (not for other pocket proteins) : mutations promote tumour development by deregulating the E2F family of transcription factors leading to uncontrolled cell cycle progression. The mitotic checkpoint protein Mad2 is a direct E2F target and, as a consequence, is aberrantly expressed in cells with Rb pathway defects. Concordantly, Mad2 is overexpressed in several tumour types, where it correlates with high E2F activity and poor patient prognosis. Generation of Rb pathway lesions in normal and transformed cells produces aberrant Mad2 expression and mitotic defects leading to aneuploidy, such that elevated Mad2 contributes directly to these defects^ref.

Web resources : RB1 gene mutation database by Dietmar Lohmann at the Institut für Humangenetik in Essen, Germany
• RBL2 / Rb2/p130 :
• p52 Wilms tumor 1 (WT1) inhibits EGR, role in Wilms' tumour, TFs in WAGR syndrome. It  is expressed in many tissues, including hematopoietic stem cells^ref and has a role in the development and antiapoptotic mechanisms of myeloid lineage^ref. Unfortunately, WT1 is expressed in lymphoid lineage cells as well as in other malignancies. Others suspect that WT1 is a surrogate marker of proliferation, due to its high levels of expression in most myeloid and lymphoid leukemias. High levels of expression have also been found in proliferating normal myeloid cells in culture^ref. There are reports that some isoforms of WT1 either inhibit or potentiate myelopoiesis in cell cultures^ref. Many series have been published using the overexpression of the WT1 gene as a marker of minimal residual disease (MRD), where the presence of expression of the WT1 gene correlates with a poor prognosis, primarily in patients with acute myeloid leukemia (AML)^ref. The presence of the chimeric gene AML1-ETO also inhibits differentiation of myeloid progenitors by suppression of clonogenic progenitors but cannot induce AML by itself, requiring a second event. In mice, the use of a transduced WT1 transgene into transplanted BM cells with AML1-ETO induces AML (Nishida S, Hosen N, Shirakata T, et al. WT1 has oncogenic functions in leukemogenesis and induces AML in cooperation with AML1-ETO. Paper presented at the 2nd International Conference on WT1 in Human Neoplasia. October 20-22, 2005. Kyoto, Japan). The speculation that this is primarily related to drug resistance, because chemotherapy agents induce apoptosis in susceptible cells, may be true; however, we will have to ask why that is the case, since this particular gene is also expressed in many other malignancies, including lymphoid malignancies, which are quite sensitive to chemotherapeutic agents. In a murine cell line the WT1 gene suppresses the expression of cyclin E, and the A1 gene (BFL1 in humans) in the family of bcl-2 is implicated in differentiation and in resistance to apoptosis in hematopoietic cells. If WT1 does indeed regulate different bcl-2 family members, causing different effects depending on the cell line being investigated, the function of A1 might be related to differentiation as well as to apoptosis. The multiple reports that correlate high levels of expression of WT1 in AML with poor prognoses may suggest that there is a relationship between drug resistance and the regulation of WT1 to the bcl-2 family members such as A1^ref
• myogenic regulatory factor (MYOD1)
• VHL (TF for elongin C) in von Hippel-Lindau syndrome (VLS)
• E2F1
• SNF5 / INI1
• b-catenin
• ovarian cancer 1 (OVCA1), despite its role as a positive regulator of cell-cycle progression, is a tumour suppressor, and causes proliferation defects only when its loss is combined with that of p53^ref
• ADP-ribosylation factor 1 (ARF1) is activated in response to a range of oncogenic signals : Arf is difficult to detect in vivo probably because cells that express Arf die or undergo growth arrest^ref
• beclin 1 (BECN1) autophagy gene is monoallelically deleted in up to 75% of ovarian cancers, 50% of breast cancer and 40% of prostate cancers. However, biallelic inactivations have not been found, so it is not a classical tumour-suppressor gene^ref. Genes best known for inducing cell growth or inhibiting apoptosis - such as PI3K, AKT and PTEN - are also involved in autophagy.
• BubR1, a component of the mitotic chekpoint machinery, is significantly reduced in cancer cells causing polyploidy^ref
• peroxiredoxin is an antioxidant which protects from oxidative DNA damage
• TIMPs and serpins
• Kruppel-like factor 6 (KLF6) inactivated in > 50-60% of all prostate cancers^ref, colorectal cancers^ref, glioblastoma multiforme^ref, and hepatocellular carcinoma (HCC)^ref.
• deletion, mutation or methylation of ADP-ribosylation factor-like tumor suppressor 1 (ARLTS1) occurs in familial forms of chronic myeloid leukemia, or thyroid, colorectal, breast, lung or early stage pancreatic cancer
• oncosuppressor RNAs :
• H19, imprinted maternally expressed untranslated mRNA
• sub-cellular mislocalization
• forkhead (FOXO) family member 1a (FOXO1A) is exported from the nucleus to the cytoplasm in PTEN-null cells^ref
• microRNAs can trigger tumours by regulating proteins that disrupt normal cellular growth. Everybody has been focused on understanding how proteins fit into cancer-causing pathways, but there is another regulatory pathway that controls not the protein product but its utilization. Some microRNAs can accelerate the development of cancer when transplanted into mice^ref. The discovery should also help researchers to identify the type of cancer that an individual has, a step that is crucial in assigning treatment. Different types of tumour express different levels of microRNAs^ref. By measuring the levels of expression of 217 genes in different types of cancers, microRNA 'profiles' of many cancers could be used to diagnose the origin of tumours that are difficult to classify by the traditional method of looking at cell shape and character under a microscope. MicroRNA profiling also worked better than existing genetic profiling methods, correctly diagnosing 12 of 17 tricky tumours. The existing method diagnosed only one of these tumours correctly. Others note that the discovery could have knock-on effects for treatment strategies. MicroRNAs are potentially therapeutic : you could deliver them to tumours, maybe in combination, or even along with chemotherapeutic drugs
DNA palindromes appear frequently and are widespread in human cancers, and identifying them could help advance the understanding of genomic instability. While the scientists did not find similar widespread palindrome formation in 4 normal cell lines studied, I anticipate we will identify palindromes on the somatic chromosomes of normal cells that might not have been mapped yet. In 2002, the molecular mechanisms for palindrome formation in the protozoan Tetrahymena was found to be conserved in mammalian cells : it is an initial, rate-limiting step in gene amplification^ref. Given amplification of large genomic regions contributes to tumor progression, the investigators explored what role DNA palindromes—already known to exist on the normal human Y chromosome—might play in human cancers. Palindromes are difficult to study due to their propensity for rapid intrastrand base pairing. In a new technique, if DNA containing palindromic regions is denatured and rapidly renatured, the results are double-stranded snap-back DNA near palindromic centers and largely single-stranded DNA in nonpalindromic regions. The snap-back DNA is resistant to single-strand–specific nuclease S1, while the rest is sensitive. When the researchers combined their technique with a cDNA-spotted array, widespread palindrome formation was not seen in one breast epithelial or 3 different fibroblast cell lines. The sensitivity is terrific, able to detect signal in a 1:40 dilution from a cell line containing only a couple of copies of the palindrome. This research provides another mechanism to investigate genomic instability and therefore will likely become widely used by both cancer and basic researchers. In the Colo320DM human colon cancer cell line, 150 genes tested significantly higher for palindromes than baseline, with significant overlap of palindrome-positive genes with breast cancer cell line MCF7. While most of the palindrome-positive genes seen in Colo320DM and MCF7 are not linked with an increase in gene copy number, as a whole these genes are more likely than any other loci to be amplified. This indicates only certain regions might be susceptible to further gene amplification. So the location of a tumor's palindromes might determine its ability to amplify genes and progress to higher stages of cancer. Others might criticize the findings because the technique might be measuring unknown features aside from palindromes. But those features, if they exist, are structures not yet imagined yet
Mutation types in human cancer :

Proportion of somatically mutated human cancer genes with translocations :

Dominant and recessive germline (a) or somatic (b) mutations in human cancer genes :

Proportion of genes with germline (a) or somatic (b) mutations associated with different tumour types :

Nuclei removed from mouse brain tumor cells and transplanted into mouse eggs whose own nuclei have been removed, give rise to cloned embryos with normal tissues, even though the mutations causing the cancer are still present : the finding demonstrates that the cancerous state can be reversed by reprogramming the genetic material underlying the cancer, and that genetic mutations alone are not always sufficient to cause a cell to become cancerous.
Oncogenes such as E1A and MYC are able to initiate both cell proliferation and cell death. E.g. E1A coordinates both processes by using the same machinery - E2F - to initiate them : caspase induction is not sufficient to induce apoptosis and, instead, seems to sensitize cells to apoptotic stimuli coming from p53-dependent pathways.
Nuclear transplantation of a cancer cell nucleus into an oocyte can reverse its cancer phenotype and produce embryonic stem cells (ESCs) with developmental potential. Although some of the cancer cell nuclei were unable to induce development, others supported organized division cleavages and produced blastocysts, while one of these, from an artificial Ras-inducible melanoma, also gave rise to embryonic stem cells, termed NT ES cells : injection of these cells into blastocysts allowed the production of chimeric mice, in which the NT ES cells contributed to multiple organs, including the skin, heart, and liver. Nevertheless, as expected, the genetic changes possessed by the original melanoma, revealed to be various chromosomal aberrations, were not reversible, resulting in the chimeric mice all developing tumors. Nonetheless, it is clear that a melanoma cell can give rise to a normal immune system, among other normal tissues, despite its multiple genetic defects
Web resources :
• Atlas of Genetics and Cytogenetics in Oncology and Haematology
• Catalogue of Somatic Mutations in Cancer (COSMIC) by the Cancer Genome Project, based at The Wellcome Trust Sanger Institute
• Cancer Chromosomes database integrates information from the NCI Mitelman Database of Chromosome Aberrations in Cancer, the NCI Recurrent Aberrations in Cancer database, and the NCI SKY/M-FISH & CGH Database
• Oncomine 2.0 (O2) - cancer microarray database : tools to query and visualize cancer microarray data for a gene or cancer type of interest
• A 'module map' showing conditional activity of expression modules in cancer at University of Stanford^ref
• Genes and disease: cancer at NCBI
• A subway map of cancer pathways at Nature Reviews Cancer
• The tumour gene database (TGDB) : proto-oncogenes and tumour-suppressor genes
• Oncogene at COPE
• Telomeres from Kimball's biology pages
• Telomeres and telomerase-related sites by Tom Cech
• Telomere information database by Washington University.
• Prostaglandins (PGs) and cancer
• The Familial Cancer Database (FaCD) from the International Union against Cancer (UICC)
• Morphology
• Plimmer's cancer bodies : small round capsulated bodies found in cancer, and thought by the discoverer to be the parasite causing the disease but now considered to be cell necrosis products
• Gompertz growth curve is f_G(x) = a ^. e^{(-e^ (-k . (x-c))}, where ...
• x : independent variable
• a : the upper border
• k : a scale factor (also a big influence to the max. slope)
• c : (c/f_G(x)) is the inflection value
• the maximum growth rate occurs at 1/e, the point at which the tumor is about 37% of its maximum size (marked with an X).
• initial diagnosis usually occurs when y = 10⁹ cells (or 10¹⁰ cell, ie. tumor weighs 1 g) = 1 cm³
• clinical failure usually occurs when y = 10¹² cells, ie. tumor weighs 1 kg
Efforts to treat the tumor and reduce its size can result in an increase in the growth fraction and an increase in growth rate.

• Tumor atlas at Weizmann Institute
• tumor size is measured using a Vernier caliper across its 2 perpendicular diameters and its depth, and its volume is calculated using the formula V= (4/3)pabc

Cell types in children : ovary (45%), sacrococcygeal region (40%, causing dystocia), testes, retroperitoneum, mediastinum (=>respiratory distress) , nasopharynx, intracranium, neck and stomach(monodermoma : a tumor that has developed from one germ layer)		benign tumor	malignant tumor
epithelial cells Laboratory examinations : IHC with epithelial markers (cytokeratins 1, 5, 10, 14; EGFR, b2-microglobulin)		adenoma : a benign epithelial tumor in which the cells form recognizable glandular structures or in which the cells are clearly derived from glandular epithelium adenoma alveolare : an adenoma whose cells are arranged like those of an alveolar gland.  mucinous adenoma : an epithelial tumor whose cells produce mucin.  embryonal or trabecular adenoma : a follicular adenoma whose cells are closely packed to form cords or trabeculae, with only a few small follicles  tubular adenoma : an adenoma whose cells are arranged in tubules, as occurs with adenomatous polyps of the colon, some fibroadenomas of the breast, and androblastoma.  papilloma / papillary tumor / villoma / villous papilloma or tumor : a benign epithelial neoplasm producing finger-like or verrucous projections from the epithelial surface polyp : a morbid excrescence, or protruding growth, from mucous membrane; classically applied to a growth on the mucous membrane of the nose, the term is now applied to such protrusions from any mucous membrane.	carcinoma : a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases adenoid cystic, adenocystic or cribriform carcinoma / cylindroma : carcinoma characterized by bands or cylinders of hyalinized or mucinous stroma separating or surrounded by nests or cords of small epithelial cells. It appears as one or more of 3 patterns: cribriform carcinoma solid carcinoma tubular carcinoma Malignant and invasive but slow growing, it spreads by infiltrating the bloodstream and perineural spaces  adnexal carcinoma : carcinoma forming structures resembling the cutaneous appendages, particularly the sweat or sebaceous glands. basosquamous or metatypical cell carcinoma : carcinoma that histologically exhibits both basal and squamous elements. cancer or carcinoma in situ / preinvasive carcinoma : a neoplastic entity wherein the tumor cells are confined to the epithelium of origin, without invasion of the basement membrane; the likelihood of subsequent invasive growth is presumed to be high carcinoma medullare, molle