The enzyme mTOR (mammalian target of rapamycin) is a major target for therapeutic intervention to treat many human diseases, including cancer, but very little is known about the processes that control levels of mTOR protein. Here, we show that mTOR is targeted for ubiquitination and consequent degradation by binding to the tumor suppressor protein FBXW7. Human breast cancer cell lines and primary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN (phosphatase and tensin homolog), which also activates mTOR. Tumor cell lines harboring deletions or mutations in FBXW7 are particularly sensitive to rapamycin treatment, which suggests that loss of FBXW7 may be a biomarker for human cancers susceptible to treatment with inhibitors of the mTOR pathway.

Integrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them were frequently silenced by epigenetic mechanisms. Notably, the pattern of genetic and epigenetic inactivation differed among B-NHL subtypes. Thus, the P53-inducible PIG7/LITAF was silenced by homozygous deletion in primary mediastinal B-cell lymphoma and by promoter hypermethylation in germinal center lymphoma, the proapoptotic BIM gene presented homozygous deletion in mantle cell lymphoma and promoter hypermethylation in Burkitt lymphoma, the proapoptotic BH3-only NOXA was mutated and preferentially silenced in diffuse large B-cell lymphoma, and INK4c/P18 was silenced by biallelic mutation in mantle-cell lymphoma. Our microarray strategy has identified novel candidate tumor suppressor genes inactivated by genetic and epigenetic mechanisms that substantially vary among the B-NHL subtypes.

Background: There is a lack of scientific consensus about cancer comorbidity in people with central nervous system (CNS) disorders. This study assesses the co-occurrence of cancers in patients with CNS disorders, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), autism spectrum disorders, Down's syndrome (DS), Huntington's disease (HD), multiple sclerosis (MS), Parkinson's disease (PD) and schizophrenia (SCZ). Method: Comprehensive search in PubMed/MEDLINE, Scopus and ISI Web of Knowledge of the literature published before March 2013. We identified 51 relevant articles from 2,229 discrete references, 50 of which contained data suitable for quantitative synthesis (577,013 participants). Pooled effect sizes (ES) were calculated using multiple random-effects meta-analyses. Sources of heterogeneity and uncertainty were explored by means of subgroup and sensitivity analyses, respectively. Results: The presence of CNS disorders was associated with a reduced co-occurrence of cancer (ES = 0.92; 95% confidence interval, CI: 0.87-0.98; I² = 94.5%). A consistently lower overall co-occurrence of cancer was detected in patients with neurodegenerative disorders (ES = 0.80; 95% CI: 0.75- 0.86; I² = 82.8%), and in those with AD (ES = 0.32; 95% CI: 0.22-0.46; I² = 0.0%), PD (ES = 0.83; 95% CI: 0.76-0.91; I² = 80.0%), MS (ES = 0.91; 95% CI: 0.87-0.95; I² = 30.3%) and HD (ES = 0.53; 95% CI: 0.42-0.67; I² = 56.4%). Patients with DS had a higher overall co-occurrence of cancer (ES = 1.46; 95% CI: 1.08-1.96; I² = 87.9%). No association was observed between cancer and ALS (ES = 0.97; 95% CI: 0.76-1.25; I² = 0.0%) or SCZ (ES = 0.98; 95% CI: 0.90-1.07; I² = 96.3%). Patients with PD, MS and SCZ showed (a) higher co-occurrence of some specific cancers (e.g. PD with melanoma, MS with brain cancers and SCZ with breast cancer), and (b) lower co-occurrence of other specific cancers (e.g. lung, prostate and colorectal cancers in PD; lung and prostate cancers in MS; and melanoma and prostate cancer in SCZ). Conclusion: Increased and decreased co-occurrence of cancer in patients with CNS disorders represents an opportunity to discover biological and non-biological connections between these complex disorders.

The MALT1 gene was identified through its involvement in t(11;18)(q21;q21), seen in 30% of cases of mucosa-associated lymphoid tissue (MALT) lymphoma. Here, we show that deregulated MALT1 expression may occur in B-cell non-Hodgkin lymphoma (B-NHL) of various histologic subtypes either through translocation to the immunoglobulin heavy chain (IGH) locus or by genomic amplification. First, 2 cases, one case of MALT lymphoma and another of aggressive marginal zone lymphoma (MZL) with t(14;18)(q32;q21), cytogenetically identical to the translocation involving BCL2, were shown by fluorescence in situ hybridization (FISH) to involve MALT1, which lies about 5 Mb centromeric of BCL2. Molecular cloning of both by long-distance inverse polymerase chain reaction showed breakpoints lying 1 to 2 kilobase (kb) centromeric of the first 5′ MALT1 exon; both cases showed MALT1 overexpression at either RNA or protein levels. Second, we examined the structure and gene expression profile of genomic amplifications involving 18q21 in a panel of 40 B-NHL cell lines using comparative genomic hybridization to microarrays (array CGH) and gene expression profiling techniques. Using array CGH, 2 peaks of genomic amplification were observed, one centered around BCL2 and the other around MALT1.Ofthe 3 cell lines with MALT1 amplification, 2 showed MALT1 overexpression as assessed by gene profiling, quantitative reverse transcription–polymerase chain reaction (QRT-PCR), and Western blotting. To determine if comparable events occurred in primary MALT and splenic MZL tumors, 40 cases were analyzed by FISH or QRT-PCR; genomic amplification and MALT1 overexpression were seen in 2 cases. Together, these data implicate MALT1 as a dominant oncogene that may play a role in the pathogenesis of B-NHL.

To identify recurrent genomic changes in mantle cell lymphoma (MCL), we used high-resolution comparative genomic hybridization (CGH) to bacterial artificial chromosome (BAC) microarrays in 68 patients and 9 MCL-derived cell lines. Array CGH defined an MCL genomic signature distinct from other B-cell lymphomas, including deletions of 1p21 and 11q22.3-ATM gene with coincident 10p12-BMI1 gene amplification and 10p14 deletion, along with a previously unidentified loss within 9q21-q22. Specific genomic alterations were associated with different subgroups of disease. Notably, 11 patients with leukemic MCL showed a different genomic profile than nodal cases, including 8p21.3 deletion at tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor gene cluster (55% versus 19%; P = .01) and gain of 8q24.1 at MYC locus (46% versus 14%; P = .015). Additionally, leukemic MCL exhibited frequent IGVH mutation (64% versus 21%; P = .009) with preferential VH4-39 use (36% versus 4%; P = .005) and followed a more indolent clinical course. Blastoid variants, increased number of genomic gains, and deletions of P16/INK4a and TP53 genes correlated with poorer outcomes, while 1p21 loss was associated with prolonged survival (P = .02). In multivariate analysis, deletion of 9q21-q22 was the strongest predictor for inferior survival (hazard ratio [HR], 6; confidence interval [CI], 2.3 to 15.7). Our study highlights the genomic profile as a predictor for clinical outcome and suggests that “genome scanning” of chromosomes 1p21, 9q21-q22, 9p21.3-P16/INK4a, and 17p13.1-TP53 may be clinically useful in MCL.

Deletions of chromosome 8p are a recurrent event in B-cell non-Hodgkin lymphoma (B-NHL), suggesting the presence of a tumor suppressor gene. We have characterized these deletions using comparative genomic hybridization to microarrays, fluorescence in situ hybridization (FISH) mapping, DNA sequencing, and functional studies. A minimal deleted region (MDR) of 600 kb was defined in chromosome 8p21.3, with one mantle cell lymphoma cell line (Z138) exhibiting monoallelic deletion of 650 kb. The MDR extended from bacterial artificial chromosome (BAC) clones RP11-382J24 and RP11-109B10 and included the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor gene loci. Sequence analysis of the individual expressed genes within the MDR and DNA sequencing of the entire MDR in Z138 did not reveal any mutation. Gene expression analysis and quantitative reverse transcriptase–polymerase chain reaction (QRT-PCR) showed down-regulation of TRAIL-R1 and TRAIL-R2 receptor genes as a consistent event in B-NHL with 8p21.3 loss. Epigenetic inactivation was excluded via promoter methylation analysis. In vitro studies showed that TRAIL-induced apoptosis was dependent on TRAIL-R1 and/or -R2 dosage in most tumors. Resistance to apoptosis of cell lines with 8p21.3 deletion was reversed by restoration of TRAIL-R1 or TRAIL-R2 expression by gene transfection. Our data suggest that TRAIL-R1 and TRAIL-R2 act as dosage-dependent tumor suppressor genes whose monoallelic deletion can impair TRAIL-induced apoptosis in B-cell lymphoma.