expression and methylation patterns partition luminal -a...
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![Page 1: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/1.jpg)
Expression and Methylation Patterns Partition Luminal-A Breast Tumors Into Distinct
Prognostic Subgroups
Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron Shamir
Breast Cancer Res. 2016 Jul 7;18(1):74.
Presentation by Nimrod Rappoport, “Towards the Precision Medicine Era: Computational challenges”
seminar, headed by Prof. Ron Shamir November 15, 2016
![Page 2: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/2.jpg)
Introduction
• Improved breast cancer clustering using new expression and methylation datasets
• Use of clustering and several classic statistic tests
Expression Methylation
Cancer Subtypes
![Page 3: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/3.jpg)
Background
• Cancer: group of diseases involving abnormal cell growth • Breast Cancer: cancer that develops from breast tissue • Most common invasive cancer in women (affects 1 in 8) • Almost half a million deaths a year
![Page 4: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/4.jpg)
Background
• Heterogeneous disease • Therapeutic decisions based on pathologic parameters and
biomarkers
Estrogen and Progesteron receptors HER2 overexpression
![Page 5: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/5.jpg)
Gene Expession
• RNA-Seq and microarrays
![Page 6: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/6.jpg)
Background
• Microarray sequencing found clusters corresponding to biomarkers
• PAM50 • Attempts to cluster using different data
![Page 7: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/7.jpg)
DNA Methylation
• Methyl group added to Cytosine (typically CpG) • Can be measured – frequency of dinucleotide methylation in tissue • Methylation of promotors typically represses gene transcription • Both hyper methylation and hypo methylation observed in cancer
![Page 8: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/8.jpg)
Background
• Dataset by The Cancer Genome Atlas (TCGA) • Gene expression (RNA-Seq) - 1148 samples of ~20500 genes • Methylation - 679 samples of 107639 probes • Methylation samples contained in gene expression samples • PAM50 classification
![Page 9: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/9.jpg)
Background
• Improved breast cancer clustering using new expression and methylation datasets
• Use of clustering and several classic statistic tests
Expression Methylation
Cancer Subtypes
![Page 10: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/10.jpg)
Clustering
• Grouping objects such that objects in same group are similar • Applications in medicine, economics, politics • Overlapping vs. strict partitioning
![Page 11: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/11.jpg)
Clustering
![Page 12: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/12.jpg)
K Means
• Choose k initial centroids • Assign each vector to the
cluster of its closest centroid • Calculate new centroids as the
mean of vectors in that cluster • Repeat until convergence •
![Page 13: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/13.jpg)
K Means
![Page 14: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/14.jpg)
Clustering Results
• Clusters fit PAM50 except Luminal-A which has a mixed cluster with Luminal-B.
![Page 15: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/15.jpg)
Luminal Clustering
• Only Luminal data is clustered with K=2.
• How can we compare which clustering better predicts prognosis?
![Page 16: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/16.jpg)
Introduction to Survival Analysis
tttTtPtf
t ∆∆+<≤
=→∆
)(lim)(0
)(1)(1)( tFtTPtS −=≤−=
![Page 17: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/17.jpg)
Introduction to Survival Analysis
tttTtPtf
t ∆∆+<≤
=→∆
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ttTttTtPth
t ∆≥∆+<≤
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tSdttf
tTPdttTtP
tTPtTdttTtPtTdttTtPdtth =
≥+<≤
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≥+<≤=≥+<≤=
![Page 18: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/18.jpg)
Kaplan Meier
![Page 19: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/19.jpg)
Luminal Clustering
![Page 20: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/20.jpg)
P value
• Hypothesis testing • Null hypothesis • Probability that the sample would be the same as or more extreme
than the observed data using the null hypothesis • p = 0.05 or 0.01 are common cutoffs for statistical significance
![Page 21: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/21.jpg)
Log Rank Test
• Nonparametric test • Compares survival distributions • Supports censoring • Confusing name
![Page 22: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/22.jpg)
Log Rank Test
![Page 23: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/23.jpg)
Log Rank Test
• K tables for different event times
• Symmetry • Best when hazards have constant ratio • Weighted logrank, stratified logrank and multiple variable
![Page 24: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/24.jpg)
Luminal Clustering
• Clustering has better prognostic value than PAM50!
![Page 25: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/25.jpg)
Luminal-A Clustering
• Reduced 5-year recurrence for R2!
![Page 26: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/26.jpg)
Chi Square
• Tests the null hypothesis that observations are statistically independent
• (Log rank?) • Microarray data fits RNA Seq
![Page 27: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/27.jpg)
Wilcoxon Rank Sum Test
![Page 28: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/28.jpg)
Wilcoxon Rank Sum Test
![Page 29: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/29.jpg)
False Discovery Rate
![Page 30: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/30.jpg)
False Discovery Rate
![Page 31: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/31.jpg)
Luminal A Clustering
• LumA-R1 associated with higher proliferation score, older age, decrease in normal cell percent, increase in tumor nuclei percent
• R1 and R2 correlate with ductal and lobular histological types
• Fit between Luminal-A and Luminal clusters
![Page 32: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/32.jpg)
Gene Enrichment for Luminal A
• All 1000 most differentially expressed genes are overexpressed in R2 • LumA-R2 overexpresses genes related to the immune system. • Overexpression of both chemokines and their receptors may indicate
increased infiltration of immune system cells. • It is unclear whether this is related to reduced
tumor recurrence.
![Page 33: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/33.jpg)
Methylation Clustering
![Page 34: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/34.jpg)
Luminal Methylation Clustering
• LumA-M1 associated with poor 5-year prognosis! • Correlation with expression partitioning (chi square)
![Page 35: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/35.jpg)
Methylation Cluster Analysis
• Comparing the LumA-M1 and LumA-M3 clusters • Finding differentially methylated CpGs
• Top 1000 hypermethylated CpGs are in LumA-M1
• Finding differentially methylated CpGs with over-expressed genes • Finding differentially methylated CpGs with under-expressed genes • Enrichment for differentially methylated CpGs and their genes
![Page 36: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/36.jpg)
Spearman Correlation
![Page 37: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/37.jpg)
Methylation and Expression Correlation
Positive correlation with expression (212 CpGs, 125 genes)
Negative correlation with expression (586 CpGs, 340 genes)
Hyper methylated CpGs (1000 CpGs, 483 genes)
Development, homeobox Tumor suppressing genes Development, homeobox, tumor suppressing genes
Gene enrichment
Gene body, under representation of TSS
TSS and 1st exon, under representation of gene body, promoter associated cell type specific
Enhancer, tissue-specific promoter, cancer DMR
CpG enrichment
![Page 38: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/38.jpg)
Cox Survival Analysis
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![Page 39: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/39.jpg)
Cox Survival Analysis
![Page 40: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/40.jpg)
Cox Survival Analysis
• Event times: 1, 3, 4, 10+, 12, 18
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![Page 41: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/41.jpg)
Cox Survival Analysis
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![Page 42: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/42.jpg)
Cox Survival Analysis Results
![Page 43: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/43.jpg)
Summary
K means Clustering gene expression data
Kaplan Meier plots, log rank test Comparing prognostic value to PAM50
Chi-square Comparing RNA-Seq clustering with microarray clustering
Rank sum test, false discovery rate Finding differentially expressed genes Hypergeometric test, false discovery rate LumA-R1 and LumA-R2 enrichment
K means Clustering methylation data Kaplan Meier plots, log rank test Comparing prognosis of different clusters Rank sum test, false discovery rate, Spearman test
Finding differentially methylated CpGs and correlation with gene expression
Hypergeometric test, false discovery rate LumA-M1 and LumA-M3 enrichment
Cox Survival Analysis Adjusting prognostic value for other variables
![Page 44: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/44.jpg)
Summary
• Clustering shows better 5-years prognostic value than PAM50 clustering
• Expression data reveals subgroup with lower 5-years recurrence rates and higher expression of immune-related genes
• Methylation data reveals subgroup of hyper methylation of developmental genes and poor survival
• Prognostic significance of partitioning confirmed by Cox analysis
![Page 45: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/45.jpg)
Discussion
• Use of new clustering to make therapeutic decisions: • Luminal-A Luminal-B partition • hypermethylation in Luminal-A
• Overexpression of chemokines and their receptors may indicate infiltration of immune system cells
• Understanding this mechanism may lead to a specific treatment
![Page 46: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/46.jpg)
Discussion
• Use this approach for additional subtype clustering • Take DNA Sequencing into account – expression correlation with
mutation • Use data taken over long periods of time
![Page 47: Expression and Methylation Patterns Partition Luminal -A ...rshamir/seminar/16/Breast-Cancer-Rapoport.pdf · Dvir Netanely , Ayelet Avraham , Adit Ben-Baruch , Ella Evron and Ron](https://reader036.vdocuments.site/reader036/viewer/2022071217/604d23532a216b77042355b3/html5/thumbnails/47.jpg)