A broad range of human malignancies is associated with nonrandom 1p36 deletions, suggesting the existence of tumor suppressors encoded in this region. Evidence for tumor-specific inactivation of 1p36 genes in the classic “two-hit” manner is scarce; however, many tumor suppressors do not require complete inactivation but contribute to tumorigenesis by partial impairment. We discuss recent data derived from both human tumors and functional cancer models indicating that the 1p36 genes CHD5, CAMTA1, KIF1B, CASZ1, and miR-34a contribute to cancer development when reduced in dosage by genomic copy number loss or other mechanisms. We explore potential interactions among these candidates and propose a model where heterozygous 1p36 deletion impairs oncosuppressive pathways via simultaneous downregulation of several dosage-dependent tumor suppressor genes. Cancer Res; 72(23); 6079–88. ©2012 AACR.

Deletions of the distal short arm of chromosome 1 (1p) are frequently observed in a broad range of human cancers, including breast cancer, cervical cancer, pancreatic cancer, pheochromocytoma, thyroid cancer, hepatocellular cancer, colorectal cancer, lung cancer, glioma, meningioma, neuroblastoma, melanoma, Merkel cell carcinoma, rhabdomyosarcoma, acute myeloid leukemia, chronic myeloid leukemia, and non-Hodgkin lymphoma (1, 2). These nonrandom aberrations suggest that loss of genetic information mapping to this region contributes to cancer development. This is supported by constitutional 1p aberrations in neuroblastoma patients (3, 4) and the association of 1p deletion with poor survival of neuroblastoma (5), breast cancer (6, 7), and colon cancer (8, 9) patients. Deletion of 1p in premalignant lesions and/or early tumor stages of colorectal, breast, and hepatocellular cancer (10–12) points to a role for 1p genes during the early steps of carcinogenesis in these entities. This is supported by loss of 1p material during in vitro progression in a cell culture model of colon carcinogenesis (13). Furthermore, transfer of 1p chromosomal material suppresses tumorigenicity of both neuroblastoma and colon carcinoma cells (14, 15).

Since the first report of 1p deletions in neuroblastomas in 1977 (16), smallest regions of overlapping heterozygous deletions (SRO) have been defined in various tumor entities in the pursuit of cancer-related genes. That 1p36 is a hot spot of chromosomal aberrations became clear early on (1), with the most detailed mapping picture appearing for neuroblastoma (Fig. 1; refs. 1, 17–29). Despite extensive 1p36 candidate gene sequence analyses, success was limited for identifying tumor-specific mutations in neuroblastomas or other malignancies, which led some to conclude that a deletion mapping approach was unlikely to deliver tumor suppressor genes. Many tumor suppressor genes, however, do not require inactivation in a classic “two-hit” manner but contribute to tumor development when their dosage is reduced, sometimes only subtly, by mechanisms such as copy number change, transcriptional repression, epigenetic downregulation, or aberrant miRNA regulation (30). Unlike in a classic “two-hit” mutational inactivation scenario, definite proof for dosage-sensitive tumor suppressor gene involvement is not offered by a single straight forward assay. Instead, evidence must be accumulated from genetic, epigenetic, and transcriptional analyses of human tumors and functional in vitro and in vivo assays. This review discusses five 1p36 genes, CHD5, CAMTA1, KIF1B, CASZ1, and miR-34a, recently suggested as tumor suppressor candidates and likely to be impaired by partial reduction as suggested by both their status in human cancers and their activity in functional cancer models.

Figure 1.

Localization of tumor suppressor candidates p73, CHD5, CAMTA1, miR-34a, KIF1β, and CASZ1 with respect to 1p36 alterations in human cancers. Horizontal bars illustrate the extension of commonly deleted regions; short vertical bars at their end represent the first nondeleted locus. Only size (5.4 Mb) and chromosomal extension (1p32.32–1p36.22) are available for the region identified by Bagchi et al. (22). Genomic positions correspond to the UCSC genome browser, assembly Feb. 2009 (GRCh37/hg19). Gray box, model illustrating potential interactions between 1p36 tumor suppressor candidates.

Figure 1.

Localization of tumor suppressor candidates p73, CHD5, CAMTA1, miR-34a, KIF1β, and CASZ1 with respect to 1p36 alterations in human cancers. Horizontal bars illustrate the extension of commonly deleted regions; short vertical bars at their end represent the first nondeleted locus. Only size (5.4 Mb) and chromosomal extension (1p32.32–1p36.22) are available for the region identified by Bagchi et al. (22). Genomic positions correspond to the UCSC genome browser, assembly Feb. 2009 (GRCh37/hg19). Gray box, model illustrating potential interactions between 1p36 tumor suppressor candidates.

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CHD5

Chromodomain helicase DNA binding (CHD) genes encode a class of ATPase-dependent DNA-binding proteins interacting with histones to modulate chromatin structure and transcription. CHD5 resides in 1p36.31, is preferentially expressed in neuronal tissues, and its product regulates genes involved in neuronal function, cell-cycle control, and chromatin remodeling (31). Functional evidence for a tumor suppressive role of mouse Chd5 derives from an elegant approach using chromosome engineering to generate mouse models with loss or gain of genomic regions corresponding to human 1p36 (22). Deletion of a Chd5-containing 4.3 Mb genomic subinterval, corresponding to 5.7 Mb of human 1p36, enhanced proliferation, loss of contact inhibition, spontaneous immortalization, and sensitivity to oncogenic transformation of cultured mouse embryonic fibroblasts. Mice with heterozygous deletion of this subinterval were prone to hyperplasia in a variety of tissues (22). Duplication of this subinterval in mouse embryonic fibroblasts inhibited proliferation and increased the senescent cell fraction. Mice with subinterval duplication had developmental abnormalities characterized by an increased apoptotic cell fraction in various tissues, including the neural tube (22). The identified subinterval includes 52 genes. Among 11 tested candidate genes, knockdown of only Chd5 functionally rescued the proliferative defect of mouse embryonic fibroblasts with duplication of the subinterval. Chd5 knockdown in wild-type cells induced phenotypic changes closely resembling the effects of the engineered deletion, including enhanced proliferation, sensitivity to oncogenic transformation, and inhibition of p19Arf/p53 (22). This suggests that Chd5 is a dose-dependent gene within the identified 4.3 Mb genomic subinterval that mediates the tumor suppressive mechanisms seen in mouse models. The functional role of human CHD5 in a cancer background was analyzed in neuroblastoma cells, where its overexpression had no impact on proliferation, morphology, differentiation, or apoptosis but significantly inhibited clonogenic growth in soft agar and xenograft tumor growth in mice (32). The absence of an impact on proliferation may indicate an already impaired p14Arf (human p19Arf homolog)/p53 pathway in these cells, a defect frequently seen in neuroblastomas (33).

CHD5 is one of 23 genes mapping to a 2 Mb SRO in neuroblastoma (34) and a 5.4 Mb SRO spanning 1p36.32 to 1p36.22 in glioma (Fig. 1; refs. 22, 34). An SRO containing Chd5 was identified in a lymphoma mouse model with chromosomal instability, and syntenic CHD5-containing deletions were discovered in human T-cell acute lymphoblastic leukemia/lymphomas (T-ALL; ref. 35). CHD5 mutations are rare in the entities analyzed so far. Heterozygous missense mutations were found in one of 30 neuroblastoma cell lines (34), 2 of 14 metastatic prostate tumors (36) and 3 of 123 primary ovarian cancers (37). Reports of CHD5 mutation frequency in breast cancer are controversial, ranging from 0% (0/60; ref. 37) to 8.5% (3/35; ref. 38). None of the studies have identified nonsense or frameshift mutations, and whether the missense mutations impair CHD5 function, remains to be investigated. Aberrant CHD5 promoter methylation in primary tumors was identified in 73% of gastric cancers, 17% of colon cancers, 10% of breast cancers, 10% of ovarian cancers, and 4% of gliomas (37, 39, 40), indicating that CHD5 downregulation via promoter methylation mediates a selective advantage in the development of a subset of human tumors. In neuroblastomas, low CHD5 expression is associated with high-risk features such as 1p deletion, amplified MYCN oncogene, and advanced stage (41). Furthermore, low CHD5 mRNA and protein expression in neuroblastomas are significantly associated with poor patient outcome, even when adjusted for established prognostic variables (32, 42). Together, this suggests that CHD5 is a neuronal gene whose dose reduction contributes to tumor development by inhibiting the p14Arf/p53 pathway. This function is likely to be mediated by CHD5 acting as a transcriptional regulator via chromatin remodeling, an idea supported by the presence of CHD5 in a multiprotein complex highly similar to NuRD chromatin remodeling complexes (31).

CAMTA1

CAMTA1 encodes a member of the calmodulin-binding transcription activator (CAMTA) protein family (43, 44), is localized in 1p36.31-p36.23 and predominantly expressed in neural tissues, including brain and spinal chord (45). CAMTA1 maps to virtually all recently described 1p36 neuroblastoma SROs (summarized in ref. 46 and Fig. 1), is the only gene mapping to a 150 Kb SRO in glioma (Fig. 1; ref. 23) and is homozygously deleted in a subgroup of glioblastomas (47). In colorectal cancers, deletion of a small region at 1p36.31-p36.23, including only the CAMTA1 gene, had the strongest impact on survival among all identified genomic alterations (48). A missense mutation was seen in one of 26 colorectal cancers (48), but somatic CAMTA1 mutations were not observed in neuroblastomas or gliomas (23, 49); however, CAMTA1 expression is significantly lower in high-risk tumors of both entities (46, 50). In neuroblastoma, low CAMTA1 mRNA expression is significantly associated with prognostic markers of poor outcome, including amplified MYCN and advanced tumor stage (46). Low CAMTA1 expression was also identified as a new independent marker of poor outcome adding prognostic information to existing risk stratification (46). Consequently, CAMTA1 is included in most recent prognostic neuroblastoma expression classifiers (51–54). Low CAMTA1 expression is also significantly associated with shorter survival in glioblastoma patients (50), and, intriguingly, low CAMTA1 expression emerged as a new independent predictor of poor outcome in patients with a tumor that is not of neural origin, colorectal cancer (48).

Functional evidence for a tumor suppressive role of CAMTA1 comes from analyses in neuroblastoma and glioblastoma cells. In neuroblastoma cells with low endogenous CAMTA1 levels, ectopic CAMTA1 expression inhibits proliferation, induces accumulation of cells in the G1–G0 phase of the cell cycle and inhibits anchorage-independent colony formation and xenograft tumor growth (55). CAMTA1 induction shifts neuroblastoma cell morphology toward a more differentiated type, including induction of neuron-specific markers. The transcriptome of CAMTA1-induced cells reflects their phenotype and is significantly enriched for genes that mediate cell-cycle inhibition and neuronal function (55). CAMTA1 is upregulated in neuroblastoma cells prompted to differentiate by retinoic acid or other stimuli (55). In glioblastoma cell models, CAMTA1 overexpression reduces both neurosphere formation and xenograft tumor growth, probably mediated by activation of natriuretic peptide A (NPPA), a secreted peptide with a strong antiproliferative effect on glioblastoma cells (50). The mechanisms downregulating CAMTA1 in high-risk tumors are largely unknown. CAMTA1 expression is significantly lower in neuroblastomas, gliomas, and colorectal cancers with 1p deletion compared with tumors retaining 1p (23, 46, 48). This conforms to a haploinsufficiency model where a single CAMTA1 copy would result in insufficient transcript levels. However, even in neuroblastomas without 1p deletion, low CAMTA1 expression predicts poor outcome (46), indicating additional CAMTA1-repressive mechanisms. No evidence for aberrant methylation of CAMTA1-associated CpG islands was found in neuroblastomas or colorectal cancers (48, 55), but other epigenetic mechanisms might be relevant, as indicated by upregulation of CAMTA1 in neuroblastoma cells treated with histone deacetylase inhibitors (55). Another mechanism of CAMTA1 downregulation was identified in glioblastoma cells, where it is targeted by miR-9/9*, a miRNA pair that is highly abundant in glioblastoma stem cell-enriched CD133+ cell populations (50). Summing up, nonrandom CAMTA1 deletions in tumors, the role of CAMTA1 in differentiation and growth suppression, and the strong association between CAMTA1 downregulation and poor survival in neuroblastoma, glioma, and colorectal cancer patients support its assignment as a dosage-dependent tumor suppressor gene.

Further evidence for an involvement of CAMTA1 in cancer comes from epithelioid hemangioendothelioma (EHE), a rare vascular sarcoma difficult to diagnose because of considerable morphological overlap with other epithelioid vascular tumors. Two independent studies identified an EHE-characteristic translocation, t(1;3)(p36.3;q25), involving WWTR1 (WW domain-containing transcription regulator 1) and CAMTA1 (45, 56). The WWTR1/CAMTA1 translocation was found in 100% (56) and 87% to 89% (45) of 2 EHE cohorts but in no other vascular neoplasm analyzed. The translocation results in a fusion gene encoding the N-terminus of WWTR1 fused in frame to the C-terminus of CAMTA1. This EHE-specific fusion has the potential to (i) serve as a new marker for tumor detection, diagnosis, and monitoring; (ii) provide a highly specific therapeutic target; and (iii) act as a study model to gather insights into the physiological functions of WWTR1 and CAMTA1. The identification of a highly specific CAMTA1-involving genomic rearrangement seen in virtually all tumors of a single cancer entity further implicates CAMTA1 in cancer development.

KIF1B

The KIF1B kinesin motor protein is involved in axon myelination and outgrowth as well as axonal transport of mitochondria and synaptic vesicles (57–59). KIF1B maps to 1p36.22 and encodes two alternatively spliced isoforms, KIF1Bα and KIF1Bβ, conferring different axonal cargo specificity. KIF1B is one of 6 genes within a 500 Kb homozygous deletion found in a neuroblastoma cell line (Fig. 1; refs. 20, 60). Sequence analysis did not reveal mutations in oligodendrogliomas or a panel of pediatric solid tumor cell lines, including rhabdomyosarcoma and Ewing sarcoma cells (61, 62). A missense variant of unknown functional significance was detected in 6 of 100 neuroblastomas (63). Another mutation screen identified missense variants in three of 111 neuroblastomas, 2 of 52 pheochromocytomas, and 1 of 14 medulloblastomas (64). Intriguingly, all variants identified in the latter study were shown to impair KIF1Bβ function in vitro (64), and one of these loss-of-function variants was present in the germline of a three-generation cancer-prone family, segregating with predisposition to pheochromocytoma, neuroblastoma, ganglioneuroma, and lung adenocarcinoma (65). This indicates that KIF1B sequence variants/mutations are infrequent but may be pathogenic in a subset of tumors, which is further supported by a KIF1B single-nucleotide polymorphism (SNP) highly associated with hepatitis virus B (HBV)-related hepatocellular carcinoma (66). KIF1B expression is significantly lower in advanced neuroblastoma stages (63, 67, 68), as is KIF1B expression in hepatocellular carcinomas from chronic HBV carriers compared with tumor-adjacent tissue (66).

Consistent with a tumor suppressive function, KIF1Bβ induction triggers apoptosis in neuroblastoma cells, pheochromocytoma cells, and rat sympathetic neurons (63, 64). KIF1Bβ knockdown in rat sympathetic neurons prevents apoptosis following nerve growth factor (NGF) withdrawal, indicating that KIF1Bβ plays a crucial role in neuronal apoptosis upon NGF limitation (64). KIF1Bβ knockdown also enhances anchorage-independent colony formation and xenograft tumor growth (63). Downregulation of KIF1B in advanced tumors can be mediated by heterozygous 1p loss, as indicated by significantly lower KIF1B levels in both gastrointestinal stromal tumors and neuroblastomas with heterozygous KIF1B deletion (63, 69). No evidence for methylation of KIF1B-associated CpG islands was found in neuroblastomas (63, 67), but chromatin remodeling mechanisms have been suggested to be relevant as the BMI1 Polycomb group protein strongly represses KIF1Bβ by direct binding to the KIF1B promoter (70). Intriguingly, MYCN/MYC oncoproteins directly bind to the BMI1 promoter and induce its transcription (70, 71), suggesting a model where MYCN/MYC represses KIF1B via BMI1-mediated epigenetic chromosome modification. Most MYCN-amplified neuroblastomas harbor 1p deletions indicating that KIF1B expression may be inhibited by both reduced copy number and amplified MYCN in this subgroup. A positive regulator of KIF1Bβ is the proapoptotic hydroxylase EGLN1, placing KIF1B in a pathway to eliminate excess neuroblasts during embryonal development (64) that is likely to be implicated in the pathogenesis of neural crest-derived tumors such as neuroblastomas and pheochromocytomas (72). The identification of functionally impairing KIF1B mutations in neuroblastoma, pheochromocytoma, and medulloblastoma, together with KIF1Bβ downregulation in advanced tumors and its inhibitory effect on cancer cells in vivo and in vitro, support a tumor suppressive function for KIF1B that is linked to its proapoptotic role.

CASZ1

Castor zinc finger 1 (CASZ1), localized in 1p36.22, is the human homolog of the Drosophila zinc finger transcription factor Castor, which is expressed in a subset of central nervous system neuroblasts and is involved in late stage neurogenesis (73). CASZ1 maps near the border of a 3 Mb SRO defined by integrating 1p deletions of neuroblastomas and germ cell tumors (Fig. 1; ref. 21). Sequence analysis did not reveal evidence for tumor-specific CASZ1 mutations (74), but low CASZ1 expression is significantly correlated with unfavorable clinical and biologic features and poor overall survival in neuroblastoma (75). Ectopic restoration of CASZ1 enhanced cell adhesion, induced morphological differentiation, accompanied by expression of neuron-specific markers, and inhibited migration, proliferation, and tumorigenicity (75). Furthermore, CASZ1 was increased in differentiating neuroblastoma cells treated with retinoic acid or cAMP-inducing agents (75, 76), which is in line with murine studies suggesting a developmental role for Casz1 in controlling neuronal subtype specification and differentiation (77). Transcriptome analysis of CASZ1-overexpressing neuroblastoma cells revealed signatures consistent with CASZ1-induced phenotypes and a significant enrichment of genes involved in cell growth regulation and developmental processes (75). One means of CASZ1 downregulation in cancer cells is genomic copy number loss, as indicated by lower CASZ1 expression in 1p-deleted tumors (75, 78). Evidence for tumor-specific promoter CpG methylation has not been reported (74, 75), but CASZ1 induction by histone deacetylase inhibitors in neuroblastoma cells (74, 75) suggests that suppressive histone modifications inhibit CASZ1 expression. This idea is corroborated by the finding that the CASZ1 locus is repressed by the enhancer of zeste homolog 2 (EZH2) Polycomb complex histone methyltransferase, an oncoprotein overexpressed in advanced tumors of various entities, including neuroblastoma (79). Together, these data suggest that CASZ1 is a cell growth and differentiation regulator that, when impaired by dosage reduction, contributes to the malignant phenotype of cancer cells.

miR-34a

MiRNAs are small noncoding RNAs involved in posttranscriptional control of gene expression, and their deregulation has been linked to a variety of diseases, including cancer. MiR-34a, localized in 1p36.22 (Fig. 1), is ubiquitously expressed, with highest levels in the brain (80). Aberrant miR-34a downregulation has been detected in many cancer types, including breast cancer (81), epithelial ovarian cancer (82), prostate carcinoma (80), pancreatic ductal adenocarcinoma (83), hepatocellular carcinoma (84), colon cancer (85), non–small cell lung cancer (86), neuroblastoma (87), glioblastoma (88), malignant peripheral nerve sheath tumors (89), melanoma (80), chronic lymphocytic leukemia (90–92), and acute myeloid leukemia (93). In many cancer entities, low miR-34a expression is associated with advanced disease and/or poor patient survival, as seen in neuroblastoma (87), epithelial ovarian cancer (82), peripheral nerve sheath tumors (89), breast cancer (81), and pancreatic ductal adenocarcinoma (83). Ectopic miR-34a expression induces cell cycle arrest, apoptosis, and senescence, and inhibits migration and invasion of cancer cells (94). MiR-34a is directly induced by p53 (95–99) and plays a pivotal role within a p53-activating positive feedback loop where mirR-34a downregulates the SIRT1 class III histone deacetylase, leading to accumulation of active acetylated p53 (100). Additional negative regulators of p53 (MTA2, HDAC1, and YY1) were identified as mir-34a targets (101, 102), indicating the existence of several mir-34a-dependent mechanisms functioning within p53-activating feed back loops. Bioinformatic analyses and global proteomic approaches indicate that regulation of hundreds of additional mir-34a targets contributes to mir-34a–associated cellular functions (101, 102). Validated direct targets include factors involved in G1/S transition (E2F3, cyclin E2, cyclin D1, CDK4, CDK6, MYC, MYCN), apoptosis (BCL2, Survivin), metastatic potential (MET, AXL), Wnt signaling (WNT1, LEF1), and glycolysis (LDHA; discussed in refs. 94 and 102). Other direct miR-34a targets play important roles in the Notch pathway (NOTCH1, NOTCH2, JAG1, DLL1; refs. 103–105), cancer stem cell functions (CD44; ref. 106), or growth factor signaling (ARAF, PIK3R2; ref. 107). Considering this broad spectrum of potentially oncogenic miR-34a targets, repression of miR-34a expression is likely to create a selective advantage for cancer cells, also supported by miR-34a downregulation during progressive carcinogenesis in a rat liver cancer model (108). Functional impairment of p53 downregulates miR-34a, as seen upon p53 knockdown in vivo (99). In line with this, low miR-34a expression is significantly associated with either deleted or mutated p53 in various malignancies (88, 90–92, 109–111). In lymphocytic leukemia, a SNP within the promoter of the p53 inhibitor MDM2 is associated with higher MDM2 levels and consequently lower miR-34a expression (111). In HPV-induced cervical cancer, the E6 oncoprotein destabilizes p53, resulting in miR-34a downregulation (112, 113). A p53-independent mechanism of miR-34a downregulation is seen in acute myeloid leukemia, where the C/EBPα gene, encoding a transcriptional activator of miR-34a, is mutated in 10% of the cases (93). Aberrant promoter CpG methylation is another frequent mechanism of miR-34a inhibition, reported with concomitant inhibition of expression in 79% of primary prostate carcinomas (80) and 74% of non–small cell lung cancer samples (86). Moreover, miR-34a promoter methylation was detected in melanoma (63%), colorectal cancer (74%), pancreatic cancer (64%), mammary cancer (60%), ovarian cancer (62%), urothelial cancer (71%), renal cell cancer (58%), soft tissue sarcoma (68%), chronic lymphocytic leukemia (4%), multiple myeloma (6%), and non-Hodgkin lymphoma (19%; refs. 80, 114, 115). An additional parameter affecting miR-34a expression is its genomic status, as indicated by significant association between lower miR-34a levels and 1p36 deletion in neuroblastomas (116, 117). In conclusion, miR-34a acts as a pivotal element in the p53 tumor suppressive pathway, and its recurrent downregulation by a broad range of mechanisms in various malignancies together with its inhibitory effect in cancer cell models suggests that aberrant reduction of miR-34a levels contributes to cancer development.

It has been recognized early on that 1p36 harbors genetic information mediating tumor suppression. Here, we summarize recent efforts substantiating the candidacy of CHD5, CAMTA1, KIF1B, CASZ1, and miR-34a to be 1p36 genes contributing to tumor development when reduced in dosage. Cancer-specific mutations of these candidates are infrequent but might play a role in a subset of tumors, as exemplified by rare KIF1B mutations impairing its in vitro function and segregating with cancer predisposition (65). However, the candidate genes seem to be impaired mainly on the transcriptional rather than the genetic level. Each of them was reported to be aberrantly downregulated in one or more cancer entity, and lower levels were associated with advanced disease and/or poor patient survival. Compensation of their dosage in cancer models via ectopic expression inhibited features of malignancy, including tumorigenicity in xenografts, and low expression of all candidates was significantly associated with 1p deletion in at least one tumor type. This may indicate that their dose reduction via single-copy loss compromises tumor suppressive functions and promotes cancer, as also seen for a growing number of haploinsufficient tumor suppressor genes (30).

Multiple tumor suppressive genes simultaneously downregulated via genomic deletion might cooperate in an additive or synergistic way, and targeting more than one component of a pathway or regulatory loop could be a mechanism of circumventing redundant backup mechanisms that compensate for the loss of single genes. Even within the limited set of 1p36 genes discussed here, potential interactions are found. It is tempting to speculate that a repressive effect of MYCN/MYC on KIF1B via BMI1 (70) may be inhibited by mir-34a impairing its direct target MYCN/MYC, thereby leading to an indirect activation of KIF1B by miR-34a. In this scenario, 1p36 deletion would affect KIF1B both by direct copy number loss and downregulation of its putative activator miR-34a. This cascade can be extended by adding p73, another 1p36 tumor suppressor candidate that has been extensively reviewed elsewhere (118, 119). p73 drives expression of miR-34a (120), so that 1p36 deletion would target an p73/miR-34a/MYC(N)/BMI1/KIF1B axis at 3 levels (Fig. 1, gray box). Another interaction level may be convergence of signals downstream of 1p36 genes on identical pathways. In an adequate cellular context, CHD5, CAMTA1, CASZ1, and miR-34a all activate genetic programs implicated in neuronal function and differentiation (31, 55, 75, 120). Expression of neuron-specific gene sets is associated with a markedly better prognosis in both neuroblastomas and gliomas (68, 121, 122). A simultaneous dosage-dependent impairment of the proneural regulators CHD5, CAMTA1, CASZ1, and miR-34a via 1p36 deletion could shift the transcriptome toward dedifferentiation, thus, contributing to neural tumor development. Taken together, dosage-dependent 1p36 genes are likely to interact on more than one level to suppress malignancy.

Considering that most 1p deletions in human tumors extend beyond 1p36 and that a certain fraction of genes reflects the copy number loss on the expression level, genes from other 1p regions may contribute to tumor suppression. Array-based expression analyses of 1p genes in oligodendrogliomas and neuroblastomas detected considerable copy number-dependent expression (123, 124). In neuroblastomas, 15% (124), 31% (125), and 61% (126) of all 1p genes were expressed significantly lower in 1p-deleted tumors compared with tumors retaining 1p, being in favor of a strong impact of heterozygous loss on the 1p transcriptome. Thus, repression of CHD5, CAMTA1, KIF1B, CASZ1, and miR-34a via genomic loss in an individual tumor is likely to be accompanied by downregulation of a set of other, potentially cancer-relevant genes, depending on extension and nature of the 1p deletion. Other 1p genes could contribute to tumor suppressive functions either by interaction with 1p36 genes or via independent routes. An example for an interregional interaction of proximal 1p genes with 1p36 genes can be proposed for CASZ1 regulation. EZH2, a potent suppressor of the CASZ1 locus (79) is a direct target of the 1p31.3-encoded miR-101 (127), and a large terminal deletion including 1p31 would affect both CASZ1 and its indirect activator, miR-101 (Fig. 1, gray box). A model where genes mapping to proximal 1p add to the tumor suppressive effect of 1p36 genes is further supported by the observation that neuroblastomas with large terminal deletions are more aggressive than neuroblastomas with small deletions confined to 1p36 (128). Interaction of cancer-relevant genes whose expression follows copy number aberrations is certainly not limited to 1p, considering that 1p deletion is associated with other genomic aberrations in most tumors. Expression of a substantial fraction of genes is altered consistently with the underlying genomic changes in a variety of malignancies, including colon cancer (129), prostate cancer (130), glioblastoma (131), neuroblastoma (125, 126), and multiple myeloma (132). An interchromosomal interaction of dosage-dependent genes can also be illustrated by the p73/miR-34a/MYC(N)/BMI1/KIF1B axis. Besides KIF1B, BMI1 suppresses CADM1 (70), a candidate for haploinsufficient tumor suppression mapping to 11q23. This region is recurrently lost in a broad range of solid tumors and hematological malignancies (133). Thus, the putative interaction cascade can be extended to p73/miR-34a/MYC(N)/BMI1/KIF1B-CADM1 and, accordingly, might be targeted by copy number–dependent gene deregulation via 1p36 deletion (p73, miR-34a, KIF1B), 11q23 deletion (CADM1), and/or MYC(N) amplification (Fig. 1, gray box). Collectively, in contrast to tumor suppressor inactivation by copy number-neutral gene-specific mutations, copy number–dependent downregulation of 1p36 candidates is likely to be accompanied by deregulation of a considerable set of other cancer-related genes. These may be either targeted by the same event (1p deletion) or genomic aberrations associated with 1p deletion. However, a large fraction of genes may passively reflect copy number change on the expression level without contributing to cancer development. Survival analyses adjusting for the respective copy number alteration may clarify whether the prognostic value of a gene's expression profile is independent of the underlying genomic alteration, as seen for CHD5 and CAMTA1 (32, 46). Such prognostic independency suggests that some tumors evolve additional, copy number–independent mechanisms to regulate these genes, and identifying such mechanisms may strengthen the position of the respective candidates.

A range of inhibitory mechanisms other than copy number loss were identified for the 1p36 candidates discussed here. Mir-34a is frequently downregulated by inactivation of upstream transcription factors, including p53 (88, 90–93, 109–111). Aberrant promoter CpG methylation for miR-34a and CHD5 was observed in a broad range of tumors (37, 39, 40, 80, 86, 114, 115). Epigenetic mechanisms acting via histone modifications have also been linked to impairment of tumor suppressive activities (134) and are likely to play a role in regulating CAMTA1 (55), CASZ1 via EZH2 (79), KIF1B via BMI1 (70), and CHD5, acting as a histone-interacting chromatin remodeler itself.

In conclusion, the 1p36 genes CHD5, CAMTA1, KIF1B, CASZ1, and miR-34a may not necessarily require biallelic inactivation in a classic “two-hit” manner but contribute to cancer development by partial dosage reduction via copy number loss or other mechanisms, including epigenetic inhibition. Functional studies indicate that these candidates cooperate to suppress tumorigenesis. Their codeletion may be one way for a developing cancer cell to acquire selective advantage by inhibiting an antioncogenic network at different positions in a single event. Aberrant expression of other dosage-dependent cancer-relevant genes on 1p or from associated copy number alterations in other chromosomes is likely to further contribute to this selective advantage. In such a setting, deletion mapping and SRO identification will not lead to identification of a single tumor suppressor gene that is completely inactivated by a second hit, but may guide the identification of a minimum gene set, whose reduction is required for tumorigenesis in a certain cellular context. Human genetics alone can deliver definitive proof of biallelic inactivation of a classic tumor suppressor gene, but unequivocal support for the dosage dependency of a tumor suppressor requires other lines of evidence, including mouse models. An elegant example of a tight correlation between tumor suppressor expression level and its functionality was shown by the generation of an allelic series of genetically engineered mice expressing varying levels of the Pten tumor suppressor (135). Surprisingly, even in animals with a subtle 20% reduction of the normal Pten level, tumor incidence was increased and survival was decreased, with the wild-type allele remaining fully functional in all induced tumors (135). A similar mouse-based assay may clarify whether a comparable dosage dependency can be modeled for the candidate genes discussed here.

In contrast to genetic inactivation of tumor suppressor genes by mutation, inhibitory mechanisms acting on the expression level are in principle reversible as long as an intact allele is present. This may pave the way for intervention strategies that restore expression of dosage-sensitive tumor suppressor genes. The genes discussed in this review are targeted by aberrant epigenetic mechanisms, at least in a subset of tumors, and recent advancements in depicting the enzymatic processes controlling the cancer epigenome should open doors for developing new therapeutic approaches (134).

No potential conflicts of interest were disclosed.

Conception and design: K.-O. Henrich, M. Schwab, F. Westermann

Development of methodology: K.-O. Henrich, M. Schwab

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): K.-O. Henrich, M. Schwab, F. Westermann

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): K.-O. Henrich, M. Schwab, F. Westermann

Writing, review, and/or revision of the manuscript: K.-O. Henrich, M. Schwab, F. Westermann

Study supervision: K.-O. Henrich, M. Schwab, F. Westermann

BMBF: NGFNPlus #01GS0896 (K.-O. Henrich, M. Schwab, and F. Westermann), MYC-NET, CancerSys #0316076A (F. Westermann), EU (FP7): ASSET #259348 (F. Westermann).

1.
Schwab
M
,
Praml
C
,
Amler
LC
. 
Genomic instability in 1p and human malignancies
.
Genes Chromosomes Cancer
1996
;
16
:
211
29
.
2.
Bagchi
A
,
Mills
AA
. 
The quest for the 1p36 tumor suppressor
.
Cancer Res
2008
;
68
:
2551
6
.
3.
Laureys
G
,
Speleman
F
,
Opdenakker
G
,
Benoit
Y
,
Leroy
J
. 
Constitutional translocation t(1;17)(p36;q12–21) in a patient with neuroblastoma
.
Genes Chromosomes Cancer
1990
;
2
:
252
4
.
4.
Biegel
JA
,
White
PS
,
Marshall
HN
,
Fujimori
M
,
Zackai
EH
,
Scher
CD
, et al
Constitutional 1p36 deletion in a child with neuroblastoma
.
Am J Hum Genet
1993
;
52
:
176
82
.
5.
Maris
JM
,
Weiss
MJ
,
Guo
C
,
Gerbing
RB
,
Stram
DO
,
White
PS
, et al
Loss of heterozygosity at 1p36 independently predicts for disease progression but not decreased overall survival probability in neuroblastoma patients: a Children's Cancer Group study
.
J Clin Oncol
2000
;
18
:
1888
99
.
6.
Ragnarsson
G
,
Eiriksdottir
G
,
Johannsdottir
JT
,
Jonasson
JG
,
Egilsson
V
,
Ingvarsson
S
. 
Loss of heterozygosity at chromosome 1p in different solid human tumours: association with survival
.
Br J Cancer
1999
;
79
:
1468
74
.
7.
Utada
Y
,
Emi
M
,
Yoshimoto
M
,
Kasumi
F
,
Akiyama
F
,
Sakamoto
G
, et al
Allelic loss at 1p34–36 predicts poor prognosis in node-negative breast cancer
.
Clin Cancer Res
2000
;
6
:
3193
8
.
8.
Ogunbiyi
OA
,
Goodfellow
PJ
,
Gagliardi
G
,
Swanson
PE
,
Birnbaum
EH
,
Fleshman
JW
, et al
Prognostic value of chromosome 1p allelic loss in colon cancer
.
Gastroenterology
1997
;
113
:
761
6
.
9.
Kambara
T
,
Sharp
GB
,
Nagasaka
T
,
Takeda
M
,
Sasamoto
H
,
Nakagawa
H
, et al
Allelic loss of a common microsatellite marker MYCL1: a useful prognostic factor of poor outcomes in colorectal cancer
.
Clin Cancer Res
2004
;
10
:
1758
63
.
10.
Di Vinci
A
,
Infusini
E
,
Peveri
C
,
Risio
M
,
Rossini
FP
,
Giaretti
W
. 
Deletions at chromosome 1p by fluorescence in situ hybridization are an early event in human colorectal tumorigenesis
.
Gastroenterology
1996
;
111
:
102
7
.
11.
Munn
KE
,
Walker
RA
,
Varley
JM
. 
Frequent alterations of chromosome 1 in ductal carcinoma in situ of the breast
.
Oncogene
1995
;
10
:
1653
7
.
12.
Kuroki
T
,
Fujiwara
Y
,
Tsuchiya
E
,
Nakamori
S
,
Imaoka
S
,
Kanematsu
T
, et al
Accumulation of genetic changes during development and progression of hepatocellular carcinoma: loss of heterozygosity of chromosome arm 1p occurs at an early stage of hepatocarcinogenesis
.
Genes Chromosomes Cancer
1995
;
13
:
163
7
.
13.
Williams
AC
,
Harper
SJ
,
Paraskeva
C
. 
Neoplastic transformation of a human colonic epithelial cell line: in vitro evidence for the adenoma to carcinoma sequence
.
Cancer Res
1990
;
50
:
4724
30
.
14.
Bader
SA
,
Fasching
C
,
Brodeur
GM
,
Stanbridge
EJ
. 
Dissociation of suppression of tumorigenicity and differentiation in vitro effected by transfer of single human chromosomes into human neuroblastoma cells
.
Cell Growth Differ
1991
;
2
:
245
55
.
15.
Tanaka
K
,
Yanoshita
R
,
Konishi
M
,
Oshimura
M
,
Maeda
Y
,
Mori
T
, et al
Suppression of tumourigenicity in human colon carcinoma cells by introduction of normal chromosome 1p36 region
.
Oncogene
1993
;
8
:
2253
8
.
16.
Brodeur
GM
,
Sekhon
G
,
Goldstein
MN
. 
Chromosomal aberrations in human neuroblastomas
.
Cancer
1977
;
40
:
2256
63
.
17.
Caron
H
,
Spieker
N
,
Godfried
M
,
Veenstra
M
,
van Sluis
P
,
de Kraker
J
, et al
Chromosome bands 1p35–36 contain two distinct neuroblastoma tumor suppressor loci, one of which is imprinted
.
Genes Chromosomes Cancer
2001
;
30
:
168
74
.
18.
Bauer
A
,
Savelyeva
L
,
Claas
A
,
Praml
C
,
Berthold
F
,
Schwab
M
. 
Smallest region of overlapping deletion in 1p36 in human neuroblastoma: a 1 Mbp cosmid and PAC contig
.
Genes Chromosomes Cancer
2001
;
31
:
228
39
.
19.
White
PS
,
Thompson
PM
,
Gotoh
T
,
Okawa
ER
,
Igarashi
J
,
Kok
M
, et al
Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma
.
Oncogene
2005
;
24
:
2684
94
.
20.
Ohira
M
,
Kageyama
H
,
Mihara
M
,
Furuta
S
,
Machida
T
,
Shishikura
T
, et al
Identification and characterization of a 500-kb homozygously deleted region at 1p36.2-p36.3 in a neuroblastoma cell line
.
Oncogene
2000
;
19
:
4302
7
.
21.
Ejeskar
K
,
Sjoberg
RM
,
Abel
F
,
Kogner
P
,
Ambros
PF
,
Martinsson
T
. 
Fine mapping of a tumour suppressor candidate gene region in 1p36.2–3, commonly deleted in neuroblastomas and germ cell tumours
.
Med Pediatr Oncol
2001
;
36
:
61
6
.
22.
Bagchi
A
,
Papazoglu
C
,
Wu
Y
,
Capurso
D
,
Brodt
M
,
Francis
D
, et al
CHD5 is a tumor suppressor at human 1p36
.
Cell
2007
;
128
:
459
75
.
23.
Barbashina
V
,
Salazar
P
,
Holland
EC
,
Rosenblum
MK
,
Ladanyi
M
. 
Allelic losses at 1p36 and 19q13 in gliomas: correlation with histologic classification, definition of a 150-kb minimal deleted region on 1p36, and evaluation of CAMTA1 as a candidate tumor suppressor gene
.
Clin Cancer Res
2005
;
11
:
1119
28
.
24.
Felsberg
J
,
Erkwoh
A
,
Sabel
MC
,
Kirsch
L
,
Fimmers
R
,
Blaschke
B
, et al
Oligodendroglial tumors: refinement of candidate regions on chromosome arm 1p and correlation of 1p/19q status with survival
.
Brain Pathol
2004
;
14
:
121
30
.
25.
Edstrom
Elder E
,
Nord
B
,
Carling
T
,
Juhlin
C
,
Backdahl
M
,
Hoog
A
, et al
Loss of heterozygosity on the short arm of chromosome 1 in pheochromocytoma and abdominal paraganglioma
.
World J Surg
2002
;
26
:
965
71
.
26.
Poetsch
M
,
Dittberner
T
,
Woenckhaus
C
. 
Microsatellite analysis at 1p36.3 in malignant melanoma of the skin: fine mapping in search of a possible tumour suppressor gene region
.
Melanoma Res
2003
;
13
:
29
33
.
27.
Girard
L
,
Zochbauer-Muller
S
,
Virmani
AK
,
Gazdar
AF
,
Minna
JD
. 
Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering
.
Cancer Res
2000
;
60
:
4894
906
.
28.
Bieche
I
,
Khodja
A
,
Lidereau
R
. 
Deletion mapping of chromosomal region 1p32-pter in primary breast cancer
.
Genes Chromosomes Cancer
1999
;
24
:
255
63
.
29.
Thorstensen
L
,
Qvist
H
,
Heim
S
,
Liefers
GJ
,
Nesland
JM
,
Giercksky
KE
, et al
Evaluation of 1p losses in primary carcinomas, local recurrences and peripheral metastases from colorectal cancer patients
.
Neoplasia
2000
;
2
:
514
22
.
30.
Berger
AH
,
Knudson
AG
,
Pandolfi
PP
. 
A continuum model for tumour suppression
.
Nature
2011
;
476
:
163
9
.
31.
Potts
RC
,
Zhang
P
,
Wurster
AL
,
Precht
P
,
Mughal
MR
,
Wood
WH
 3rd
, et al
CHD5, a brain-specific paralog of Mi2 chromatin remodeling enzymes, regulates expression of neuronal genes
.
PLoS One
2011
;
6
:
e24515
.
32.
Fujita
T
,
Igarashi
J
,
Okawa
ER
,
Gotoh
T
,
Manne
J
,
Kolla
V
, et al
CHD5, a tumor suppressor gene deleted from 1p36.31 in neuroblastomas
.
J Natl Cancer Inst
2008
;
100
:
940
9
.
33.
Van
Maerken
T
,
Vandesompele
J
,
Rihani
A
,
De Paepe
A
,
Speleman
F
. 
Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14(ARF)-MDM2-p53 axis
.
Cell Death Differ
2009
;
16
:
1563
72
.
34.
Okawa
ER
,
Gotoh
T
,
Manne
J
,
Igarashi
J
,
Fujita
T
,
Silverman
KA
, et al
Expression and sequence analysis of candidates for the 1p36.31 tumor suppressor gene deleted in neuroblastomas
.
Oncogene
2008
;
27
:
803
10
.
35.
Maser
RS
,
Choudhury
B
,
Campbell
PJ
,
Feng
B
,
Wong
KK
,
Protopopov
A
, et al
Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers
.
Nature
2007
;
447
:
966
71
.
36.
Robbins
CM
,
Tembe
WA
,
Baker
A
,
Sinari
S
,
Moses
TY
,
Beckstrom-Sternberg
S
, et al
Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors
.
Genome Res
2011
;
21
:
47
55
.
37.
Gorringe
KL
,
Choong
DY
,
Williams
LH
,
Ramakrishna
M
,
Sridhar
A
,
Qiu
W
, et al
Mutation and methylation analysis of the chromodomain-helicase-DNA binding 5 gene in ovarian cancer
.
Neoplasia
2008
;
10
:
1253
8
.
38.
Sjoblom
T
,
Jones
S
,
Wood
LD
,
Parsons
DW
,
Lin
J
,
Barber
TD
, et al
The consensus coding sequences of human breast and colorectal cancers
.
Science
2006
;
314
:
268
74
.
39.
Mulero-Navarro
S
,
Esteller
M
. 
Chromatin remodeling factor CHD5 is silenced by promoter CpG island hypermethylation in human cancer
.
Epigenetics
2008
;
3
:
210
5
.
40.
Wang
X
,
Lau
KK
,
So
LK
,
Lam
YW
. 
CHD5 is down-regulated through promoter hypermethylation in gastric cancer
.
J Biomed Sci
2009
;
16
:
95
.
41.
Thompson
PM
,
Gotoh
T
,
Kok
M
,
White
PS
,
Brodeur
GM
. 
CHD5, a new member of the chromodomain gene family, is preferentially expressed in the nervous system
.
Oncogene
2003
;
22
:
1002
11
.
42.
Garcia
I
,
Mayol
G
,
Rodriguez
E
,
Sunol
M
,
Gershon
TR
,
Rios
J
, et al
Expression of the neuron-specific protein CHD5 is an independent marker of outcome in neuroblastoma
.
Mol Cancer
2010
;
9
:
277
.
43.
Bouche
N
,
Scharlat
A
,
Snedden
W
,
Bouchez
D
,
Fromm
H
. 
A novel family of calmodulin-binding transcription activators in multicellular organisms
.
J Biol Chem
2002
;
277
:
21851
61
.
44.
Henrich
KO
. 
CAMTA1 (calmodulin binding transcription activator 1)
.
Atlas Genet Cytogenet Oncol Haematol
2011
;
15
:
441
2
.
45.
Tanas
MR
,
Sboner
A
,
Oliveira
AM
,
Erickson-Johnson
MR
,
Hespelt
J
,
Hanwright
PJ
, et al
Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma
.
Sci Transl Med
2011
;
3
:
98ra82
.
46.
Henrich
KO
,
Fischer
M
,
Mertens
D
,
Benner
A
,
Wiedemeyer
R
,
Brors
B
, et al
Reduced expression of CAMTA1 correlates with adverse outcome in neuroblastoma patients
.
Clin Cancer Res
2006
;
12
:
131
8
.
47.
Ichimura
K
,
Vogazianou
AP
,
Liu
L
,
Pearson
DM
,
Backlund
LM
,
Plant
K
, et al
1p36 is a preferential target of chromosome 1 deletions in astrocytic tumours and homozygously deleted in a subset of glioblastomas
.
Oncogene
2008
;
27
:
2097
108
.
48.
Kim
MY
,
Yim
SH
,
Kwon
MS
,
Kim
TM
,
Shin
SH
,
Kang
HM
, et al
Recurrent genomic alterations with impact on survival in colorectal cancer identified by genome-wide array comparative genomic hybridization
.
Gastroenterology
2006
;
131
:
1913
24
.
49.
Henrich
KO
,
Claas
A
,
Praml
C
,
Benner
A
,
Mollenhauer
J
,
Poustka
A
, et al
Allelic variants of CAMTA1 and FLJ10737 within a commonly deleted region at 1p36 in neuroblastoma
.
Eur J Cancer
2007
;
43
:
607
16
.
50.
Schraivogel
D
,
Weinmann
L
,
Beier
D
,
Tabatabai
G
,
Eichner
A
,
Zhu
JY
, et al
CAMTA1 is a novel tumour suppressor regulated by miR-9/9(*) in glioblastoma stem cells
.
EMBO J
2011
;
30
:
4309
22
.
51.
Asgharzadeh
S
,
Pique-Regi
R
,
Sposto
R
,
Wang
H
,
Yang
Y
,
Shimada
H
, et al
Prognostic significance of gene expression profiles of metastatic neuroblastomas lacking MYCN gene amplification
.
J Natl Cancer Inst
2006
;
98
:
1193
203
.
52.
Oberthuer
A
,
Berthold
F
,
Warnat
P
,
Hero
B
,
Kahlert
Y
,
Spitz
R
, et al
Customized oligonucleotide microarray gene expression-based classification of neuroblastoma patients outperforms current clinical risk stratification
.
J Clin Oncol
2006
;
24
:
5070
8
.
53.
Vermeulen
J
,
De Preter
K
,
Naranjo
A
,
Vercruysse
L
,
Van Roy
N
,
Hellemans
J
, et al
Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study
.
Lancet Oncol
2009
;
10
:
663
71
.
54.
Warnat
P
,
Oberthuer
A
,
Fischer
M
,
Westermann
F
,
Eils
R
,
Brors
B
. 
Cross-study analysis of gene expression data for intermediate neuroblastoma identifies two biological subtypes
.
BMC Cancer
2007
;
7
:
89
.
55.
Henrich
KO
,
Bauer
T
,
Schulte
J
,
Ehemann
V
,
Deubzer
H
,
Gogolin
S
, et al
CAMTA1, a 1p36 tumor suppressor candidate, inhibits growth and activates differentiation programs in neuroblastoma cells
.
Cancer Res
2011
;
71
:
3142
51
.
56.
Errani
C
,
Zhang
L
,
Sung
YS
,
Hajdu
M
,
Singer
S
,
Maki
RG
, et al
A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites
.
Genes Chromosomes Cancer
2011
;
50
:
644
53
.
57.
Nangaku
M
,
Sato-Yoshitake
R
,
Okada
Y
,
Noda
Y
,
Takemura
R
,
Yamazaki
H
, et al
KIF1B, a novel microtubule plus end-directed monomeric motor protein for transport of mitochondria
.
Cell
1994
;
79
:
1209
20
.
58.
Lyons
DA
,
Naylor
SG
,
Scholze
A
,
Talbot
WS
. 
Kif1b is essential for mRNA localization in oligodendrocytes and development of myelinated axons
.
Nat Genet
2009
;
41
:
854
8
.
59.
Zhao
C
,
Takita
J
,
Tanaka
Y
,
Setou
M
,
Nakagawa
T
,
Takeda
S
, et al
Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta
.
Cell
2001
;
105
:
587
97
.
60.
Yang
HW
,
Chen
YZ
,
Takita
J
,
Soeda
E
,
Piao
HY
,
Hayashi
Y
. 
Genomic structure and mutational analysis of the human KIF1B gene which is homozygously deleted in neuroblastoma at chromosome 1p36.2
.
Oncogene
2001
;
20
:
5075
83
.
61.
Alonso
ME
,
Bello
MJ
,
Arjona
D
,
Gonzalez-Gomez
P
,
Aminoso
C
,
Lopez-Marin
I
, et al
Mutational study of the 1p located genes p18ink4c, Patched-2, RIZ1 and KIF1B in oligodendrogliomas
.
Oncol Rep
2005
;
13
:
539
42
.
62.
Chen
YY
,
Takita
J
,
Chen
YZ
,
Yang
HW
,
Hanada
R
,
Yamamoto
K
, et al
Genomic structure and mutational analysis of the human KIF1Balpha gene located at 1p36.2 in neuroblastoma
.
Int J Oncol
2003
;
23
:
737
44
.
63.
Munirajan
AK
,
Ando
K
,
Mukai
A
,
Takahashi
M
,
Suenaga
Y
,
Ohira
M
, et al
KIF1Bbeta functions as a haploinsufficient tumor suppressor gene mapped to chromosome 1p36.2 by inducing apoptotic cell death
.
J Biol Chem
2008
;
283
:
24426
34
.
64.
Schlisio
S
,
Kenchappa
RS
,
Vredeveld
LC
,
George
RE
,
Stewart
R
,
Greulich
H
, et al
The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor
.
Genes Dev
2008
;
22
:
884
93
.
65.
Yeh
IT
,
Lenci
RE
,
Qin
Y
,
Buddavarapu
K
,
Ligon
AH
,
Leteurtre
E
, et al
A germline mutation of the KIF1B beta gene on 1p36 in a family with neural and nonneural tumors
.
Hum Genet
2008
;
124
:
279
85
.
66.
Zhang
H
,
Zhai
Y
,
Hu
Z
,
Wu
C
,
Qian
J
,
Jia
W
, et al
Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers
.
Nat Genet
2010
;
42
:
755
8
.
67.
Caren
H
,
Ejeskar
K
,
Fransson
S
,
Hesson
L
,
Latif
F
,
Sjoberg
RM
, et al
A cluster of genes located in 1p36 are down-regulated in neuroblastomas with poor prognosis, but not due to CpG island methylation
.
Mol Cancer
2005
;
4
:
10
.
68.
Ohira
M
,
Morohashi
A
,
Inuzuka
H
,
Shishikura
T
,
Kawamoto
T
,
Kageyama
H
, et al
Expression profiling and characterization of 4200 genes cloned from primary neuroblastomas: identification of 305 genes differentially expressed between favorable and unfavorable subsets
.
Oncogene
2003
;
22
:
5525
36
.
69.
Astolfi
A
,
Nannini
M
,
Pantaleo
MA
,
Di Battista
M
,
Heinrich
MC
,
Santini
D
, et al
A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number
.
Lab Invest
2010
;
90
:
1285
94
.
70.
Ochiai
H
,
Takenobu
H
,
Nakagawa
A
,
Yamaguchi
Y
,
Kimura
M
,
Ohira
M
, et al
Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1Bbeta and TSLC1 in neuroblastoma
.
Oncogene
2010
;
29
:
2681
90
.
71.
Huang
R
,
Cheung
NK
,
Vider
J
,
Cheung
IY
,
Gerald
WL
,
Tickoo
SK
, et al
MYCN and MYC regulate tumor proliferation and tumorigenesis directly through BMI1 in human neuroblastomas
.
FASEB J
2011
;
25
:
4138
49
.
72.
Lee
S
,
Nakamura
E
,
Yang
H
,
Wei
W
,
Linggi
MS
,
Sajan
MP
, et al
Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer
.
Cancer Cell
2005
;
8
:
155
67
.
73.
Mellerick
DM
,
Kassis
JA
,
Zhang
SD
,
Odenwald
WF
. 
Castor encodes a novel zinc finger protein required for the development of a subset of CNS neurons in Drosophila
.
Neuron
1992
;
9
:
789
803
.
74.
Caren
H
,
Fransson
S
,
Ejeskar
K
,
Kogner
P
,
Martinsson
T
. 
Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours
.
Br J Cancer
2007
;
97
:
1416
24
.
75.
Liu
Z
,
Yang
X
,
Li
Z
,
McMahon
C
,
Sizer
C
,
Barenboim-Stapleton
L
, et al
CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression
.
Cell Death Differ
2011
;
18
:
1174
83
.
76.
Liu
Z
,
Yang
X
,
Tan
F
,
Cullion
K
,
Thiele
CJ
. 
Molecular cloning and characterization of human Castor, a novel human gene upregulated during cell differentiation
.
Biochem Biophys Res Commun
2006
;
344
:
834
44
.
77.
Vacalla
CM
,
Theil
T
. 
Cst, a novel mouse gene related to Drosophila Castor, exhibits dynamic expression patterns during neurogenesis and heart development
.
Mech Dev
2002
;
118
:
265
8
.
78.
Fransson
S
,
Martinsson
T
,
Ejeskar
K
. 
Neuroblastoma tumors with favorable and unfavorable outcomes: significant differences in mRNA expression of genes mapped at 1p36.2
.
Genes Chromosomes Cancer
2007
;
46
:
45
52
.
79.
Wang
C
,
Liu
Z
,
Woo
CW
,
Li
Z
,
Wang
L
,
Wei
JS
, et al
EZH2 mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3 and NGFR
.
Cancer Res
2012
;
72
:
315
24
.
80.
Lodygin
D
,
Tarasov
V
,
Epanchintsev
A
,
Berking
C
,
Knyazeva
T
,
Korner
H
, et al
Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer
.
Cell Cycle
2008
;
7
:
2591
600
.
81.
Peurala
H
,
Greco
D
,
Heikkinen
T
,
Kaur
S
,
Bartkova
J
,
Jamshidi
M
, et al
MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer
.
PLoS One
2011
;
6
:
e26122
.
82.
Corney
DC
,
Hwang
CI
,
Matoso
A
,
Vogt
M
,
Flesken-Nikitin
A
,
Godwin
AK
, et al
Frequent downregulation of miR-34 family in human ovarian cancers
.
Clin Cancer Res
2010
;
16
:
1119
28
.
83.
Jamieson
NB
,
Morran
DC
,
Morton
JP
,
Ali
A
,
Dickson
EJ
,
Carter
CR
, et al
MicroRNA molecular profiles associated with diagnosis, clinicopathologic criteria, and overall survival in patients with Resectable Pancreatic Ductal Adenocarcinoma
.
Clin Cancer Res
2012
;
18
:
534
45
.
84.
Li
N
,
Fu
H
,
Tie
Y
,
Hu
Z
,
Kong
W
,
Wu
Y
, et al
miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells
.
Cancer Lett
2009
;
275
:
44
53
.
85.
Tazawa
H
,
Tsuchiya
N
,
Izumiya
M
,
Nakagama
H
. 
Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells
.
Proc Natl Acad Sci U S A
2007
;
104
:
15472
7
.
86.
Gallardo
E
,
Navarro
A
,
Vinolas
N
,
Marrades
RM
,
Diaz
T
,
Gel
B
, et al
miR-34a as a prognostic marker of relapse in surgically resected non-small-cell lung cancer
.
Carcinogenesis
2009
;
30
:
1903
9
.
87.
Welch
C
,
Chen
Y
,
Stallings
RL
. 
MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells
.
Oncogene
2007
;
26
:
5017
22
.
88.
Li
Y
,
Guessous
F
,
Zhang
Y
,
Dipierro
C
,
Kefas
B
,
Johnson
E
, et al
MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes
.
Cancer Res
2009
;
69
:
7569
76
.
89.
Subramanian
S
,
Thayanithy
V
,
West
RB
,
Lee
CH
,
Beck
AH
,
Zhu
S
, et al
Genome-wide transcriptome analyses reveal p53 inactivation mediated loss of miR-34a expression in malignant peripheral nerve sheath tumours
.
J Pathol
2010
;
220
:
58
70
.
90.
Dijkstra
MK
,
van Lom
K
,
Tielemans
D
,
Elstrodt
F
,
Langerak
AW
,
van 't Veer
MB
, et al
17p13/TP53 deletion in B-CLL patients is associated with microRNA-34a downregulation
.
Leukemia
2009
;
23
:
625
7
.
91.
Mraz
M
,
Malinova
K
,
Kotaskova
J
,
Pavlova
S
,
Tichy
B
,
Malcikova
J
, et al
miR-34a, miR-29c and miR-17–5p are downregulated in CLL patients with TP53 abnormalities
.
Leukemia
2009
;
23
:
1159
63
.
92.
Zenz
T
,
Mohr
J
,
Eldering
E
,
Kater
AP
,
Buhler
A
,
Kienle
D
, et al
miR-34a as part of the resistance network in chronic lymphocytic leukemia
.
Blood
2009
;
113
:
3801
8
.
93.
Pulikkan
JA
,
Peramangalam
PS
,
Dengler
V
,
Ho
PA
,
Preudhomme
C
,
Meshinchi
S
, et al
C/EBPalpha regulated microRNA-34a targets E2F3 during granulopoiesis and is down-regulated in AML with CEBPA mutations
.
Blood
2010
;
116
:
5638
49
.
94.
Hermeking
H
. 
The miR-34 family in cancer and apoptosis
.
Cell Death Differ
2010
;
17
:
193
9
.
95.
Chang
TC
,
Wentzel
EA
,
Kent
OA
,
Ramachandran
K
,
Mullendore
M
,
Lee
KH
, et al
Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis
.
Mol Cell
2007
;
26
:
745
52
.
96.
He
L
,
He
X
,
Lim
LP
,
de Stanchina
E
,
Xuan
Z
,
Liang
Y
, et al
A microRNA component of the p53 tumour suppressor network
.
Nature
2007
;
447
:
1130
4
.
97.
Raver-Shapira
N
,
Marciano
E
,
Meiri
E
,
Spector
Y
,
Rosenfeld
N
,
Moskovits
N
, et al
Transcriptional activation of miR-34a contributes to p53-mediated apoptosis
.
Mol Cell
2007
;
26
:
731
43
.
98.
Tarasov
V
,
Jung
P
,
Verdoodt
B
,
Lodygin
D
,
Epanchintsev
A
,
Menssen
A
, et al
Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest
.
Cell Cycle
2007
;
6
:
1586
93
.
99.
Bommer
GT
,
Gerin
I
,
Feng
Y
,
Kaczorowski
AJ
,
Kuick
R
,
Love
RE
, et al
p53-mediated activation of miRNA34 candidate tumor-suppressor genes
.
Curr Biol
2007
;
17
:
1298
307
.
100.
Yamakuchi
M
,
Ferlito
M
,
Lowenstein
CJ
. 
miR-34a repression of SIRT1 regulates apoptosis
.
Proc Natl Acad Sci U S A
2008
;
105
:
13421
6
.
101.
Chen
QR
,
Yu
LR
,
Tsang
P
,
Wei
JS
,
Song
YK
,
Cheuk
A
, et al
Systematic proteome analysis identifies transcription factor YY1 as a direct target of miR-34a
.
J Proteome Res
2011
;
10
:
479
87
.
102.
Kaller
M
,
Liffers
ST
,
Oeljeklaus
S
,
Kuhlmann
K
,
Roh
S
,
Hoffmann
R
, et al
Genome-wide characterization of miR-34a induced changes in protein and mRNA expression by a combined pulsed SILAC and microarray analysis
.
Mol Cell Proteomics
2011
;
10
:
M111 010462
.
103.
de Antonellis
P
,
Medaglia
C
,
Cusanelli
E
,
Andolfo
I
,
Liguori
L
,
De Vita
G
, et al
MiR-34a targeting of Notch ligand delta-like 1 impairs CD15+/CD133+ tumor-propagating cells and supports neural differentiation in medulloblastoma
.
PLoS One
2011
;
6
:
e24584
.
104.
Guessous
F
,
Zhang
Y
,
Kofman
A
,
Catania
A
,
Li
Y
,
Schiff
D
, et al
microRNA-34a is tumor suppressive in brain tumors and glioma stem cells
.
Cell Cycle
2010
;
9
:
1031
6
.
105.
Pang
RT
,
Leung
CO
,
Ye
TM
,
Liu
W
,
Chiu
PC
,
Lam
KK
, et al
MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells
.
Carcinogenesis
2010
;
31
:
1037
44
.
106.
Liu
C
,
Kelnar
K
,
Liu
B
,
Chen
X
,
Calhoun-Davis
T
,
Li
H
, et al
The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44
.
Nat Med
2011
;
17
:
211
5
.
107.
Lal
A
,
Thomas
MP
,
Altschuler
G
,
Navarro
F
,
O'Day
E
,
Li
XL
, et al
Capture of microRNA-bound mRNAs identifies the tumor suppressor miR-34a as a regulator of growth factor signaling
.
PLoS Genet
2011
;
7
:
e1002363
.
108.
Tryndyak
VP
,
Ross
SA
,
Beland
FA
,
Pogribny
IP
. 
Down-regulation of the microRNAs miR-34a, miR-127, and miR-200b in rat liver during hepatocarcinogenesis induced by a methyl-deficient diet
.
Mol Carcinog
2009
;
48
:
479
87
.
109.
Zenz
T
,
Habe
S
,
Denzel
T
,
Mohr
J
,
Winkler
D
,
Buhler
A
, et al
Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial
.
Blood
2009
;
114
:
2589
97
.
110.
Mraz
M
,
Pospisilova
S
,
Malinova
K
,
Slapak
I
,
Mayer
J
. 
MicroRNAs in chronic lymphocytic leukemia pathogenesis and disease subtypes
.
Leuk Lymphoma
2009
;
50
:
506
9
.
111.
Asslaber
D
,
Pinon
JD
,
Seyfried
I
,
Desch
P
,
Stocher
M
,
Tinhofer
I
, et al
microRNA-34a expression correlates with MDM2 SNP309 polymorphism and treatment-free survival in chronic lymphocytic leukemia
.
Blood
2010
;
115
:
4191
7
.
112.
Wang
X
,
Wang
HK
,
McCoy
JP
,
Banerjee
NS
,
Rader
JS
,
Broker
TR
, et al
Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6
.
RNA
2009
;
15
:
637
47
.
113.
Li
B
,
Hu
Y
,
Ye
F
,
Li
Y
,
Lv
W
,
Xie
X
. 
Reduced miR-34a expression in normal cervical tissues and cervical lesions with high-risk human papillomavirus infection
.
Int J Gynecol Cancer
2010
;
20
:
597
604
.
114.
Chim
CS
,
Wong
KY
,
Qi
Y
,
Loong
F
,
Lam
WL
,
Wong
LG
, et al
Epigenetic inactivation of the miR-34a in hematological malignancies
.
Carcinogenesis
2010
;
31
:
745
50
.
115.
Vogt
M
,
Munding
J
,
Gruner
M
,
Liffers
ST
,
Verdoodt
B
,
Hauk
J
, et al
Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas
.
Virchows Arch
2011
;
458
:
313
22
.
116.
Cole
KA
,
Attiyeh
EF
,
Mosse
YP
,
Laquaglia
MJ
,
Diskin
SJ
,
Brodeur
GM
, et al
A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene
.
Mol Cancer Res
2008
;
6
:
735
42
.
117.
Feinberg-Gorenshtein
G
,
Avigad
S
,
Jeison
M
,
Halevy-Berco
G
,
Mardoukh
J
,
Luria
D
, et al
Reduced levels of miR-34a in neuroblastoma are not caused by mutations in the TP53 binding site
.
Genes Chromosomes Cancer
2009
;
48
:
539
43
.
118.
Rufini
A
,
Agostini
M
,
Grespi
F
,
Tomasini
R
,
Sayan
BS
,
Niklison-Chirou
MV
, et al
p73 in Cancer
.
Genes Cancer
2011
;
2
:
491
502
.
119.
Oswald
C
,
Stiewe
T
. 
In good times and bad: p73 in cancer
.
Cell Cycle
2008
;
7
:
1726
31
.
120.
Agostini
M
,
Tucci
P
,
Killick
R
,
Candi
E
,
Sayan
BS
,
Rivetti di Val Cervo
P
, et al
Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets
.
Proc Natl Acad Sci U S A
2011
;
108
:
21093
8
.
121.
Fischer
M
,
Oberthuer
A
,
Brors
B
,
Kahlert
Y
,
Skowron
M
,
Voth
H
, et al
Differential expression of neuronal genes defines subtypes of disseminated neuroblastoma with favorable and unfavorable outcome
.
Clin Cancer Res
2006
;
12
:
5118
28
.
122.
Phillips
HS
,
Kharbanda
S
,
Chen
R
,
Forrest
WF
,
Soriano
RH
,
Wu
TD
, et al
Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis
.
Cancer Cell
2006
;
9
:
157
73
.
123.
Mukasa
A
,
Ueki
K
,
Matsumoto
S
,
Tsutsumi
S
,
Nishikawa
R
,
Fujimaki
T
, et al
Distinction in gene expression profiles of oligodendrogliomas with and without allelic loss of 1p
.
Oncogene
2002
;
21
:
3961
8
.
124.
Janoueix-Lerosey
I
,
Novikov
E
,
Monteiro
M
,
Gruel
N
,
Schleiermacher
G
,
Loriod
B
, et al
Gene expression profiling of 1p35–36 genes in neuroblastoma
.
Oncogene
2004
;
23
:
5912
22
.
125.
Lastowska
M
,
Viprey
V
,
Santibanez-Koref
M
,
Wappler
I
,
Peters
H
,
Cullinane
C
, et al
Identification of candidate genes involved in neuroblastoma progression by combining genomic and expression microarrays with survival data
.
Oncogene
2007
;
26
:
7432
44
.
126.
Wang
Q
,
Diskin
S
,
Rappaport
E
,
Attiyeh
E
,
Mosse
Y
,
Shue
D
, et al
Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number
.
Cancer Res
2006
;
66
:
6050
62
.
127.
Varambally
S
,
Cao
Q
,
Mani
RS
,
Shankar
S
,
Wang
X
,
Ateeq
B
, et al
Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer
.
Science
2008
;
322
:
1695
9
.
128.
Takeda
O
,
Homma
C
,
Maseki
N
,
Sakurai
M
,
Kanda
N
,
Schwab
M
, et al
There may be two tumor suppressor genes on chromosome arm 1p closely associated with biologically distinct subtypes of neuroblastoma
.
Genes Chromosomes Cancer
1994
;
10
:
30
9
.
129.
Tsafrir
D
,
Bacolod
M
,
Selvanayagam
Z
,
Tsafrir
I
,
Shia
J
,
Zeng
Z
, et al
Relationship of gene expression and chromosomal abnormalities in colorectal cancer
.
Cancer Res
2006
;
66
:
2129
37
.
130.
Wolf
M
,
Mousses
S
,
Hautaniemi
S
,
Karhu
R
,
Huusko
P
,
Allinen
M
, et al
High-resolution analysis of gene copy number alterations in human prostate cancer using CGH on cDNA microarrays: impact of copy number on gene expression
.
Neoplasia
2004
;
6
:
240
7
.
131.
Nigro
JM
,
Misra
A
,
Zhang
L
,
Smirnov
I
,
Colman
H
,
Griffin
C
, et al
Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma
.
Cancer Res
2005
;
65
:
1678
86
.
132.
Walker
BA
,
Leone
PE
,
Jenner
MW
,
Li
C
,
Gonzalez
D
,
Johnson
DC
, et al
Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma
.
Blood
2006
;
108
:
1733
43
.
133.
Knuutila
S
,
Aalto
Y
,
Autio
K
,
Bjorkqvist
AM
,
El-Rifai
W
,
Hemmer
S
, et al
DNA copy number losses in human neoplasms
.
Am J Pathol
1999
;
155
:
683
94
.
134.
Baylin
SB
,
Jones
PA
. 
A decade of exploring the cancer epigenome – biological and translational implications
.
Nat Rev Cancer
2011
;
11
:
726
34
.
135.
Alimonti
A
,
Carracedo
A
,
Clohessy
JG
,
Trotman
LC
,
Nardella
C
,
Egia
A
, et al
Subtle variations in Pten dose determine cancer susceptibility
.
Nat Genet
2010
;
42
:
454
8
.