Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

“More recently, a report broadly analyzing the landscape of focal amplifications in cancers found MYC amplification to be among the most frequent of all such events (Beroukhim et al., 2010).”

“…to modulate epithelial-mesenchymal transition (EMT) by forming a negative feedback loop with the master transcription factors ZEB1 and ZEB2 (Burk et al., 2008; Gregory et al., 2008; Korpal et al., 2008; Park (B) The table lists the top four genes most mutually exclusive with respect to MYC .”

“Studies in mouse models of human cancers have demonstrated that this cluster, also known as Oncomir1, is a bona fide oncogene and a direct MYC transcriptional target (He et al., 2005; O’Donnell et al., 2005).”

“Studies in mouse models of human cancers have demonstrated that this cluster, also known as Oncomir-1, is a bona fide oncogene and a direct MYC transcriptional target (He et al., 2005; O’Donnell et al., 2005).”

“These miRNAs have been previously shown to be directly repressed by MYC (Chang et al., 2007), and are suspected to act as potential tumor suppressors.”

“…ability to modulate epithelial-mesenchymal transition (EMT) by forming a negative feedback loop with the master transcription factors ZEB1 and ZEB2 (Burk et al., 2008; Gregory et al., 2008; Korpal et al., 2008; Park (B) The table lists the top four genes most mutually exclusive with respect to MYC…”

“Consistent with this model, downregulation of these two miRNAs has been shown to be sufficient to promote EMT, while their overexpression can prevent EMT and inhibit cancer cell migration (Korpal et al., 2008).”

“The involvement of MYC as an oncogenic driver was described in a wide spectrum of tumor types as shown by early reports in leukemia (Dalla-Favera et al., 1983; Nowell et al., 1983), B cell lymphomas (Hayward et al., 1981), lung cancer (Little et al., 1983), and neuroblastoma (Schwab et al., 1983).”

“…addition, a role for MYC in the global mRNA amplification observed during transition from quiescence to proliferation was proposed by examining gene expression changes in a B cell line, whose proliferative state was strictly dependent on a conditional MYC allele (Lin et al., 2012; Nie et al., 2012).”

“The involvement of MYC as an oncogenic driver was described in a wide spectrum of tumor types as shown by early reports in leukemia (Dalla-Favera et al., 1983; Nowell et al., 1983), B cell lymphomas (Hayward et al., 1981), lung cancer (Little et al., 1983), and neuroblastoma (Schwab et al., 1983).”

“Colorectal cancer was the third highest cancer with MYC protein level, possibly explained by the activation of the Wnt/ b -catenin signaling pathway occurring in the majority of colorectal cancer samples (Ciriello et al., 2013).”

“Earlier studies showed that multiple cancer types exhibit alterations at MYC family gene loci, usually associated with increased MYC mRNA and/or protein levels (Nesbit et al., 1999; Vita and Henriksson, 2006).”

“…addition, a role for MYC in the global mRNA amplification observed during transition from quiescence to proliferation was proposed by examining gene expression changes in a B cell line, whose proliferative state was strictly dependent on a conditional MYC allele (Lin et al., 2012; Nie et al., 2012).”

“miR-21, another bona fide human oncogene (Medina et al., 2010), and miR-27a, also are also generally positively correlating with MYC expression.”

“MYC functions with its heterodimerization partner MAX, through recognition of specific DNA elements (Blackwell et al., 1993; Fernandez et al., 2003; Grandori et al., 1996; Guc-cione et al., 2006), and recruitment of transcriptional co-regula-tory molecules linked to histone acetylation (Bouchard et…”

“, 1981), lung cancer (Little et al., 1983), and neuroblastoma (Schwab et al.”

“A Pan-cancer MicroRNA Signature Associated with MYC MicroRNAs (miRNAs) are key regulators of gene expression and important players in the pathogenesis of human cancers (Bartel, 2004; Ventura and Jacks, 2009).”

“…al., 2000; Hemann et al., 2005); (2) mutation or rare amplification of distal enhancers (Sur et al., 2012; Zhang et al., 2016); and (3) activating mutations in signal transduction pathways (e.g., Wnt, Notch) that augment MYC expression (Herranz et al., 2014; Muncan et al., 2006; Weng et al., 2006).”

“Experiments in a number of tumor lines and in animal models of cancer indicated that, in many cases, MYC expression is required for tumor initiation, progression, or maintenance (for review see Gabay et al., 2014; Vita and Henriksson, 2006).”

“This pattern has been observed in classical tumor suppressors as described for TP53 and P27KIP1 (Fero et al., 1998; Payne and Kemp, 2005), and is shown in this dataset and a recent publication (Vidotto et al., 2018) for PTEN , which exhibits a group with shallow deletions (one copy loss) and a wide range of the chromo…”

“MAX, in addition to dimerizing with MYC paralogs, also forms heterodimers with the MXD family, comprised of MXI1, MNT, and MGA (Ayer et al., 1993; Hurlin et al., 1995, 1997, 1999; Meroni et al., 1997; Zervos et al., 1993) (Figure 1A).”

“In contrast to the predominant transcriptional activation function of MYC, the MXD, MXI1, MNT, and MGA proteins repress transcription through the recruitment of corepressor complexes (for reviews see Conacci-Sorrell et al., 2014; Link and Hurlin, 2015).”

“P74 is within the MYC box 1 phosphodegron (sequence conserved for all FBXW7 degrons) and is strongly predicted to inactivate the degron and lead to increased stability of MYC (O’Neil et al., 2007).”

“, 1987), and translational processes (Cowling and Cole, 2007), including gene sets corresponding to ribosomal structural components and rRNA synthetic apparatus (Grandori et al., 2005; Grewal et al., 2005), as well as DNA replication and repair (Dominguez-Sola and Gautier, 2014; Rohban and Campaner, 2015).”

“Altogether, we referred to these gene sets as canonical pathways, as previously observed in experimental systems upon manipulation of MYC levels (Dominguez-Sola et al., 2007; Gomez-Roman et al., 2006; Grandori et al., 2003, 2005; Grewal et al., 2005; Hnisz et al., 2013; Johnston et al., 1999; Moser…”

“…observed in experimental systems upon manipulation of MYC levels (Dominguez-Sola et al., 2007; Gomez-Roman et al., 2006; Grandori et al., 2003, 2005; Grewal et al., 2005; Hnisz et al., 2013; Johnston et al., 1999; Moser et al., 2012; Robinson et al., 2009; for a review see Ruggero, 2009).”

“…to be crucial for tumor cell survival and for tumor progression in multiple cancer types (Han et al., 2015; Li et al., 2014; Mu et al., 2009; Olive et al., 2009). miR-21, another bona fide human oncogene (Medina et al., 2010), and miR-27a, also are also generally positively correlating with…”

“Earlier studies showed that multiple cancer types exhibit alterations at MYC family gene loci, usually associated with increased MYC mRNA and/or protein levels (Nesbit et al., 1999; Vita and Henriksson, 2006).”

“…critical for its transforming potential in cell culture assays, recurrent shallow deletions of MAX were observed in some cancers, particularly pheochromocytomas and gastrointestinal stromal tumors (Burnichon et al., 2012; Comino-Me´ndez et al., 2011; Pantaleo et al., 2017; Schaefer et al., 2017).”

“Pan-cancer Canonical and Non-canonical MYC-Specific Gene Set Enrichment Alteration of MYC expression leads to broad transcriptional changes through both direct and indirect effects, as observed in many experimental systems (as reviewed in Kress et al., 2015).”

“The functional consequences of MYC de-regulated expression and its influence on gene expression programs and DNA replication or repair processes during normal and oncogenic proliferation have been a subject of intense research (Dominguez-Sola and Gautier, 2014; Sabo and Amati, 2014; Walz et al., 2014).”

“…2003; Grandori et al., 1996; Guc-cione et al., 2006), and recruitment of transcriptional co-regula-tory molecules linked to histone acetylation (Bouchard et al., 2001; Frank et al., 2001) to elevate expression of a broad, but selective, set of genes via the activation of specific chromatin marks.”

“…and miR-222, which have been proposed to promote cell proliferation and tumorigenesis, at least in part via p27-Kip repression (Kedde et al., 2010; Kim et al., 2009; Korpal et al., 2008; le Sage et al., 2007), positively correlated with MYC levels in PCPG, BLCA, CESC, and TGCT, but negatively…”

“Even relatively small constitutive changes in MYC expression level (>2-fold relative to normal) have been demonstrated to have biological consequences and influence tumorigenesis (Bazarov et al., 2001; Hofmann et al., 2015; Murphy et al., 2008).”

“…coding region that appear to increase MYC protein stability and activity as secondary events to trans-locations in lymphoma (Bahram et al., 2000; Hemann et al., 2005); (2) mutation or rare amplification of distal enhancers (Sur et al., 2012; Zhang et al., 2016); and (3) activating mutations in…”

“Furthermore, induction of miR-17–92 by MYC has been reported to be crucial for tumor cell survival and for tumor progression in multiple cancer types (Han et al., 2015; Li et al., 2014; Mu et al., 2009; Olive et al., 2009).”

“Pan-cancer Frequency of Mutations in PMN Mutations in MYC that may affect MYC protein stability and/or activity have been described to occur in Burkitt’s lymphoma and diffuse large B cell lymphoma (Adhikary et al., 2005; Salghetti et al., 1999; Zhang et al., 2013).”

“In contrast to the predominant transcriptional activation function of MYC, the MXD, MXI1, MNT, and MGA proteins repress transcription through the recruitment of corepressor complexes (for reviews see Conacci-Sorrell et al., 2014; Link and Hurlin, 2015).”

“…of miR-221 and miR-222, which have been proposed to promote cell proliferation and tumorigenesis, at least in part via p27-Kip repression (Kedde et al., 2010; Kim et al., 2009; Korpal et al., 2008; le Sage et al., 2007), positively correlated with MYC levels in PCPG, BLCA, CESC, and…”

“Mutations in MYC that may affect MYC protein stability and/or activity have been described to occur in Burkitt’s lymphoma and diffuse large B cell lymphoma (Adhikary et al., 2005; Sal-ghetti et al., 1999; Zhang et al., 2013).”

“…observed in experimental systems upon manipulation of MYC levels (Dominguez-Sola et al., 2007; Gomez-Roman et al., 2006; Grandori et al., 2003, 2005; Grewal et al., 2005; Hnisz et al., 2013; Johnston et al., 1999; Moser et al., 2012; Robinson et al., 2009; for a review see Ruggero, 2009).”

“MYC functions with its heterodimerization partner MAX, through recognition of specific DNA elements (Blackwell et al., 1993; Fernandez et al., 2003; Grandori et al., 1996; Guccione et al., 2006), and recruitment of transcriptional co-regulatory molecules linked to histone acetylation (Bouchard et al.”

“…to trans-locations in lymphoma (Bahram et al., 2000; Hemann et al., 2005); (2) mutation or rare amplification of distal enhancers (Sur et al., 2012; Zhang et al., 2016); and (3) activating mutations in signal transduction pathways (e.g., Wnt, Notch) that augment MYC expression (Herranz et al.,…”

“MAX, in addition to dimerizing with MYC paralogs, also forms heterodimers with the MXD family, comprised of MXI1, MNT, and MGA (Ayer et al., 1993; Hurlin et al., 1995, 1997, 1999; Meroni et al., 1997; Zervos et al., 1993) (Figure 1A).”

“…critical for its transforming potential in cell culture assays, recurrent shallow deletions of MAX were observed in some cancers, particularly pheochromocytomas and gastrointestinal stromal tumors (Burnichon et al., 2012; Comino-Me´ndez et al., 2011; Pantaleo et al., 2017; Schaefer et al., 2017).”

“Even relatively small constitutive changes in MYC expression level (>2-fold relative to normal) have been demonstrated to have biological consequences and influence tumorigenesis (Bazarov et al., 2001; Hofmann et al., 2015; Murphy et al., 2008).”

“Such alterations include (1) point mutations in the MYC coding region that appear to increase MYC protein stability and activity as secondary events to translocations in lymphoma (Bahram et al., 2000; Hemann et al., 2005); (2) mutation or rare amplification of distal enhancers (Sur et al.”

“…al., 2000; Hemann et al., 2005); (2) mutation or rare amplification of distal enhancers (Sur et al., 2012; Zhang et al., 2016); and (3) activating mutations in signal transduction pathways (e.g., Wnt, Notch) that augment MYC expression (Herranz et al., 2014; Muncan et al., 2006; Weng et al., 2006).”

“In addition, MYC activity can also be enhanced by loss of MNT (Hurlin et al., 1997, 1999), which is focally deleted in 10% of all samples, or by inactivation of MGA, which occurs by focal deletions and by truncating mutations (with 9% and 4% frequency, respectively, Figures 1 and S2).”

“In the case of APC and PIK3CA alterations, MYC expression was elevated suggesting that these alterations are sufficient to activate MYC expression, without the need of gene amplification, consistent with previous reports (Ilic et al., 2011; Muncan et al., 2006).”

“…as secondary events to trans-locations in lymphoma (Bahram et al., 2000; Hemann et al., 2005); (2) mutation or rare amplification of distal enhancers (Sur et al., 2012; Zhang et al., 2016); and (3) activating mutations in signal transduction pathways (e.g., Wnt, Notch) that augment MYC expression…”

“MYC functions with its heterodimerization partner MAX, through recognition of specific DNA elements (Blackwell et al., 1993; Fernandez et al., 2003; Grandori et al., 1996; Guc-cione et al., 2006), and recruitment of transcriptional co-regula-tory molecules linked to histone acetylation (Bouchard et…”

“Impor-tantly, the nuclear localization and transcriptional activity of MLXIP and MLXIPL is highly dependent on nutrient flux, potentially connecting the functions of MYC and other PMN members to cellular metabolic state (Carroll et al., 2015; Diolaiti et al., 2015; Wilde and Ayer, 2015).”

“…observed in experimental systems upon manipulation of MYC levels (Dominguez-Sola et al., 2007; Gomez-Roman et al., 2006; Grandori et al., 2003, 2005; Grewal et al., 2005; Hnisz et al., 2013; Johnston et al., 1999; Moser et al., 2012; Robinson et al., 2009; for a review see Ruggero, 2009).”

“This pattern has been observed in classical tumor suppressors as described for TP53 and P27KIP1 (Fero et al., 1998; Payne and Kemp, 2005), and is shown in this dataset and a recent publication (Vidotto et al., 2018) for PTEN , which exhibits a group with shallow deletions (one copy loss) and a wide…”

“In addition, MYC activity can also be enhanced by loss of MNT (Hurlin et al., 1997, 1999), which is focally deleted in 10% of all samples, or by inactivation of MGA, which occurs by focal deletions and by truncating mutations (with 9% and 4% frequency, respectively, Figures 1 and S2).”

“…pathways, as previously observed in experimental systems upon manipulation of MYC levels (Dominguez-Sola et al., 2007; Gomez-Roman et al., 2006; Grandori et al., 2003, 2005; Grewal et al., 2005; Hnisz et al., 2013; Johnston et al., 1999; Moser et al., 2012; Robinson et al., 2009; for a review…”

“These results support and broaden, at a pan-cancer level, previous studies demonstrating a distinction between MYC and MYCN overexpression on determining spe-cific cell lineages in genetic models of medulloblastoma (Roussel and Robinson, 2013; Vo et al., 2016).”

“…of miR-17–92 by MYC has been reported to be crucial for tumor cell survival and for tumor progression in multiple cancer types (Han et al., 2015; Li et al., 2014; Mu et al., 2009; Olive et al., 2009). miR-21, another bona fide human oncogene (Medina et al., 2010), and miR-27a, also are also…”

“We used the DISCOVER method (Canisius et al., 2016) to calculate the significance that alterations in a given gene are less likely to co-occur with MYC.”

“…with previous knowledge and are therefore referred as ‘‘canonical’’ MYC gene sets, such as transcription and RNA processing, chromatin remodeling (L € uscher and Vervoorts, 2012; Nakagawara et al., 1987), and translational processes (Cowling and Cole, 2007), including gene sets corresponding to…”

“FUBP1 is known to bind to regulatory sequences of MYC and in the absence of this transcription factor, endogenous expression of MYC is blocked (He et al., 2000), indicating the functional dependence of MYC from FUBP1.”

“…such as transcription and RNA processing, chromatin remodeling (L € uscher and Vervoorts, 2012; Nakagawara et al., 1987), and translational processes (Cowling and Cole, 2007), including gene sets corresponding to ribosomal structural components and rRNA synthetic apparatus (Grandori et al.,…”

“The involvement of MYC as an oncogenic driver was described in a wide spectrum of tumor types as shown by early reports in leukemia (Dalla-Favera et al., 1983; Nowell et al., 1983), B cell lymphomas (Hayward et al., 1981), lung cancer (Little et al., 1983), and neuroblastoma (Schwab et al., 1983).”

“MYC functions with its heterodimerization partner MAX, through recognition of specific DNA elements (Blackwell et al., 1993; Fernandez et al., 2003; Grandori et al., 1996; Guc-cione et al., 2006), and recruitment of transcriptional co-regula-tory molecules linked to histone acetylation (Bouchard et…”

“These opposing transcriptional activities, together with functional assays showing that MXDs, MNT, and MGA proteins can antagonize the transforming activity of MYC in cell culture assays, raised the possibility that they function as tumor suppressors.”

“…PMN members and their interacting proteins may influence oncogenesis by increasing MYC expression, co-operating with or antagonizing MYC activity, and directly altering gene expression patterns independent of MYC, or a combination of these mechanisms (Diolaiti et al., 2015; Yang and Hurlin, 2017).”

“Furthermore, induction of miR-17–92 by MYC has been reported to be crucial for tumor cell survival and for tumor progression in multiple cancer types (Han et al., 2015; Li et al., 2014; Mu et al., 2009; Olive et al., 2009). miR-21, another bona fide human oncogene (Medina et al., 2010), and miR-27a,…”

“…functional consequences of MYC de-regulated expression and its influence on gene expression programs and DNA replication or repair processes during normal and oncogenic proliferation have been a subject of intense research (Domi-nguez-Sola and Gautier, 2014; Sabo and Amati, 2014; Walz et al., 2014).”

“…these gene sets as canonical pathways, as previously observed in experimental systems upon manipulation of MYC levels (Dominguez-Sola et al., 2007; Gomez-Roman et al., 2006; Grandori et al., 2003, 2005; Grewal et al., 2005; Hnisz et al., 2013; Johnston et al., 1999; Moser et al., 2012; Robinson…”

“The partial loss of MAX, an essential dimerization partner of MYC, seems to be counterintuitive, but loss of MAX dimerization with MXD, MNT, and MGA, all transcriptional MYC antagonists, may play a critical role in tumorigenesis for some cell types by reducing negative control of the PMN (Diolaiti et al., 2015; Nilsso…”

“, 2005), as well as DNA replication and repair (Dominguez-Sola and Gautier, 2014; Rohban and Campaner, 2015).”

“…function mutations in MGA, an essential gene encoding a >3,000 amino acid protein that contains both T-box and bHLHZ DNA binding domains, were recently reported to occur in chronic lymphocytic leukemia (De Paoli et al., 2013) and lung adenocarcinomas (Cancer Genome Atlas Research Network, 2014a).”

“These results support and broaden, at a pan-cancer level, previous studies demonstrating a distinction between MYC and MYCN overexpression on determining spe-cific cell lineages in genetic models of medulloblastoma (Roussel and Robinson, 2013; Vo et al., 2016).”

“…observed in experimental systems upon manipulation of MYC levels (Dominguez-Sola et al., 2007; Gomez-Roman et al., 2006; Grandori et al., 2003, 2005; Grewal et al., 2005; Hnisz et al., 2013; Johnston et al., 1999; Moser et al., 2012; Robinson et al., 2009; for a review see Ruggero, 2009).”

“Interestingly, MYC-synthetic lethal genes are enriched for similar pathways to the canonical MYC signature (Cermelli et al., 2014).”

“The functional consequences of MYC de-regulated expression and its influence on gene expression programs and DNA replication or repair processes during normal and oncogenic proliferation have been a subject of intense research (Domi-nguez-Sola and Gautier, 2014; Sabo and Amati, 2014; Walz et al., 2014).”

“…critical for its transforming potential in cell culture assays, recurrent shallow deletions of MAX were observed in some cancers, particularly pheochromocytomas and gastrointestinal stromal tumors (Burnichon et al., 2012; Comino-Me´ndez et al., 2011; Pantaleo et al., 2017; Schaefer et al., 2017).”

“…critical for its transforming potential in cell culture assays, recurrent shallow deletions of MAX were observed in some cancers, particularly pheochromocytomas and gastrointestinal stromal tumors (Burnichon et al., 2012; Comino-Me´ndez et al., 2011; Pantaleo et al., 2017; Schaefer et al., 2017).”

“Moreover, the MAX-like protein MLX forms dimers with MLXIP and MLXIPL transcription factors (also known as MONDOA and CHREBP, respectively), which can either support or antagonize MYC function depending on cell context (Wilde and Ayer, 2015).”

“Upon dysregulation and overexpression, MYC binds to lower-affinity sites in promoters and enhancers in a dose-dependent manner resulting in ectopic regulation (activation or repression) of thousands of genes (between (cid:1) 2,000 and 4,000 genes [de Pretis et al., 2017; Sabo` et al., 2014]).”

“…observed in experimental systems upon manipulation of MYC levels (Dominguez-Sola et al., 2007; Gomez-Roman et al., 2006; Grandori et al., 2003, 2005; Grewal et al., 2005; Hnisz et al., 2013; Johnston et al., 1999; Moser et al., 2012; Robinson et al., 2009; for a review see Ruggero, 2009).”

“Pan-cancerMYCNAlterations and Associated Pathways To date, MYCN has been largely considered a driver of selected pediatric cancers, such as neuroblastoma, where 25% of cases exhibit high levels ofMYCN copy-number gains with clear prognostic significance (Nakagawara et al., 1987).”

“Mutations in MYC that may affect MYC protein stability and/or activity have been described to occur in Burkitt’s lymphoma and diffuse large B cell lymphoma (Adhikary et al., 2005; Sal-ghetti et al., 1999; Zhang et al., 2013).”

“Similar to MAX, shallow deletion of MLX could interfere with the repressor activity of MXD and MNT, as well as alter MYC-induced metabolic reprogramming by disabling of MLXIP and MLXIPL (O’Shea and Ayer, 2013).”

“By contrast, loss of MNT, such as dysregulated MYC, is pro-apoptotic, can exacerbate the apoptotic activity of MYC, and abrogate MYC-driven tumorigenesis (Link et al., 2012).”

“In contrast to the predominant transcriptional activation function of MYC, the MXD, MXI1, MNT, and MGA proteins repress transcription through the recruitment of corepressor complexes (for reviews see Conacci-Sorrell et al., 2014; Link and Hurlin, 2015).”

“Shallow deletions of MAX were found in 5% of all TCGA samples.”

“…PMN members and their interacting proteins may influence oncogenesis by increasing MYC expression, co-operating with or antagonizing MYC activity, and directly altering gene expression patterns independent of MYC, or a combination of these mechanisms (Diolaiti et al., 2015; Yang and Hurlin, 2017).”

“Supporting this hypothesis, recurrent deletions in MXDs , MNT , and MGA genes have been identified in some human tumors (Edelmann et al., 2017), and mouse studies suggest that at least MNT and MXI1 can behave as tumor suppressors (Dezfouli et al., 2006).”

“…classical tumor suppressors as described for TP53 and P27KIP1 (Fero et al., 1998; Payne and Kemp, 2005), and is shown in this dataset and a recent publication (Vidotto et al., 2018) for PTEN , which exhibits a group with shallow deletions (one copy loss) and a wide range of the chromosome affected.”

“The involvement of MYC as an oncogenic driver was described in a wide spectrum of tumor types as shown by early reports in leukemia (Dalla-Favera et al., 1983; Nowell et al., 1983), B cell lymphomas (Hayward et al., 1981), lung cancer (Little et al., 1983), and neuroblastoma (Schwab et al., 1983).”

“Supporting this hypothesis, recurrent deletions in MXDs , MNT , and MGA genes have been identified in some human tumors (Edelmann et al., 2017), and mouse studies suggest that at least MNT and MXI1 can behave as tumor suppressors (Dezfouli et al., 2006).”

“…pancreatic and gastrointestinal cancers, while renal and brain cancers, among others, had almost no alterations in this pathway; and (3) Myc pathway (Schaub et al., 2018): Myc pathway alterations were most common in tumor types with amplification of chromosome 8, which contains MYC, such as breast…”

“MYC is overexpressed by different mechanisms in 60–70% of human solid and hematopoietic tumors [1,2,3,4,5].”

“As MYC governs this many processes, the notion that it could be modulated directly has proven to be difficult [269,270].”

“Whereas c-Myc plays a fundamental role as a “double-edged sword” promoting both iPS cells generation and malignant transformation, L-Myc contributes to the nuclear reprogramming with the significant down-regulation of differentiation-associated genetic expression.”

“T e Cancer Genome Atlas (TCGA) database shows that 28% of all cancer patients have the genetic abno maliti s in t least one of the Myc family co posed of c-Myc, n-Myc, and l-Myc [49].”

“The transcription factors MYC and MYCN, for instance, are recurrently amplified or translocated in a subset of cancers, and the MYC network is dysregulated in a significant percentage of human cancers (Dang, 2012; Schaub et al., 2018).”

“All these members dimerize with MAX, MLX, or both, and have different functions that can cooperate with Myc activity, antagonize it, alter gene expression directly and independently of Myc, or a combination of these mechanisms [3].”

“Deregulated and enhanced expression of the MYC proto-oncogene contributes to the development of most human tumors (Dang, 2012; Schaub et al., 2018), and mouse models demonstrate that many cancer cells depend on high levels of MYC (Gabay et al.”

“All Myc proteins are frequently deregulated in human cancers, where their expression level generally correlate with tumor aggressiveness [8,9].”

“Gene ampli fi cation can result from DNA replication errors, chromosome translocations or gene rearrangements (Albertson, 2006; Beroukhim et al., 2010; Matsui et al., 2013; Schaub et al., 2018).”

“Discussion Pan-cancer analysis can reveal similarities and differences in tumors, providing insights into cancer prevention and the design of therapeutic targets [30].”

“Given that MYC family members are focally amplified in 28% of human cancers (87), these results have broad implications for metastasis in tumor types other than PDAC (88).”

“PIK3CA-mutated cancers may be less likely to have oncogenic dysregulation of the MYC axis; however, evasion of PI3Ktargeted therapy can occur via MYC/eIF4E amplification, thus this pathway remains potentially important for acquired resistance to PI3K-directed therapy (24).”

“Recent analyses of TCGA data across many cancer types highlight frequent mutations and deletions in genes encoding MAX dimerization partners such as MNT, MGA, MXD3 and others (Schaub et al., 2018).”

“143,144 All these alterations result in higher or aberrantly sustained levels of MYC protein 145 (Fig.”

“The MYC oncogene is part of the gene superfamily, and its product is commonly activated in human cancers (94, 95).”

“c-MYC is a strong oncogenic driver in many cancers including acute leukemia [79].”

“Notably, chr8 harbors the MYC gene, which is one of the most frequently amplified genes in human cancers (17), whereas chr17 contains the ERBB2 gene, which is amplified in about 20% of all invasive breast cancers (18).”

“Genomic and proteomic features associated with MYC and the proximal MYC network were defined across the 33 cancers of TCGA by using computational approaches [8].”

“A recent systematic genomic analysis has demonstrated that altered expression and mutations in other members of this network expand the range of tumors in which MYC function is perturbed (Schaub et al. 2018).”

“A recent analysis of TCGA revealed that gene amplification of Myc paralogs occurs in 28% of samples analyzed, spanning the 33 solid cancer types available in TCGA, emphasizing the importance of this genetic alteration in tumorigenesis (Schaub et al., 2018).”

“Indeed, common genetic alterations such as amplification of the MYC oncogenes, (~28% pan-cancer) [15], mutations of the RAS family (~16% of cancers) [22], or alterations of tumor suppressor genes such as TP53 (mutated in 50% of cancers) [23] are difficult to target directly and currently lack FDA approved drugs.”

“MYC is a proproliferative oncogene, which has in recent years been reported to have various immunosuppressive functions (27, 35, 36, 37), and to have specific involvement in melanoma metastasis and invasiveness (38).”

“MYC oncoproteins in solid tumors are frequently activated by copy gains but may be also induced by a variety of other mechanisms (24); importantly, it is well established that even small changes in MYC levels can drive ectopic proliferation of somatic cells and oncogenesis (25–27).”

“This balance process is disrupted in tumor development since ampli fi cation of MYC and loss of MXD family genes occur during tumorigenesis, leading to the magni fi cation of MYC function [46].”

“Cancer Res; 81(2) January 15, 2021 CANCER RESEARCH 250”

“Among these, MYC gene amplification, copy-number variation, and somatic mutations are frequent in both adult and pediatric AML (1, 3, 4).”

“…mechanisms, with nuances observed across di ff erent cancer types [17,20]. mechanisms, with nuances observed across different cancer types [17,20] For example, MYC amplification is particularly common in breast cancer, neuroblastoma and For example, MYC ampli fi cation is particularly common…”

“Amplification of the gene encoding MYC is frequently observed in human cancers ((Dang et al., 2006, Schaub et al., 2018).”

“The activity of the MYC protein is tightly regulated by a protein interaction network that is centered on the MAX protein (10).”

“A recent study found that across the 33 tumor types included in The Cancer Genome Atlas, 28% have amplifications of at least one of the MYC paralogs (4).”

“Studies demonstrate that ovarian cancer and breast cancer cells highly depend on Myc for maintaining their tumoral growth, which can serve as a valuable target for the treatment of affected patients [26].”

“Overall, N-MYC and L-MYC are reportedly amplified in less than 7% of cancers[79], whereas C-MYC is amplified in 21%[87].”

“0 1000 2000 3000 Time since diagnosis (days) Su rv iv al p ro ba bi lit y low (61) medium (60) high (61) TCGA-PAAD +++++ ++ + ++++ ++++++++++++++ ++ ++ + ++ + + ++ + ++ ++ + + +++ + + + ++ + +++ + ++++++++++++++ + ++++ + + +++ ++ +++ ++ ++ + + +”

“participation in cancer pathogenesis, most studies only focused on the interconnection of this factor with varied intra‐ and extracellular programs, considering this protein as an intermediate molecule.(2) The first breakthrough in the identification of a leading role for c‐Myc in the initiation of ALL placed this mol…”

“TCGA analyzes 33 common tumor types using multi-omics data, offering the opportunity to uncover molecular aberrations across cancer types [34,35].”