Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers

AbstractThe classic two-hit model posits that both alleles of a tumor suppressor gene (TSG) must be inactivated to cause cancer. In contrast, for some oncogenes and haploinsufficient TSGs, a single genetic alteration can suffice to increase tumor fitness. Here, by quantifying the interactions between mutations and copy number alterations (CNAs) across 10,000 tumors, we show that many cancer genes actually switch between acting as one-hit or two-hit drivers. Third order genetic interactions identify the causes of some of these switches in dominance and dosage sensitivity as mutations in other genes in the same biological pathway. The correct genetic model for a gene thus depends on the other mutations in a genome, with a second hit in the same gene or an alteration in a different gene in the same pathway sometimes representing alternative evolutionary paths to cancer.

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Recurrent DNA copy number alterations in intestinal-type sinonasal adenocarcinoma

Rhinology Journal ◽

10.4193/rhino15.382 ◽

2016 ◽

Vol 54 (3) ◽

pp. 278-286

Author(s):

J. Perez-Escuredo ◽

A. Lopez-Hernandez ◽

M. Costales ◽

F. Lopez ◽

S.P. Ares ◽

...

Keyword(s):

Clinical Outcome ◽

Copy Number ◽

Genetic Alterations ◽

Intestinal Type ◽

Dust Exposure ◽

Copy Number Alterations ◽

A Genome ◽

Sinonasal Adenocarcinoma ◽

Gains And Losses ◽

Microarray Cgh

Background: Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour related to occupational wood dust exposure. Few studies have described recurrent genetic changes on a genome-wide scale. The aim of this study was to obtain a high resolution map of recurrent genetic alterations in ITAC. Material and methods: Copy number alterations were evaluated by microarray CGH and MLPA in 37 primary tumours. The results were correlated with pathological characteristics and clinical outcome. Results: Microarray CGH identified the following recurrent aberrations, in descending order: gains at 5p15 (22 cases, 60%), 8q24 (21 cases, 57%), 20q13 (20 cases, 54%), 20q11, and 8q21 (19 cases, 51%), 20p13, and 7p11 (16 cases, 43%), and losses at 5q11-qter, 8p12-pter, and 18q12-23 (15 cases, 40%), and 17p13, and 19p13 (13 cases, 35%). MLPA analysis confirmed this global pattern of gains and losses. Chromosomal loss at 4q32-ter and gains at 1q22, 6p22 and 3q29, as well as deletion of TIMP2 and CRK correlated with unfavourable clinical outcome. Conclusion: ITACs have a unique pattern of chromosomal abnormalities. The four different histological subtypes of ITAC appeared genetically similar. Four chromosomal gains and losses and two specific genes showed prognostic value and may be involved in tumour progression.

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Abstract 1304: Whole-exome analysis of 1,135 melanomas reveals new significantly mutated cancer genes and copy number alterations

10.1158/1538-7445.am2018-1304 ◽

2018 ◽

Author(s):

Jake R. Conway ◽

David Liu ◽

Stephanie Wankowicz ◽

Amaro Taylor-Weiner ◽

Felix Dietlein ◽

...

Keyword(s):

Copy Number ◽

Cancer Genes ◽

Copy Number Alterations ◽

Whole Exome ◽

Exome Analysis

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Comparative Genomic Hybridization to Dna Microarrays

Microscopy and Microanalysis ◽

10.1017/s1431927600007911 ◽

1997 ◽

Vol 3 (S2) ◽

pp. 205-206

Author(s):

D. Pinkel ◽

R. Segraves ◽

D. Sudar ◽

L. van Vliet ◽

S. Clark ◽

...

Keyword(s):

Comparative Genomic Hybridization ◽

Copy Number ◽

Dna Microarrays ◽

Suppressor Gene ◽

Comparative Genomic ◽

Cancer Genes ◽

Genomic Hybridization ◽

Metaphase Chromosomes ◽

Number Variation ◽

Genetic Events

Comparative genomic hybridization (CGH), which involves the simultaneous hybridization of differentially labeled total genomic DNA from test cells and reference normal cells to metaphase chromosomes, has been used extensively to screen tumor genomes for regions of DNA sequence copy number variation. Analysis of these hybridizations requires quantitative analysis of the ratio of intensities of the fluorescent hybridization signals as a function of position along the chromosomes, which basically serve as a convenient genetic map. The ratios need to be measured very accurately since changes of about ± 20% from the average for the genome indicate important genetic events. Widespread use of CGH over the past several years has identified numerous regions of the genome that may contain currently unknown cancer genes. For example, regions of increased copy number may indicate sites of oncogenes, while regions of copy number decrease relative to average for the genome may signify the presence of a tumor suppressor gene.

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Identifying Key Somatic Copy Number Alterations Driving Dysregulation of Cancer Hallmarks in Lower-Grade Glioma

Frontiers in Genetics ◽

10.3389/fgene.2021.654736 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yao Zhou ◽

Shuai Wang ◽

Haoteng Yan ◽

Bo Pang ◽

Xinxin Zhang ◽

...

Keyword(s):

Copy Number ◽

Lower Grade ◽

Cancer Genes ◽

Copy Number Alterations ◽

Driver Genes ◽

Functional Roles ◽

Active Gene ◽

Gene Sets ◽

Lower Grade Glioma ◽

Somatic Copy Number Alterations

Somatic copy-number alterations (SCNAs) are major contributors to cancer development that are pervasive and highly heterogeneous in human cancers. However, the driver roles of SCNAs in cancer are insufficiently characterized. We combined network propagation and linear regression models to design an integrative strategy to identify driver SCNAs and dissect the functional roles of SCNAs by integrating profiles of copy number and gene expression in lower-grade glioma (LGG). We applied our strategy to 511 LGG patients and identified 98 driver genes that dysregulated 29 cancer hallmark signatures, forming 143 active gene-hallmark pairs. We found that these active gene-hallmark pairs could stratify LGG patients into four subtypes with significantly different survival times. The two new subtypes with similar poorest prognoses were driven by two different gene sets (one including EGFR, CDKN2A, CDKN2B, INFA8, and INFA5, and the other including CDK4, AVIL, and DTX3), respectively. The SCNAs of the two gene sets could disorder the same cancer hallmark signature in a mutually exclusive manner (including E2F_TARGETS and G2M_CHECKPOINT). Compared with previous methods, our strategy could not only capture the known cancer genes and directly dissect the functional roles of their SCNAs in LGG, but also discover the functions of new driver genes in LGG, such as IFNA5, IFNA8, and DTX3. Additionally, our method can be applied to a variety of cancer types to explore the pathogenesis of driver SCNAs and improve the treatment and diagnosis of cancer.

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A genome-wide query of somatic copy number alterations to predict lymph node metastases and survival in patients with muscle-invasive bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.325 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 325-325

Author(s):

Karla Lindquist ◽

Thomas Sanford ◽

Terence W. Friedlander ◽

Pamela Paris ◽

Sima P. Porten

Keyword(s):

Bladder Cancer ◽

Copy Number ◽

Treatment Decisions ◽

Invasive Bladder Cancer ◽

Copy Number Alterations ◽

Muscle Invasive Bladder Cancer ◽

Genome Wide ◽

A Genome ◽

Muscle Invasive ◽

One Year

325 Background: Patients with muscle-invasive bladder cancer (MIBC) have a poor prognosis if the cancer has metastasized to surrounding lymph nodes (LN). Adding tumor-based genomic tests that improve prediction of LN status and prognosis over clinical variables alone would be useful to clinicians in making treatment decisions, potentially improving outcomes for these patients. Methods: We performed a genome-wide query of copy number alterations (CNAs) in MIBC tumors from 237 patients in The Cancer Genome Atlas who had radical cystectomy and lymphadenectomy ( ≥ 10 nodes) without neoadjuvant treatment. We independently analyzed pathology reports and copy number data to confirm LN status and gene-level CNAs. Using elastic net and logistic regression models, we sought to identify a set of genes with CNAs that predict LN status. We also tested for association between CNAs and survival. Results: We identified 26 genes with CNAs that predicted LN status. Those located on chr3p25 and chr11p11 had gains associated with LN positivity after adjusting for age, gender, race, pathological tumor stage, histology, and number of nodes examined (p = 0.03). CNAs at these loci were also associated with one-year survival in the cohort overall (p < 0.01), as well as in LN-positive patients after adjusting for node stage, LN density, and extracapsular extension (p < 0.01). Conclusions: We have identified a small set of genes with CNAs in MIBC tumors that robustly predict LN status and one-year survival. A simple copy number-based test based on these genes could potentially improve preoperative LN status determination and help inform adjuvant treatment decisions to improve outcomes in MIBC patients.

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Overlapping high-resolution copy number alterations in cancer genomes identified putative cancer genes in hepatocellular carcinoma

Hepatology ◽

10.1002/hep.23847 ◽

2010 ◽

Vol 52 (5) ◽

pp. 1690-1701 ◽

Cited By ~ 38

Author(s):

Chian-Feng Chen ◽

En-Chi Hsu ◽

Kuen-Tyng Lin ◽

Pang-Hsien Tu ◽

Hung-Wei Chang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

High Resolution ◽

Copy Number ◽

Cancer Genes ◽

Copy Number Alterations ◽

Cancer Genomes

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Whole-genome sequencing of follicular thyroid carcinomas reveal recurrent mutations in microRNA processing subunit DGCR8

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab471 ◽

2021 ◽

Author(s):

Johan O Paulsson ◽

Nima Rafati ◽

Sebastian DiLorenzo ◽

Yi Chen ◽

Felix Haglund ◽

...

Keyword(s):

Copy Number ◽

Somatic Mutations ◽

Whole Genome ◽

Cancer Genes ◽

Copy Number Alterations ◽

Thyroid Carcinomas ◽

Future Studies ◽

Recurrent Mutations ◽

Microrna Processing ◽

Widely Invasive

Abstract Background The genomic and transcriptomic landscape of widely invasive follicular thyroid carcinomas (wiFTCs) and Hürthle cell carcinoma (HCC) are poorly characterized and subsets of these tumors lack information on genetic driver events. The aim of this study was to bridge this gap. Methods We performed whole-genome and RNA sequencing and subsequent bioinformatic analyses of 11 wiFTCs and 2 HCCs with a particularly poor prognosis, and matched normal tissue. Results All wiFTCs exhibited one or several mutations in established thyroid cancer genes, including TERT (n=4), NRAS (n=3), HRAS, KRAS, AKT, PTEN, PIK3CA, MUTYH, TSHR and MEN1 (n=1 each). MutSig2CV analysis revealed recurrent somatic mutations in FAM72D (n=3, in two wiFTCs and in a single HCC), TP53 (n=3, in two wiFTCs and a single HCC) and EIF1AX (n=3), with DGCR8 (n=2) as borderline significant. The DGCR8 mutations were recurrent p.E518K missense alterations, known to cause familial multinodular goiter via disruption of microRNA processing. Expression analyses showed reduced DGCR8 mRNA expression in FTCs in general, and the two DGCR8 mutants displayed a distinct miRNA profile compared to DGCR8 wildtypes. Copy number analyses revealed recurrent gains on chromosomes 4, 6 and 10, and fusiongene analyses revealed 27 high-quality events. Both HCCs displayed hyperploidy, which was fairly unusual in the FTC cohort. Based on the transcriptome data tumors amassed in two principal clusters. Conclusion We describe the genomic and transcriptomic landscape in wiFTCs and HCCs and identify novel recurrent mutations and copy number alterations with possible driver properties and lay the foundation for future studies.

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DNA Copy Number Changes Have Gene Dosage Effects with Consequent Impact On Disease Biology and Prognosis in Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.3984.3984 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3984-3984

Author(s):

Mehmet Kemal Samur ◽

Parantu K Shah ◽

Xujun Wang ◽

Norman Huang ◽

Stephane Minvielle ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Copy Number ◽

Dosage Effect ◽

Chromosome 9 ◽

Copy Number Alterations ◽

Dna Copy Number ◽

A Genome ◽

The Impact ◽

Affect Gene Expression

Abstract Abstract 3984 Copy number alterations, deletions and amplifications, are very frequent in multiple myeloma (MM), however, it is less clear how these alterations affect gene expression. We performed a genome-wide analysis of 170 newly-diagnosed uniformly treated MM patients using high-density SNP arrays and Exon ST 1.0 gene expression arrays, and evaluated how copy number alterations affect gene expression in MM. Using SNP array data just over 40% patients had hyperdiploid MM (HMM) while the rest had non-hyperdiploid MM (N-HMM). We used two-step procedure to identify dosage effect scores of genes. At first, for each gene, percentage of copy number altered samples was calculated. Then for each gene percentage of samples that had dosage effect was calculated. Finally dosage effect score for each gene was calculated as a ratio of dosage effect samples percentage to copy number alteration sample percentage. We show that dosage effect in MM is wide-spread and some chromosomal locations are affected by dosage effect more compared to other locations. The dosage effect tracks can be observed at trisomy chromosomes and chromosome 1q, but most explicitly at chromosome 9, 11, 15 and 19. Also for deleted genes, dosage effect can be mostly observed at chromosome 13 and 16q. Separate analysis of HMM and N-HMM patients also showed that HMM patients have higher dosage effect especially in chromosome 15 compared to the others. In addition, relation between dosage effect and gene expression analysis show that the highly expressed genes have significantly higher dosage effect compared to the lowly expressed genes. Also function enrichment analysis showed that genes involved with crucial biological processes including translation, RNA processing and transcription factor genes are enriched in genes with higher dosage effect. Interstingly, dosage resistant genes are enriched in cell death and GTPase processes. These results help us understand the impact of aneuploidy in MM on global gene expression changes. In conclusion, our analysis identifies concordant and discordant gene expression changes associated with DNA copy number alterations, identifying genes and pathways that may play an important role in myeloma disease behavior as well as prognosis. Disclosures: No relevant conflicts of interest to declare.

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Profiling diverse sequence tandem repeats in colorectal cancer reveals co-occurrence of microsatellite and chromosomal instability involving Chromosome 8

10.1101/2020.12.23.422767 ◽

2020 ◽

Author(s):

GiWon Shin ◽

Stephanie U. Greer ◽

Erik Hopmans ◽

Susan M. Grimes ◽

HoJoon Lee ◽

...

Keyword(s):

Mismatch Repair ◽

Genomic Instability ◽

Copy Number ◽

Chromosomal Instability ◽

Tandem Repeats ◽

Chromosome 8 ◽

Molecular Testing ◽

Cancer Genes ◽

Copy Number Alterations ◽

High Coverage

ABSTRACTColorectal carcinomas (CRCs) which have lost DNA mismatch repair display hypermutability evident in a molecular phenotype called microsatellite instability (MSI). These mismatch repair deficient tumors are thought to lack widespread genomic instability features, such as copy number changes and rearrangements. To identify MSI for clinical diagnosis, current molecular testing looks for changes in mononucleotide or dinucleotide repeats. However, microsatellites have other types of sequence tandem repeats such as tri- and tetranucleotide motifs. These additional classes of microsatellites are generally not examined for MSI but are known to be unstable in a phenotype known as elevated microsatellite alterations at selected tetranucleotide repeats, or EMAST. We developed a sequencing approach that provides ultra-high coverage (>2500X) of microsatellite targets and cancer genes for profiling genomic instability. We assessed the diverse repeat motifs across 200 microsatellites. Our approach provides highly sensitive detection of MSI with high specificity, evaluates copy number alterations with high accuracy, delineates chromosomal instability (CIN) classification and deconvolutes subclonal architecture. By examining both MSI and CIN, we discovered mutations and copy number alterations that defined mixed genomic instability states of CIN and MSI, which are normally considered exclusive. An increase in copy number of chromosome arm 8q was prevalent among MSI tumors. Moreover, we identified an inter-chromosomal translocation event from a CRC with co-occurrence of MSI. Subclonal analysis demonstrated that mutations which are typically considered to be exclusive in MSI, shows mutual occurrence in MSI tumors with more sensitive characterization. Our approach revealed that MSH3 mutations are a potential source of mixed genomic instability features. Overall, our study demonstrates that some colorectal cancers have features of both microsatellite and chromosomal instability. This result may have implications for immunotherapy treatment.

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