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178


The connectome of a decision-making neural network

Jarrell, Travis A; Wang, Yi; Bloniarz, Adam E; Brittin, Christopher A; Xu, Meng; Thomson, J Nichol; Albertson, Donna G; Hall, David H; Emmons, Scott W
In order to understand the nervous system, it is necessary to know the synaptic connections between the neurons, yet to date, only the wiring diagram of the adult hermaphrodite of the nematode Caenorhabditis elegans has been determined. Here, we present the wiring diagram of the posterior nervous system of the C. elegans adult male, reconstructed from serial electron micrograph sections. This region of the male nervous system contains the sexually dimorphic circuits for mating. The synaptic connections, both chemical and gap junctional, form a neural network with four striking features: multiple, parallel, short synaptic pathways directly connecting sensory neurons to end organs; recurrent and reciprocal connectivity among sensory neurons; modular substructure; and interneurons acting in feedforward loops. These features help to explain how the network robustly and rapidly selects and executes the steps of a behavioral program on the basis of the inputs from multiple sensory neurons.
PMID: 22837521
ISSN: 0036-8075
CID: 372492

ESR1 amplification in breast cancer: controversy resolved? [Comment]

Albertson, Donna G
The determination of oestrogen receptor alpha (ERalpha) expression in breast cancers has been for many years the standard of care for guiding patient management. In 2007, Holst and colleagues published the previously unappreciated observation that the ERalpha gene, ESR1, was amplified in 21% of breast cancers, and that ESR1 gene amplification identified those individuals with high ERalpha expression in their tumours and who were likely to respond to hormonal manipulation. This has been a controversial area. Others have tried to reproduce these findings but the results have been mixed with respect to amplification frequency, and even contradictory with respect to prognostic and predictive value. The controversy may have now been resolved. Ooi et al, in this issue of the journal, show that the large clustered FISH signals that have been interpreted as ESR1 amplification are sensitive to RNase treatment, indicating that FISH is detecting accumulation of ESR1 transcripts in the nucleus of breast cancer cells expressing high levels of ERalpha, rather than gene amplification events. This story has important lessons for translational cancer research, and in particular FISH studies of gene copy number.
PMID: 22322671
ISSN: 0022-3417
CID: 372502

A genomic copy number biomarker to identify oral cancer patients at low risk for metastasis [Meeting Abstract]

Bhattacharya, Aditi; Snijders, Antoine M; Roy, Ritu; Hamilton, Gregory; Paquette, Jesse; Tokuyasu, Taku; Bengtsson, Henrik; Jordan, Richard CK; Olshen, Adam; Pinkel, Daniel; Schmidt, Brian L; Albertson, Donna G
ISI:000209701606284
ISSN: 1538-7445
CID: 2433392

Genomic DNA copy number alterations in mouse cancer models and human cancer

Chapter by: Albertson, Donna G.
in: Genetically Engineered Mice for Cancer Research: Design, Analysis, Pathways, Validation and Pre-Clinical Testing by
[S.l. : s.n.], 2012
pp. 181-191
ISBN: 9780387698038
CID: 2785542

Cooperativity of Rb, Brca1, and p53 in malignant breast cancer evolution

Kumar, Prashant; Mukherjee, Malini; Johnson, Jacob P S; Patel, Milan; Huey, Bing; Albertson, Donna G; Simin, Karl
Breast cancers that are "triple-negative" for the clinical markers ESR1, PGR, and HER2 typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that the combined inactivation of Rb and p53 pathways is sufficient to suppress the physiological cell death of mammary involution. Furthermore, concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, metastatic adenocarcinomas. The tumors are poorly differentiated and have histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Gene expression analyses demonstrate that the tumors share attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader, triple-negative class defined by clinical markers.
PMCID:3500050
PMID: 23173005
ISSN: 1553-7390
CID: 372482

Two distinct routes to oral cancer differing in genome instability and risk for cervical node metastasis

Bhattacharya, Aditi; Roy, Ritu; Snijders, Antoine M; Hamilton, Gregory; Paquette, Jesse; Tokuyasu, Taku; Bengtsson, Henrik; Jordan, Richard C K; Olshen, Adam B; Pinkel, Daniel; Schmidt, Brian L; Albertson, Donna G
PURPOSE: Problems in management of oral cancers or precancers include identification of patients at risk for metastasis, tumor recurrence, and second primary tumors or risk for progression of precancers (dysplasia) to cancer. Thus, the objective of this study was to clarify the role of genomic aberrations in oral cancer progression and metastasis. EXPERIMENTAL DESIGN: The spectrum of copy number alterations in oral dysplasia and squamous cell carcinomas (SCC) was determined by array comparative genomic hybridization. Associations with clinical characteristics were studied and results confirmed in an independent cohort. RESULTS: The presence of one or more of the chromosomal aberrations +3q24-qter, -8pter-p23.1, +8q12-q24.2, and +20 distinguishes a major subgroup (70%-80% of lesions, termed 3q8pq20 subtype) from the remainder (20%-30% of lesions, non-3q8pq20). The 3q8pq20 subtype is associated with chromosomal instability and differential methylation in the most chromosomally unstable tumors. The two subtypes differ significantly in clinical outcome with risk for cervical (neck) lymph node metastasis almost exclusively associated with the 3q8pq20 subtype in two independent oral SCC cohorts. CONCLUSIONS: Two subtypes of oral lesions indicative of at least two pathways for oral cancer development were distinguished that differ in chromosomal instability and risk for metastasis, suggesting that +3q,-8p, +8q, and +20 constitute a biomarker with clinical utility for identifying patients at risk for metastasis. Moreover, although increased numbers of genomic alterations can be harbingers of progression to cancer, dysplastic lesions lacking copy number changes cannot be considered benign as they are potential precursors to non-3q8pq20 locally invasive, yet not metastatic oral SCC.
PMCID:3226754
PMID: 22068658
ISSN: 1078-0432
CID: 155557

Network analysis of skin tumor progression identifies a rewired genetic architecture affecting inflammation and tumor susceptibility

Albertson, Donna G; Rose, Ann M; Villeneuve, Anne M; Quigley, David A; To, Minh D; Kim, Il Jin; Lin, Kevin K; Albertson, Donna G; Sjolund, Jonas; Perez-Losada, Jesus; Balmain, Allan
BACKGROUND: Germline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility. We and others have shown that analysis of this genetic architecture can identify single genes and whole pathways that influence complex traits, including inflammation and cancer susceptibility. Whether germline variants affect gene expression in tumors that have undergone somatic alterations, and the extent to which these variants influence tumor progression, is unknown. RESULTS: Using an integrated linkage and genomic analysis of a mouse model of skin cancer that produces both benign tumors and malignant carcinomas, we document major changes in germline control of gene expression during skin tumor development resulting from cell selection, somatic genetic events, and changes in the tumor microenvironment. The number of significant expression quantitative trait loci (eQTL) is progressively reduced in benign and malignant skin tumors when compared to normal skin. However, novel tumor-specific eQTL are detected for several genes associated with tumor susceptibility, including IL18 (Il18), Granzyme E (Gzme), Sprouty homolog 2 (Spry2), and Mitogen-activated protein kinase kinase 4 (Map2k4). CONCLUSIONS: We conclude that the genetic architecture is substantially altered in tumors, and that eQTL analysis of tumors can identify host factors that influence the tumor microenvironment, mitogen-activated protein (MAP) kinase signaling, and cancer susceptibility.
PMCID:3091303
PMID: 21244661
ISSN: 1474-7596
CID: 372512

A metastasis or a second independent cancer? Evaluating the clonal origin of tumors using array copy number data

Ostrovnaya, Irina; Olshen, Adam B; Seshan, Venkatraman E; Orlow, Irene; Albertson, Donna G; Begg, Colin B
When a cancer patient develops a new tumor it is necessary to determine if it is a recurrence (metastasis) of the original cancer, or an entirely new occurrence of the disease. This is accomplished by assessing the histo-pathology of the lesions. However, there are many clinical scenarios in which this pathological diagnosis is difficult. Since each tumor is characterized by a distinct pattern of somatic mutations, a more definitive diagnosis is possible in principle in these difficult clinical scenarios by comparing the two patterns. In this article we develop and evaluate a statistical strategy for this comparison when the data are derived from array copy number data, designed to identify all of the somatic allelic gains and losses across the genome. First a segmentation algorithm is used to estimate the regions of allelic gain and loss. The correlation in these patterns between the two tumors is assessed, and this is complemented with more precise quantitative comparisons of each plausibly clonal mutation within individual chromosome arms. The results are combined to determine a likelihood ratio to distinguish clonal tumor pairs (metastases) from independent second primaries. Our data analyses show that in many cases a strong clonal signal emerges. Sensitivity analyses show that most of the diagnoses are robust when the data are of high quality.
PMCID:3145177
PMID: 20205270
ISSN: 0277-6715
CID: 372522

Loss of Blm enhances basal cell carcinoma and rhabdomyosarcoma tumorigenesis in Ptch1+/- mice

Davari, Parastoo; Hebert, Jennifer L; Albertson, Donna G; Huey, Bing; Roy, Ritu; Mancianti, Maria L; Horvai, Andrew E; McDaniel, Lisa D; Schultz, Roger A; Epstein, Ervin H Jr
Basal cell carcinomas (BCCs) have relative genomic stability and relatively benign clinical behavior but whether these two are related causally is unknown. To investigate the effects of introducing genomic instability into murine BCCs, we have compared ionizing radiation-induced tumorigenesis in Ptch1(+/-) mice versus that in Ptch1(+/-) mice carrying mutant Blm alleles. We found that BCCs in Ptch1(+/-) Blm(tm3Brd/tm3Brd) mice had a trend toward greater genomic instability as measured by array comprehensive genomic hybridization and that these mice developed significantly more microscopic BCCs than did Ptch1(+/-) Blm(+/tm3Brd) or Ptch1(+/-) Blm(+/+) mice. The mutant Blm alleles also markedly enhanced the formation of rhabdomyosarcomas (RMSs), another cancer to which Ptch1(+/)(-) mice and PTCH1(+/)(-) (basal cell nevus syndrome) patients are susceptible. Highly recurrent but different copy number changes were associated with the two tumor types and included losses of chromosomes 4 and 10 in all BCCs and gain of chromosome 10 in 80% of RMSs. Loss of chromosome 11 and 13, including the Trp53 and Ptch1 loci, respectively, occurred frequently in BCCs, suggesting tissue-specific selection for genes or pathways that collaborate with Ptch deficiency in tumorigenesis. Despite the quantitative differences, there was no dramatic qualititative difference in the BCC or RMS tumors associated with the mutant Blm genotype.
PMCID:2878356
PMID: 19995795
ISSN: 0143-3334
CID: 372532

Identification of driver genes for amplification of the narrow amplicon at 2q11 present in oral cancers and pre-cancers [Meeting Abstract]

Lin, Mauting; Snijders, Antoine M; Bhattacharya, Aditi; Paquette, Jesse; Jordan, Richard CK; Schmidt, Brian L; Albertson, Donna G
ISI:000209823901171
ISSN: 1538-7445
CID: 2433402