31

文献笔记-2015-nature-molecular analysis of gastric cancer新的分类及预后调查

文献:Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes

A small pre-defined set of gene expression signatures

epithelial-to-mesenchymal transition (EMT)  上皮细胞向间充质细胞转化
microsatellite instability (MSI) 微卫星不稳定性
cytokine signaling 细胞因子信号
cell proliferation  细胞增殖
DNA methylation DNA甲基化
TP53 activity TP53活性
gastric tissue 胃组织

 

经典的分类方法是:Gastric cancer may be subdivided into 3 distinct subtypes—proximal, diffuse, and distal gastric cancer—based on histopathologic and anatomic criteria. Each subtype is associated with unique epidemiology.

我们用主成分分析Principal component anaylsis (PCA)

PC1

PC2

PC3

这三个主成分与上面的七个特征是相关联的。

根据我们的主成分分析,可以把我们的300个GC样本分成如下四组,命名如下:

Gene expression signatures define four molecular subtypes of GC:

MSI (n = 68),

MSS/EMT (n = 46),

MSS/TP53+ (n = 79)

MSS/TP53− (n = 107)

然后用本文的分类方法,测试了另外另个published数据,还是分成四个组

(MSI, MSS/EMT, MSS/TP53+ and MSS/TP53-)

分别是TCGA数据库的;n = 46, n = 62, n = 50 and n = 47.

Singapore的研究; n = 12, n = 85, n = 39 and n = 63 respectively

我们这样的分组可以得到一些规律:

(i) The MSS/EMT subtype occurred at a significantly younger age (P = 3e-2) than did other subtypes. The majority (>80%) of the subjects in this subtype were diagnosed with diffuse-type (P < 1e-4) at stage III/IV(P = 1e-3).

(ii) The MSI subtype occurred predominantly in the antrum (75%), >60% of subjects had the intestinal subtype, and >50% of subjects were diagnosed at an early stage (I/II).

(iii) Epstein-Barr virus (EBV) infection occurred more frequently in the MSS/TP53+ group (n = 12/18, P = 2e-4) than in the other groups.

 

然后我们对我们的300个样本做了生存分析:

预后: MSI  >   MSS/TP53+    >   MSS/TP53 >  MSS/EMT

Next, we validated the survival trend of GC subtypes in three independent cohorts: Samsung Medical Center cohort 2 (SMC-2,n = 277, GSE26253)31,

Singapore  cohort(n = 200, GSE15459)21 and

TCGA gastric cohort (n = 205).

We saw that the GC subtypes showed a significant association with overall survival

结论:我们这样的分类是最合理的,跟各个类别的预后非常相关。

 

然后我们看看突变模式:

the MSI~ hypermutation ~KRAS (23.3%), the PI3K-PTEN-mTOR pathway (42%), ALK (16.3%) and ARID1A (44.2%)18.

We observed enrichment of PIK3CA H1047R mutations in the MSI samples

we saw enrichment of E542K and E545K mutations in MSS tumors

The EMT subtype had a lower number of mutation events when compared to the other MSS groups(P = 1e−3).

The MSS/TP53− subtype showed the highest prevalence of TP53 mutations (60%), with a low frequency of other mutations

the MSS/TP53+ subtype showed a relatively higher prevalence (compared to MSS/TP53−) of mutations in APC, ARID1A, KRAS, PIK3CA and SMAD4.

再看看拷贝数变异情况:

再看看与另外两个研究团队的分类情况的比较

The TCGA study reported expression clusters (subtypes named C1–C4) and genomic subtypes (subtypes named EBV+, MSI, Genome Stable (GS) and Chromosomal Instability (CIN)).

A follow-up study of the Singapore cohort21 described three expression subtypes (Proliferative, Metabolic and Reactive)

However, a consensus on clinically relevant subtypes that encompasses molecular heterogeneity and that can be used in preclinical and clinical research has not been reported.

Here we report the molecular classification of GC linked not only to distinct patterns of genomic alterations, but also to recurrence pattern and prognosis across multiple GC cohorts.

 

 

microsatellite instability

英文简称 : MI
中文全称 : 微卫星不稳定性
所属分类 : 生物科学
词条简介 : 微卫星不稳定性(microsatellite instability,MI)检测是基于VNTR的发现,细胞内基因组含有大量的碱基重复序列,一般将6-7bp的串联重称为小卫星DNA(minisatellite DNA),又称为VNTR。而将1-4bp的串联重复称为微卫星DNA,又称简单重复序列(simple repeat sequence,SRS)。SRS是一种最常见的重复序列之一,具有丰富的多态性、高度杂合性、重组纺低等优点。最常见的为双核苷酸重复,即(AC)n和(TG)n。研究表胆,在n≥104时,2bp重复序列在人群中呈高度多态性。SRS广泛存在于原核和真核基因组中,约占真核基因组的5%,是近年来快速发展起来的新的DNA多态性标志之一。策卫星稳定性(MI)是指简重复序列的增加或丢失。MI首先在结肠癌中观察到,1993年在HNPCC中观察到多条染色体均有(AC)n重复序列的增加或毛失,以后相继在胃癌、胰腺癌、肺癌、膀胱癌、乳腺癌、前列腺癌及其他肿瘤等也好现存在微卫星不稳定现象,提示MI可能是肿瘤细胞的另一重要分子结果显示 ,MI与肿瘤与发展有关,MI仅在肿瘤细胞中发现,从未在正常组织中检测到。在原发与移肿瘤中,MI均交分布于整个肿瘤。晚期胃癌的MI频率显著高于早期胃癌。

 

31

文献笔记-2010-R-softeware-identify-cancer_driver_genes

我们用188 non-small cell lung tumors数据来测试了一个R语言程序,find driver genes in cancer ~
软件地址如下:http://linus.nci.nih.gov/Data/YounA/software.zip
这是一个R语言程序,里面有readme,用法很简单。
准备好两个文件,分别是silent_mutation_table.txt and nonsilent_mutation_table.txt ,它们都是普通文本格式数据,内容如下,就是把找到的snp格式化,根据注释结果分成silent和nonsilent即可。
#Ensembl_gene_id Chromosome Start_position Variant_Type Reference_Allele Tumor_Seq_Allele1 Tumor_Seq_Allele2 Tumor_Sample_Barcode
#ENSG00000122477 1 100390656 SNP G G A TCGA-23-1022-01A-02W-0488-09
然后直接运行程序包里面的主程序,在R语言里面source("main_R_script.r")
We reanalyzed sequence data for 623 candidate genes in 188 non-small cell lung tumors using the new method.
to identify genes that are frequently mutated and thereby are expected to have primary roles in thedevelopment of tumor
To find these driver genes, each gene is tested for whether its mutation rate is significantly higher than the background (or passenger) mutation rate.

Some investigators (Sjoblom et al., 2006) further divide mutations into several types according to the nucleotide and the neighboring nucleotides of the mutations.

Ding et al. (2008)的方法的三个缺点:
1、different types of mutations can have different impact on proteins.(越影响蛋白功能的突变,越有可能是driver mutation)
2、different samples have different background mutation rates. (在高突变背景的样本中的突变,很可能是高突变背景的原因,而不是因为癌症)
3、a different number of non-silent mutations can occur at each base pair according to the genetic code.(比如Tryptophan仅仅只有一个密码子,而arginine高达6个密码子)

我们提出的方法的4个优点是:
1,我们对非同义突变根据它们对蛋白功能的影响进行了评级打分。
2,我们允许不同的样品有着不同的BMR
3,that whether the mutation is non-silent or silent depends on the genetic code
4,we take into account uncertainties in the background mutation rate by using empirical Bayes methods

还有5个需要改进的地方:
1,However, the functional impact is also dependent on the position in which a mutation occurs.(我们仅仅考虑了突变对氨基酸的改变)
2,the current scoring system which assigns mutation scores in the order: missense mutation<inframe indel<mutation in splice sites<frameshift indel=nonsense mutation may be biased toward identifying tumor suppressor genes over oncogenes.
3,we may refine our background mutation model in Table 1 so that all six types of mutations, A:T→G:C, A:T→C:G, A: T→T :A,G:C→A:T, G:C→T :A, G:C→C:G have separate mutation rates.
4,we did not take into account correlations among mutations in identifying driver genes.
5,one might combine both copy number variation and sequencing data to identify driver genes.

HGNC定义的gene Symbol转为ensemble数据库的ID,的R语言代码:
library(biomaRt)
ensembl=useMart("ensembl",dataset = "hsapiens_gene_ensembl")
all.gene.table = read.table("all_gene.symbol", header=F)
convert=getBM(attributes = c("chromosome_name","ensembl_gene_id","hgnc_symbol"),filters =c("hgnc_symbol"),values=all.gene.table[,1],mart=ensembl)
chromosome=c(1:22,"X","Y","M")
convert=convert[!is.na(match(convert[,1],chromosome)),2:3] #remove names whose matching chromosome is not 1-22, X, or Y.
convert=convert[rowSums(convert=="")==0,]
write.table(convert,"ensembl2symbol.list",quote = F,row.names =F,col.names =F)
write.table(convert,"all_gene_name.txt",quote = F,row.names =F,col.names =F)

一个gene Symbol可能对应着多个ensemble ID号,但是在每个染色体上面是一对一的关系。
有些gene Symbol可能找不到ensemble ID号,一般情况是因为这个gene Symbol并不是纯粹的HGNC定义的,或者是比较陈旧的ID。
比如下面的TIGAR ,就很可能被写作是C12orf5
Aliases for TIGAR Gene
TP53 Induced Glycolysis Regulatory Phosphatase 2 3
TP53-Induced Glycolysis And Apoptosis Regulator 2 3 4
C12orf5 3 4 6
Probable Fructose-2,6-Bisphosphatase TIGAR 3
Fructose-2,6-Bisphosphate 2-Phosphatase 3
Chromosome 12 Open Reading Frame 5 2
Fructose-2,6-Bisphosphatase TIGAR 3
Transactivated By NS3TP2 Protein 3
EC 3.1.3.46 4
FR2BP 3
External Ids for TIGAR Gene
HGNC: 1185 Entrez Gene: 57103 Ensembl: ENSG00000078237 OMIM: 610775 UniProtKB: Q9NQ88
Previous HGNC Symbols for TIGAR Gene
C12orf5
Export aliases for TIGAR gene to outside databases

29

研究癌症领域必看文献

最近需要了解一些癌症相关知识,看到了这个文献列表,觉得非常棒,所以推荐给大家。

抽时间慢慢看,一个月应该可以把这些文献看完的。

癌症种类大全 http://www.cancer.gov/types
癌症药物大全 http://www.cancer.gov/about-cancer/treatment/drugs
癌症所有的信息几乎都能在这个网站上面找到 http://www.cancer.gov/
包括癌症的科普、treatment、diagnosis,prognosis,classification,drugs、prediction等等

different_kinds_of_cancer_in_CCLE

Cancer Precision Medicine: Improving Evidence in Practice - August 24, 2015

NCI-MATCH Trial Opens,External Web Site Icon AACR blog post, August 2015

NCI-MATCH launch highlights new trial design in precision-medicine eraExternal Web Site Icon
McNeal C , JNCI, August 2015

The Cancer Genomics Resource List, 2014External Web Site Icon
Zutter MM et al. CAP Lab Improvement Program,Archives of Pathology, August 2015

Personalized medicine and economic evaluation in oncology: all theory and no practice?External Web Site Icon
Garattini L et al. Expert Rev Pharmacoecon Outcomes Res 2015 Aug 9. 1-6

Precision medicine trials bring targeted treatments to more patients,External Web Site Icon C. Helwick, ASCO Post, Jul 25

Next-generation sequencing to guide cancer therapy External Web Site Icon
Gagan J et al, Genome Medicine, July 29, 2015

Feasibility of large-scale genomic testing to facilitate enrollment onto genomically matched clinical trials.External Web Site Icon
Meric-Bernstam F et al. J. Clin. Oncol. 2015 May 26.

Brave-ish new world-what's needed to make precision oncology a practical reality.External Web Site Icon
MacConaill LE et al. JAMA Oncol 2015 Jul 16.

Genomic profiling: Building a continuum from knowledge to careExternal Web Site Icon
Helen C et al. JAMA Oncology, July 2015

Are we there yet?External Web Site Icon
When it comes to curing cancer, targeted therapies and genomic sequencing are helping, but we still have far to go. Genome Magazine, June 29, 2015

Artificial intelligence, big data, and cancerExternal Web Site Icon
Kantarjian H et al, JAMA Oncology, June 2015

Multigene panel testing in oncology practice - how should we respond?External Web Site Icon
Kurian AW et al. JAMA Oncology, June 2015

Use of whole genome sequencing for diagnosis and discovery in the cancer genetics clinic.External Web Site Icon
Foley SB et al. EBioMedicine 2015 Jan 2(1) 74-81

The future of molecular medicine: biomarkers, BATTLEs, and big data External Web Site Icon
ES Kim, ASCO University, June 2015

NCI-MATCH trial will link targeted cancer drugs to gene abnormalitiesExternal Web Site Icon

Targeted agent and profiling utilization registry study,External Web Site Icon from the American Society for Clinical Oncology

ASCO study aims to learn from patient access to targeted cancer drugs used off-label,External Web Site Icon American Society for Clinical Oncology

Improving evidence developed from population-level experience with targeted agents Adobe PDF file [PDF 462.93 KB]External Web Site Icon
McLellan M et al Issue Brief. Conference on Clinical Cancer Research November 2014

Implementing personalized cancer care.External Web Site Icon
Schilsky RL et al. Nat Rev Clin Oncol 2014 Jul (7) 432-8

Accelerating the delivery of patient-centered, high-quality cancer care.External Web Site Icon
Abrahams E et al. Clin. Cancer Res. 2015 May 15. (10) 2263-7

Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity.External Web Site Icon
Catenacci DV et al. Mol Oncol 2015 May (5) 967-996

Cancer Precision Medicine: Improving Evidence in Practice - May 29, 2015

Diagnosis and treatment of cancer using genomicsExternal Web Site Icon
Vockley JG et al. BMJ, May 28, 2015

Targeted agent and profiling utilization registry study,External Web Site Icon from the American Society for Clinical Oncology

ASCO study aims to learn from patient access to targeted cancer drugs used off-label,External Web Site Icon American Society for Clinical Oncology

Improving evidence developed from population-level experience with targeted agents Adobe PDF file [PDF 462.93 KB]External Web Site Icon
McLellan M et al Issue Brief. Conference on Clinical Cancer Research November 2014

Implementing personalized cancer care.External Web Site Icon
Schilsky RL et al. Nat Rev Clin Oncol 2014 Jul (7) 432-8

Accelerating the delivery of patient-centered, high-quality cancer care.External Web Site Icon
Abrahams E et al. Clin. Cancer Res. 2015 May 15. (10) 2263-7

Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity.External Web Site Icon
Catenacci DV et al. Mol Oncol 2015 May (5) 967-996

Precision Medicine: Cancer and Genomics - May 12, 2015

Promise, peril seen in personalized cancer therapy,External Web Site Iconby Marie McCullough, Philadelphia Inquirer, May 10

A decision support framework for genomically informed investigational cancer therapy.External Web Site Icon
Meric-Bernstam F et al. J. Natl. Cancer Inst. 2015 Jul (7)

Divide and conquer: The molecular diagnosis of cancer,External Web Site Icon by Louis M. Staudt, National Cancer Insitute, Apr 13

Health: Make precision medicine work for cancer careExternal Web Site Icon
To get targeted treatments to more cancer patients pair genomic data with clinical data, and make the information widely accessible, Mark A. Rubin. Nature News, Apr 15

Using somatic mutations to guide treatment decisionsExternal Web Site Icon
Horlings H et al. JAMA Oncology, March 12, 2015

The landscape of precision cancer medicine clinical trials in the United StatesExternal Web Site Icon
Roper N et al. Cancer Treatment Reviews 2015

What is “precision medicine?External Web Site Icon Information from the National Cancer Institute

Impact of cancer genomics on precision medicine for the treatment of cancer,External Web Site Icon from the Cancer Genome Atlas, NCI

US precision-medicine proposal sparks questions,External Web Site Icon by Sara Reardon, Nature News, Jan 22

Obama's 'precision medicine' means gene mapping,External Web Site IconNBC News, Jan 21

What is President Obama's 'precision medicine' plan, and how might it help you?External Web Site Icon By Lenny Bernstein, Jan 21

Recent reviews

Companion diagnostics: the key to personalized medicine.External Web Site Icon
Jørgensen JT. Expert Rev Mol Diagn. 2015 Feb;15(2):153-6

Promoting precision cancer medicine through a community-driven knowledgebase.External Web Site Icon
Geifman N, et al. J Pers Med. 2014 Dec 15;4(4):475-88.

Toward a prostate cancer precision medicine.External Web Site Icon
Rubin MA. Urol Oncol. 2014 Nov 20.

Prioritizing targets for precision cancer medicine.External Web Site Icon
Andre F, et al. Ann Oncol. 2014 Dec;25(12):2295-303

Toward precision medicine with next-generation EGFR inhibitors in non-small-cell lung cancer.External Web Site Icon
Yap TA, Popat S. Pharmgenomics Pers Med. 2014 Sep 19;7:285-95.

Genomically driven precision medicine to improve outcomes in anaplastic thyroid cancer.External Web Site Icon
Pinto N, et al.  J Oncol. 2014;936285

Translating genomics for precision cancer medicine.External Web Site Icon
Roychowdhury S, Chinnaiyan AM. Annu Rev Genomics Hum Genet. 2014;15:395-415

The Cancer Genome Atlas: Accomplishments and Future - April 3, 2015

The Cancer Genome Atlas (TCGA): an immeasurable source of knowledgeExternal Web Site Icon
Tomczak K, et al. Contemp Oncol (Pozn). 2015; 19(1A): A68-A77.

The Cancer Genome Atlas' 4th Annual Scientific SymposiumExternal Web Site Icon
May 11-12 ~ Bethesda, MD

The Cancer Genome Atlas (TCGA) Data Portal External Web Site Icon
Portal provides a platform for researchers to search, download, and analyze data sets generated by TCGA

Cancer Genomics Hub: A resource of the National Cancer Institute,External Web Site Icon from the USC Genome Browser

Molecular classification of gastric adenocarcinoma: translating new insights from The Cancer Genome Atlas Research Network.External Web Site Icon
Sunakawa Y et al. Curr Treat Options Oncol 2015 Apr (4) 331

TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis.External Web Site Icon
Gore J et al. Oncotarget 2015 Feb 25.

Radiogenomics of clear cell renal cell carcinoma: preliminary findings of The Cancer Genome Atlas-Renal Cell Carcinoma (TCGA-RCC) Imaging Research Group.External Web Site Icon
Shinagare AB et al. Abdom Imaging 2015 Mar 10.

Proteomics of colorectal cancer in a genomic context: First large-scale mass spectrometry-based analysis from the Cancer Genome Atlas.External Web Site Icon
Jimenez CR et al. Clin. Chem. 2015 Feb 26.

End of cancer-genome project prompts rethinkExternal Web Site Icon
Geneticists debate whether focus should shift from sequencing genomes to analysing function. Heidi Ledford, Nature News and Comments, January 2015

Cancer Genomics: Insights into Driver Mutations - March 10, 2015

Seek and destroy: Relating cancer drivers to therapiesExternal Web Site Icon
E. Martinez-Ledesma et al. Cell, March 9, 2015

In silico prescription of anticancer drugs to cohorts of 28 tumor types reveals targeting opportunitiesExternal Web Site Icon
C Rubio-Perez et al. Cancer Cell, March 9, 2015

MADGiC: a model-based approach for identifying driver genes in cancer. Adobe PDF file [PDF 373.56 KB]External Web Site Icon
Keegan D. Korthauer et al. Bioinformatics, January 2015

Identifying driver mutations in sequenced cancer genomes: computational approaches to enable precision medicine.External Web Site Icon
Benjamin J Raphael et al. Genome Medicine 2014

Novel recurrently mutated genes in African American colon cancers.External Web Site Icon
Guda K et al. Proc Natl Acad Sci U S A. 2015 Jan 12

Sparse expression bases in cancer reveal tumor drivers.External Web Site Icon
Logsdon BA, et al. Nucleic Acids Res. 2015 Jan 12

Patient-specific driver gene prediction and risk assessment through integrated network analysis of cancer omics profiles.External Web Site Icon
Bertrand D, et al. Nucleic Acids Res. 2015 Jan 8

Identification of constrained cancer driver genes based on mutation timing.External Web Site Icon
Sakoparnig T, et al. PLoS Comput Biol. 2015 Jan 8;11(1):e1004027

CaMoDi: a new method for cancer module discovery.External Web Site Icon
Manolakos A, et al. BMC Genomics. 2014 Dec 12;15 Suppl 10:S8.

VHL, the story of a tumour suppressor gene.External Web Site Icon
Gossage L, et al. Nat Rev Cancer. 2014 Dec 23;15(1):55-64

Targeting the MET pathway for potential treatment of NSCLC.External Web Site Icon
Li A, et al. Expert Opin Ther Targets. 2014 Dec 23:1-12

Deciphering oncogenic drivers: from single genes to integrated pathways.External Web Site Icon
Chen J, et al. Brief Bioinform. 2014 Nov 5.

Driver and passenger mutations in cancer.External Web Site Icon
Pon JR, et al. Annu Rev Pathol. 2014 Oct 17

Hereditary Cancer Genetic Testing: Where are We? - December 18, 2014

NCI paper:Prevalence and correlates of receiving and sharing high-penetrance cancer genetic test results: Findings from the Health Information National Trends SurveyExternal Web Site Icon
Taber J.M. et al Public Health Genomics, January 2015

Clinical decisions: Screening an asymptomatic person for genetic risk--polling resultsExternal Web Site Icon
Schulte J, et al. N Engl J Med 2014 Nov;371(20):e30

Testing for hereditary breast cancer: Panel or targeted testing? Experience from a clinical cancer genetics practice.External Web Site Icon
Doherty J, J Genet Couns. 2014 Dec 5

Hereditary colorectal cancer syndromes: American Society of Clinical Oncology clinical practice guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology clinical practice guidelines.External Web Site Icon
Stoffel EM, et al. J Clin Oncol. 2014 Dec 1

Population testing for cancer predisposing BRCA1/BRCA2 mutations in the Ashkenazi-Jewish community: A randomized controlled trial.External Web Site Icon
Manchanda R, et al. J Natl Cancer Inst. 2014 Nov 30;107(1)

Cost-effectiveness of population screening for BRCA mutations in Ashkenazi Jewish women compared with family history-based testing.External Web Site Icon
Manchanda R et al. J Natl Cancer Inst. 2014 Nov 30;107(1). pii: dju380. doi: 10.1093/jnci/dju380. Print 2015 Jan.

Check out our Cancer Genetic Testing  Update Page for additional information and links

Cancer Genomic Tests (October 30, 2014)

Cancer Precision Medicine: Where Are We? - September 18, 2014

NIH announces the launch of 3 integrated precision medicine trials; ALCHEMIST is for patients with certain types of early-stage lung cancer,External Web Site Icon August 2014

National Cancer Institute's Precision Medicine Initiatives for the New National Clinical Trials Network.External Web Site Icon Jeffrey Abrams et al. ASCO Annual Meeting 2014

Personalized medicine: Special treatment.External Web Site Icon
Michael Eisenstein. Nature, September 11, 2014

Why the controversy? Start sequencing tumor genes at diagnosis. Tumor sequencing at the time of diagnosis can give significant insight for successful cancer treatment,External Web Site Icon by Shelly Gunn, Genetic Engineering & Biotechnology News, Sep 10

National Cancer Institute information: Precision medicine and targeted therapyExternal Web Site Icon

Genomics and precision oncology: What's a targeted therapy for cancer?External Web Site Icon An updated list of approved drugs from the National Cancer Institute (2014)

Therapy: This time it's personalExternal Web Site Icon
Gravitz L Nature 509, S52-S54 2014 May 29

Multi-marker solid tumor panels using next-generation sequencing to direct molecularly targeted therapiesExternal Web Site Icon
Michael Marrone, et al. PLoS Currents Evidence on Genomic Tests 2014 May 27

Impact of cancer genomics on precision medicine for the treatment of cancer,External Web Site Icon from the National Cancer Institute

Cancer genomics and precision medicine in the 21st century Adobe PDF file [PDF 2.20 MB]External Web Site Icon, power point presentation from the National Human Genome Research Institute