©Edited by Mingrui Zhang, CS Department, Winona State University, 2008 Identifying Lung Cancer...

©Edited by Mingrui Zhang, CS Department, Winona State University, 2008

Identifying Lung Cancer RisksIdentifying Lung Cancer Risks


Lung CancerLung Cancer

• Lung cancer is the leading cause of death among cancer victims in the United States.

– It claims more lives than colon, prostate, and breast cancer combined.

– Smoking is the most significant factor for lung cancer. But, only 10% of ever smokers have lung cancers.


Observed and projected lung cancer death Observed and projected lung cancer death rates, United States, 1930–2003 rates, United States, 1930–2003

The observed death rates are based on data published by the National Center for Health Statistics, Centers for Disease Control. The dotted lines represent straight line projections of the observed slope from 1950–1975 in men and from 1975–1990 in women. (http://tobaccocontrol.bmj.com)


National Expenditures for Medical National Expenditures for Medical Treatment for the Most Common CancersTreatment for the Most Common Cancers

Based on Cancer Prevalence in 1998 and Cancer-Specific Costs for 1997-1999, projected to 2004 using the medical care component of the Consumer Price Index. (http://progressreport.cancer.gov)


Survival Rate is Low for Lung CancerSurvival Rate is Low for Lung Cancer

Type 5-Year survival for all stages

Early Detection

Late Detection

Lung 14.9% 48.7% 21%

Breast 86.6% 97.0% 23.2%

Prostate 97.5% 100% 34.0%

Colon 62.3% 90.1% 9.2%


Lung CancerLung Cancer

• Two interesting questions:1. Are the remaining 90% of ever smokers genetically protected

from cancer diseases?

2. Are there factors other than smoking attributed to lung cancers?

3. How does second-hand smoking contribute to cancer?

• Case control studies– Cases are group of lung cancer patients– Controls are group of normal people


Never SmokersNever Smokers

• Identify causal factors for lung cancer other than smoking– Environmental factors– Genetic factors: metabolic pathway genes– Interaction between environmental factors and the metabolic

pathway genes

• Subjects under investigation– Never smokers

• Smoking is a dominating factor, may confound genetic factors and environmental agents


Interactions of Genes to Lung Interactions of Genes to Lung CancerCancer

Histological Information

SNP

MicroarrayLung Tissue Genetic Information

Blood Sample


Microarray Technology:Microarray Technology:Genes Attributed to CancerGenes Attributed to Cancer


Microarray ExperimentMicroarray Experiment

• To understand the roles certain genes play in the progression of cancer, cancer tissue is taken and used in microarray experiment.


Microarray ExperimentMicroarray Experiment

• “Normal” and tumor cells are grown in two separate populations.• CDNA from the two populations are dyed with green/red fluorescence.• Two populations are incubated with the chip.• After scanning the chip, the color represents the ratio of two

populations.


Gene ExpressionGene Expression

• There are over 10,000 different probes used.

• Each dot represents the location of a gene probe.

Probe GSM109662GSM109663GSM109664GSM109665GSM109666GSM109667GSM109668GSM109669Hs.544577 39513.15 37409.76 29715.27 20536.73 12636.55 30290.4 5380.344 8963.756Hs.561260 9229.464 21894.5 16412.41 12636.55 17446.9 13930.68 5254.592 24600.7Hs.567356 19056.91 32565.55 26372.36 19455.14 23552.87 22335.71 17281.12 21230.21Hs.436873 35737.01 35313.64 38926 21348.13 23681.18 42374.79 28674.05 12128.16Hs.517792 9468.588 14035.96 5919.428 5919.428 14174.17 11231.28 17788.3 24389.6Hs.487027 29305.41 36906.58 21473.12 22962.5 41911.48 34204.18 28017.95 33684.04Hs.1422 15283.12 25165 23287.42 15057.2 23223.62 15438.6 19509.78 8151.832Hs.202453 15641.64 20993.95 18437.06 18131.26 20888.96 20207.75 18781.45 19350.3Hs.592158 22163.46 37996.65 26291.84 30290.4 36422.28 30758.42 24600.7 23980.17Hs.525622 15737.5 24801.41 17638.29 19056.91 23429.47 20444.12 20089.34 19633.77Hs.226755 28674.05 33514.62 19799.32 24314.99 28297.22 41428.3 28781.67 20327.08Hs.250687 13646.48 28297.22 19860.2 16085.3 16269.2 14468.99 34204.18 12725.62Hs.425633 8644.256 5516.18 11838.31 6331.144 2745.636 4145.204 10042.56 5919.428Hs.386168 9999.856 30404.73 16830.96 25076.12 23820.99 12172.11 9736.256 6141.688Hs.584908 24600.7 27737.02 24923.88 24243.52 16573.38 27044.52 7832.452 10143.37Hs.133379 31731.44 19350.3 12991.75 19118 31893.15 29930.01 15781.63 31497.45Hs.150423 5061.944 12172.11 9780.32 10709.47 8246.392 5868.392 1589.784 3577.928Hs.175473 33684.04 33356.45 24243.52 28569.07 43439.98 37409.76 22699.38 21473.12Hs.83169 39184.98 31232.35 33026.59 6282.64 3898.764 31132.38 30883.74 10624.71Hs.532325 2344.252 1622.224 4019.816 2998.332 997.068 2784.528 12269.02 1310.164Hs.518267 13831.62 15188.12 8554.644 15587.79 18781.45 17593.42 7651.908 12588.82


Co-regulated GenesCo-regulated Genes

• Intensities of genes change together if they are regulated by the same biological functions.


GEO DatabasesGEO Databases

• http://www.ncbi.nlm.nih.gov/geo/


Single Nucleotide Polymorphisms:Single Nucleotide Polymorphisms:

Genomic Variations in DiseaseGenomic Variations in Disease


Single Nucleotide PolymorphismsSingle Nucleotide Polymorphisms

• SNPs are single bases at a particular locus where individual people have differences in their sequences.

– SNPs are another form of genomic variation in population


Population BasedPopulation Based

• Each ethnic group has its own collection of SNPs.• Human SNPs classified by major or minor alleles.

– major alleles are common for all human– minor alleles are useful within an ethnic group

• You should know the average frequency of alleles of the population you are studying!!


HapMap ProjectHapMap Project

• The international HapMap consortium has identified >1 million SNPs– Samples from four populations– 1 SNP every 2 kb of genomic sequence


Use SNPs as MarkersUse SNPs as Markers

• SNPs are reliable markers– Most genes contain at least one SNP

– Combinations of alleles are associated with particular disease.

• Study of evolution– Understand how a subpopulation adapted to the environment by

comparing the differences in their SNPs

• DNA fingerprinting for criminal or parental verification.

• Genotype-specific medication


Example 2: Demographic DistributionsExample 2: Demographic Distributions

• Comparison between case and control– Case: a patient who has been diagnosed with lung cancer

– Control: person without any cancer

Control N=883

Case N=538

P-value

Age Mean ± SD

63.3±15.7

62.4±13.7

P=0.30

Race Caucasian

809 (92)

494 (92)

P=0.74

No-Caucasian 73 ( 8) 44 ( 8) Unknown 1( 0.1) 0 Gender Female

607 (69)

391(73)

P=0.12

Male 276 (31) 147( 27)


Example 2: Genomic VariationsExample 2: Genomic Variations

• Now, we feel comfortable comparing two populations• Human inherits a pair of chromosomes, so the variations are paired as GSTP1 II

Exposed to Chemical Not Exposed to Chemicals Markers Control

N=31 (%) Cases

N=50 (%) P

Control N=286 (%)

Cases N=158 (%)

P

GSTM1 0.36 0.90 Null 16 (52) 31 (62) 152 (53) 83 (53) Present 15 (48) 19 (38) 134 (47) 75 (47)

GSTT1 0.31 0.32 Null 3 (10) 9 (18) 65 (23) 30 (19) Present 28 (90) 41 (82) 220 (77) 128 (81)

γGCS 0.57 0.71 77 15 (48) 21 (42) 101 (35) 53 (34) Null 77 16 (52) 29 (58) 185 (65) 105 (66)

GSTP1 (I105V) 0.65 0.73 II 11 (35) 23 (46) 121 (42) 63 (40) IV 14 (45) 19 (38) 124 (44) 74 (47) VV 6 (19) 8 (16) 41 (14) 20 (13)

GSTP1 (A114V) 0.06 0.51 CC 23 (74) 45 (90) 244 (85) 133 (84) CT/TT 8 (26) 5 (10) 42 (15) 25 (16)

GPX1 0.9 0.62 CC 12 (39) 21 (42) 146 (51) 73 (46) CT 15 (48) 24 (48) 112 (39) 68 (43) TT 4 (13) 5 (10) 27 (10) 17 (11)


SNPs DatabasesSNPs Databases

• http://www.ncbi.nlm.nih.gov/SNP/

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©Edited by Mingrui Zhang, CS Department, Winona State University, 2008 Identifying Lung Cancer...

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