Upload File

mutation hotspots are associated with gene expression ...mutation hotspots are associated with gene...

  • Home
  • Documents
  • Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg
36
Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg Brady Bernard Ilya Shmulevich William Poole

Upload: others

Post on 14-Aug-2020

2 views

Category:

Documents


0 download

Report

TRANSCRIPT

Page 1: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response

Theo Knijnenburg

Brady Bernard

Ilya Shmulevich

William Poole

Page 2: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

The location of mutations in a gene matters

GDSC

Mutations in BRAF

Page 3: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Finding mutation hotspots

Page 4: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Finding mutation hotspots EGFR in PANCAN11

Amino Acid Position

Mutation count

Page 5: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Finding mutation hotspots EGFR in PANCAN11

Mutation count

Smoothed at multiple

bandwidths

Page 6: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Finding mutation hotspots EGFR in PANCAN11

Mutation count

Multiscale clusters

Smoothed at multiple

bandwidths

Page 7: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Finding mutation hotspots EGFR in PANCAN11

Pkinase_Tyr Recep_L_domain Furin-like

Amino Acid Position

Mutation count

Multiscale clusters

Smoothed at multiple

bandwidths

• 75% of the mutations in hotspots are inside protein domains

Page 8: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Mutation hotspots vary substantially in size ~15,000 hotspots in ~2500 genes in PANCAN11

Page 9: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Mutation hotspots vary substantially in size ~15,000 hotspots in ~2500 genes in PANCAN11

Page 10: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Mutation hotspots vary substantially in size ~15,000 hotspots in ~2500 genes in PANCAN11

• 84% of the OncoDrive clusters overlap with the Multiscale clusters

Page 11: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Are these mutation hotspots functional?

Page 12: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Are these mutation hotspots functional? Identify statistical associations with: • Protein domains • Gene expression • Signaling pathways • Drug response

Page 13: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and gene expression

Binary mutation

calls

Mutation hotspots

Sam

ples

Continuous gene expression profiles

Genes

Sam

ples

Page 14: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and gene expression

Binary mutation

calls

Mutation hotspots

Sam

ples

Continuous gene expression profiles

Genes

Sam

ples

Pairwise

Statistical Tests Pipeline

Pairwise Correlations and P-values between hotspots and genes

Mut

atio

n ho

tspo

ts

Genes

Page 15: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and gene expression in UCEC

P=4·10-8

P=1·10-7

Page 16: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and gene expression in UCEC

P=8·10-9 P=2·10-3

Page 17: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and gene expression in UCEC

Type # Significant associations

Only in hotspot (hotspot P<10-4, all mutations P>10-2)

60

Only in gene (all mutations P<10-4, hotspot P>10-2)

1350

Both in gene and hotspot (all mutations P<10-4, hotspot P<10-4)

1360

Page 18: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and signaling pathways

Pairwise Correlations and P-values between hotspots and genes

Mut

atio

n ho

tspo

ts

Genes

Pathway membership in NCI/PID

Genes

Pat

hway

s

Page 19: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and signaling pathways

Combine P-values of genes in a pathway using Brown’s

method

Pairwise Correlations and P-values between hotspots and genes

Mut

atio

n ho

tspo

ts

Genes

Pathway membership in NCI/PID

Genes

Pat

hway

s P-values between hotspots

and pathways M

utat

ion

hots

pots

Pathways

Page 20: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between PTEN hotspots and signaling pathways in GBM

Mutations in PTEN

n=27 n=73 n=7 n=10 n=7 n=5 n=6 n=8

Page 21: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between PTEN hotspots and signaling pathways in GBM

Mutations in PTEN

n=27 n=73 n=7 n=10 n=7 n=5 n=6 n=8

Page 22: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between PTEN hotspots and signaling pathways in GBM

Mutations in PTEN

n=27 n=73 n=7 n=10 n=7 n=5 n=6 n=8

Page 23: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between PTEN hotspots and signaling pathways in GBM

Mutations in PTEN

n=27 n=73 n=7 n=10 n=7 n=5 n=6 n=8

Page 24: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

P Lo

op

cα2

cα2

WPD

Lo

op

TI Loop

TI L

oop

Lee et al. Crystal Structure of the PTEN Tumor Suppressor: Implications for Its Phosphoinositide Phosphatase Activity and

Membrane Association. Cell, 1999.

Statistical association between PTEN hotspots and signaling pathways in GBM

WPD Loop

P Loop

Phosphatase domain C2 domain

Page 25: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Drug response depends on mutation hotspots

GDSC Mutations in PIK3CA

EGFR/ERBB2 inhibitor

Page 26: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Drug response depends on mutation hotspots

GDSC Mutations in PIK3CA

PIK3CA inhibitor

Page 27: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Summary

• We have developed a novel multiscale clustering algorithm to robustly identify mutation hotspots in genes

• We uncovered statistical associations between many of these mutation hotspots and gene expression, signaling pathways and drug response

Page 28: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Future work

• From PANCAN11 to the PANCAN Atlas • Integrate the mutation hotspots into Regulome

Explorer (RE) • Make code and hotspots available

Page 29: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Acknowledgements

• William Poole • Brady Bernard • Ilya Shmulevich • Sheila Reynolds • Vesteinn Thorsson • TCGA Genome Data Analysis Center (GDAC)

for Systems Analysis of the Cancer Regulome (CSACR)

Page 30: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Poster: 57

Page 31: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and gene expression in UCEC

Page 32: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and gene expression in UCEC

Page 33: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and gene expression in UCEC

Page 34: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and gene expression in UCEC

Page 35: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and gene expression in UCEC

Page 36: Mutation hotspots are associated with gene expression ...Mutation hotspots are associated with gene expression, signaling pathways, protein domains and drug response Theo Knijnenburg

Statistical association between hotspots and gene expression in UCEC


Identification and mutation analysis of the complete gene

Ch12 Gene Mutation

FGFR3 gene mutation plus GRB10 gene duplication in a patient … · 2017. 8. 23. · RESEARCH Open Access FGFR3 gene mutation plus GRB10 gene duplication in a patient with achondroplasia

Gene Mutation. Mutation Mutation: change in DNA sequence Causes of mutation: Spontaneous Due to naturally- occurring errors in DNA replication Induced

Hepatocyte Growth Factor Gene Mutation in Human Colorectal ...d-scholarship.pitt.edu/21345/1/Seneviratne_DS... · Hepatocyte Growth Factor Gene Mutation in Human Colorectal Cancer:

Gene mutation and its types

Mutation Gene Disorders Epidermodysplasia verruciformis

Gene Mutations. Mutation Vocabulary Gene Mutation Point Mutation – Substitution – Silent – Missense – Nonsense Frameshift – Insertion – Deletion Chromosomal

Gene Mutation, DNA Repair, and Transposition

Full coding sequence mutation screening of KRAS gene in ... · Full coding sequence mutation screening of KRAS gene in gastric ... Full coding sequence mutation screening of KRAS

WT1 GENE MUTATION project

Truncating mutation in intracellular phospholipase A1 gene ... · Truncating mutation in intracellular phospholipase A 1 gene (DDHD2) ... Khadijah Bakur1, ... (Novocraft Technologies

Gene & Chromosomal mutation Chicken - SUNY- · PDF filemain types: 1. Single-gene mutations Relatively small changes in DNA structure that ... mutation rate - likelihood that a gene

Genome,Chromosome&Gene Mutation

Gene Structure and Mutation

Generation of mutation hotspots in ageing bacterial colonies

Hypokalemic periodic paralysis due to CACNA1S gene mutation

The relationship between KRAS gene mutation and intestinal

STRUCTURE OF GENE AND TYPES OF MUTATION

Chapter 12.4 gene regulation & mutation

MUTATION JARGON GENE MUTATION = POINT …fire.biol.wwu.edu/trent/trent/13.02.15lecture2.pdf2015/02/13  · 1 MUTATION JARGON GENE MUTATION = POINT MUTATION (scale of mutation is small

Gene Regulation in Prokaryotes Mutation(Permanent, heritable DNA changes) Point mutation (base substitutions) Missense mutation Nonsense mutation (premature

Mechanisms of Gene Mutation

New Strategies and Therapeutic Targets in PDA - seom.org · Selected Somatic Mutation Mutation Position Gene Symbol Gene Description Pathway / Functional Group Transcript Accession

Stickler syndrome, Gene Mutation: COL11A1 Stickler syndrome, Gene Mutation: COL11A2 Stickler syndrome, Gene Mutation: COL2A1

Natural History of Achondroplasia Autosomal Dominant Gene Mutation

PUMA NOXA Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene

Two Types of Mutations Gene mutation: single gene defective Insertion Substitution Deletion Chromosomal mutation: missing or extra chromosome Monosomy

Protein Annotation & Advanced Insilico Based Mutation ... · Keywords: Protein Annotation, Insilico Characterization, Mutation hotspots, CDPK, Cold tolerance I. Introduction: Rice

Gene-Lecture 13- Gene Mutation and Repair

Gene Linkage and Mutation

DETERMINATION OF DUSP6 GENE MUTATION AND ITS …

Heredity, Gene Regulation, and Development Mutation A. Overview

Human Gene Mutation Database

Dominant-negative missense p53 gene mutation Upstream tumour suppressor gene mutation (ATM) Oncogene amplification (MDM2) Viral oncogene