Download Non-small-cell lung carcinoma

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Non-small-cell lung carcinoma
Non-small-cell lung carcinoma (NSCLC) is any type of
epithelial lung cancer other than small cell lung carcinoma (SCLC).
As a class, NSCLCs are relatively insensitive to chemotherapy,
compared to small cell carcinoma.
 The most common types of NSCLC are squamous cell
carcinoma(鳞状细胞癌), large cell carcinoma(大细胞癌), and
adenocarcinoma(腺癌)
 but there are several other types that occur less frequently, and all
types can occur in unusual histologic variants and as mixed celltype combinations.
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Lung adenocarcinoma
Adenocarcinoma of the lung is currently the most common type of
lung cancer in "never smokers". Adenocarcinomas account for
approximately 40% of lung cancers.
Squamous cell lung carcinoma
Squamous cell carcinoma (SCC) of the lung is more common in
men than in women. It is closely correlated with a history of
tobacco smoking, more so than most other types of lung cancer.
Large-cell lung carcinoma
Large cell lung carcinoma (LCLC) is a heterogeneous group of
undifferentiated malignant neoplasms originating from transformed
epithelial cells in the lung
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Copy-number variation
 Copy-number
variations (CNVs)—a form
of structural variation—are
alterations of the DNA of a genome
that results in the cell having an
abnormal number of copies of one
or more sections of the DNA.
 CNVs contrast with singlenucleotide polymorphisms (SNPs),
which affect only one single
nucleotide base.
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Identification
Copy number variation can be discovered by cytogenetic techniques
1. fluorescent in situ hybridization(荧光原位杂交)
2. comparative genomic hybridization
3. array comparative genomic hybridization
4. virtual karyotyping with SNP arrays.
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1. fluorescent in situ hybridization
FISH样本的制备
→探针的制备
→探针标记
→杂交
→（染色体显带）
→荧光显微镜检测
→结果分析。
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2. comparative genomic hybridization
CGH 只能检测不平衡的
染色体改变
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3. Array comparative genome hybridization (aCGH)
1. DNA from a test sample and normal reference sample are
labelled differentially, using different fluorophores,
2. hybridized to several thousand probes. The probes are
derived from most of the known genes and non-coding
regions of the genome, printed on a glass slide.
3. The fluorescence intensity of the test and of the reference
DNA is then measured, to calculate the ratio between them
and subsequently the copy number changes for a particular
location in the genome.
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Prevalence in humans
DNA copy number variation is a widespread and common
phenomenon among humans
Role in disease
 some CNVs have been associated with susceptibility or
resistance to disease
 Gene copy number can be elevated in cancer cells.
 the EGFR copy number can be higher than normal in
non-small cell lung cancer
Datasetes
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Copy-number variation: the end of the
human genome?
 Paul H. Dear
 Trends in Biotechnology
 2009
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文献内容：
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1. 简略提Copy-number variation的概念，鉴定的
方法，及简要的历史
2. Copy-number variation和phenotype
3. Copy-number changes 和 cancer
4. MCC and mMCC – a digital genomics approach
to CNVs
5. Location, location, location!
6. Somatic CNV
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CNVs and phenotype
 Almost by definition, most CNVs have either no phenotypic
consequences or only subtle or benign ones
 they are comparable to the majority of SNPs
 some CNVs do indeed have phenotypic consequences
 CNVs in genes known to be implicated in disease
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Copy-number changes and cancer
 CNVs have clearly been shown to have the potential to indirectly
influence a healthy individual’s susceptibility to cancer，for
example by varying the gene dosage of tumour suppressors or
oncogenes
 Changes in copy number of parts of the genome are known to be
a feature of many cancers
 it difficult to determine which copy-number changes are
significant or causative and which are purely incidental or of
minor importance.
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MCC and uMCC – a digital genomics approach to CNVs
molecular copy-number counting
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 The initial results, however, were distorted owing to the
extreme fragmentation of the DNA; as with any PCRbased method, longer target sequences are more
susceptible than shorter ones to destruction caused by
DNA damage
 by choosing targets of short and approximately
uniform length, this problem could be overcome, and this
led to the modified method of uMCC.
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Location, location, location!
In a few cases, usually those showing large structural
abnormalities, the whereabouts of the extra copies are
known, but in most cases they are not. Indeed, it is extremely
difficult to determine where the further copies of a CNV are
located in the genome unless they are large enough to be
discerned by fluorescence in situ hybridization.
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Somatic CNV
 Copy-number differences between somatic cells could
potentially be quite widespread without our being aware
of it.
 The authors used CGH to reveal copy-number differences
between different tissues that were sample dpost-mortem
from single individuals who had died from apparently
non-genomic causes.
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Integrated analysis of DNA copy number and gene
expression microarray data using gene sets
 Renée X Menezes
 BMC Bioinformatics
 2009
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propose to look for associations between copy number and
expression not only using individual genes, but also using gene
sets.
We wish to find which individual copy number changes
affect gene expression levels within the same chromosomal region.
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Methods
The gene-to-gene model
consider copy number as the dependent variable, so
expression is handled as the independent variable. The
simplest model to consider is
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The gene-set model
An ideal way to avoid these problems is to include
in the model all expression probes within the same
large region. This leads us to the model, for each copy
number probe i,
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