Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES...
Transcript of Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES...
![Page 1: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/1.jpg)
Mutational processes
in the human genome
Serena Nik-Zainal
CRUK Advanced Clinician Scientist
Honorary Consultant in Clinical Genetics
Cambridge Society for the Application of Research Talk, June 19th 2017
![Page 2: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/2.jpg)
![Page 3: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/3.jpg)
normal cell
![Page 4: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/4.jpg)
normal cell
![Page 5: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/5.jpg)
normal cell
![Page 6: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/6.jpg)
normal cell
![Page 7: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/7.jpg)
normal cell
![Page 8: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/8.jpg)
normal cell
![Page 9: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/9.jpg)
normal cell
![Page 10: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/10.jpg)
100% cells
26,700 mutations
10 CN changes
PIK3CA, TP53, GATA3,
SMAD4, NCOR1 muts
normal cell
![Page 11: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/11.jpg)
cancer cell
![Page 12: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/12.jpg)
Gel-based
Kb/day/machine
Massively-parallel sequencing
![Page 13: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/13.jpg)
Gel-basedCapillary
Kb/day/machine
Massively-parallel sequencing
![Page 14: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/14.jpg)
Gel-basedCapillary
Kb/day/machine
Massively-parallel sequencing
![Page 15: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/15.jpg)
Gel-basedCapillary
Massively parallel sequencing
Kb/day/machine
Massively-parallel sequencing
![Page 16: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/16.jpg)
Massively-parallel sequencing:
Sequencing information from individual DNA molecules
![Page 17: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/17.jpg)
Massively-parallel sequencing:
Sequencing information from individual DNA molecules
![Page 18: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/18.jpg)
Massively-parallel sequencing: Gives us unprecedented access to the entire human genome
• Human genome ~ 3,000,000,000
--> Whole genome sequencing
• ~ 20,000 genes encompassing ~ 1-2% of human genome
--> Whole exome sequencing
![Page 19: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/19.jpg)
Massively-parallel sequencing: Gives us unprecedented access to the entire human genome
• Human genome ~ 3,000,000,000
--> Whole genome sequencing
• ~ 20,000 genes encompassing ~ 1-2% of human genome
--> Whole exome sequencing
![Page 20: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/20.jpg)
Massively-parallel sequencing: Gives us unprecedented access to the entire human genome
• Human genome ~ 3,000,000,000
--> Whole genome sequencing
• ~ 20,000 genes encompassing ~ 1-2% of human genome
--> Whole exome sequencing
![Page 21: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/21.jpg)
Genomic abnormalities
exon intron UTR
![Page 22: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/22.jpg)
Genomic abnormalities
exon intron UTR
TTCACG
![Page 23: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/23.jpg)
Genomic abnormalities
exon intron UTR
TTCACG
TTTACG
substitution
![Page 24: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/24.jpg)
Genomic abnormalities
exon intron UTR
TTCACG
TTTACG TTT-CG
substitution deletion/
insertion
![Page 25: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/25.jpg)
base pair resolution
Genomic abnormalities
exon intron UTR
TTCACG
TTTACG TTT-CG
substitution deletion/
insertion
![Page 26: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/26.jpg)
base pair resolution
Genomic abnormalities
exon intron UTR
TTCACG
TTTACG TTT-CG
substitution deletion/
insertion
duplication
![Page 27: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/27.jpg)
base pair resolution
Genomic abnormalities
exon intron UTR
TTCACG
TTTACG TTT-CG
substitution deletion/
insertion
duplication
deletion
![Page 28: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/28.jpg)
base pair resolution
Genomic abnormalities
exon intron UTR
TTCACG
TTTACG TTT-CG
substitution deletion/
insertion
duplication
deletion
inversion
![Page 29: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/29.jpg)
base pair resolution
Genomic abnormalities
exon intron UTR
TTCACG
TTTACG TTT-CG
substitution deletion/
insertion
duplication
deletion
inversion
translocation
![Page 30: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/30.jpg)
Genomic abnormalities
exon intron UTR
TTCACG
TTTACG TTT-CG
substitution deletion/
insertion
duplication
deletion
inversion
translocation
base pair resolution
chromosomal scale
![Page 31: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/31.jpg)
Driver mutations in cancer genes
![Page 32: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/32.jpg)
• Genomic scenario
• ERBB2 - breast cancer
• BCR-ABL – leukaemia
• EGFR – lung cancer
• BRAF - metastatic melanoma
Driver mutations in cancer genes
![Page 33: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/33.jpg)
• Genomic scenario
• ERBB2 - breast cancer
• BCR-ABL – leukaemia
• EGFR – lung cancer
• BRAF - metastatic melanoma
• Targeted drug
• Herceptin, Lapatinib
• Imatinib
• Erlotinib, Gefitinib
• Vemurafenib
Driver mutations in cancer genes
![Page 34: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/34.jpg)
ER positive ER negative
Driver mutations in cancer genes
![Page 35: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/35.jpg)
ER positive ER negative
Driver mutations in cancer genes
![Page 36: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/36.jpg)
ER positive ER negative
Driver mutations in cancer genes
![Page 37: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/37.jpg)
Wagle et al. JCO, 2011
Pre-treatment 15 Weeks 23 Weeks
Driver mutations in cancer genes
![Page 38: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/38.jpg)
Many thousands of passenger mutations
![Page 39: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/39.jpg)
![Page 40: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/40.jpg)
![Page 41: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/41.jpg)
![Page 42: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/42.jpg)
![Page 43: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/43.jpg)
![Page 44: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/44.jpg)
![Page 45: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/45.jpg)
![Page 46: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/46.jpg)
Mutation signatures in human cells
![Page 47: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/47.jpg)
Extracting mutation signatures
![Page 48: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/48.jpg)
Extracting mutation signatures
![Page 49: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/49.jpg)
Extracting mutation signatures
![Page 50: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/50.jpg)
Extracting mutation signatures
![Page 51: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/51.jpg)
C>T = G>A
C>A = G>T
C>G = G>C
T>A = A>T
T>C = A>G
T>G = A>C
6 mutation classes
Classification of base substitution mutations
![Page 52: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/52.jpg)
C>T
C>A
C>G
T>A
T>C
T>G
6 mutation classes
Classification of base substitution mutations
![Page 53: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/53.jpg)
C>T
C>A
C>G
T>A
T>C
T>G
ACA>ATA
ACC>ATC
ACG>ATG
ACT>ATT
CCA>CTA
CCC>CTC
CCG>CTG
CCT>CTT
GCA>GTA
GCC>GTC
GCG>GTG
GCT>GTT
TCA>TTA
TCC>TTC
TCG>TTG
TCT>TTT
6 mutation classes
Classification of base substitution mutations
![Page 54: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/54.jpg)
C>T
C>A
C>G
T>A
T>C
T>G
ACA>ATA
ACC>ATC
ACG>ATG
ACT>ATT
CCA>CTA
CCC>CTC
CCG>CTG
CCT>CTT
GCA>GTA
GCC>GTC
GCG>GTG
GCT>GTT
TCA>TTA
TCC>TTC
TCG>TTG
TCT>TTT
6 mutation classes
Classification of base substitution mutations
![Page 55: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/55.jpg)
C>T
C>A
C>G
T>A
T>C
T>G
ACA>ATA
ACC>ATC
ACG>ATG
ACT>ATT
CCA>CTA
CCC>CTC
CCG>CTG
CCT>CTT
GCA>GTA
GCC>GTC
GCG>GTG
GCT>GTT
TCA>TTA
TCC>TTC
TCG>TTG
TCT>TTT
6 mutation classes
Classification of base substitution mutations
![Page 56: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/56.jpg)
C>T
C>A
C>G
T>A
T>C
T>G
ACA>ATA
ACC>ATC
ACG>ATG
ACT>ATT
CCA>CTA
CCC>CTC
CCG>CTG
CCT>CTT
GCA>GTA
GCC>GTC
GCG>GTG
GCT>GTT
TCA>TTA
TCC>TTC
TCG>TTG
TCT>TTT
6 mutation classes
Classification of base substitution mutations
![Page 57: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/57.jpg)
C>T
C>A
C>G
T>A
T>C
T>G
ACA>ATA
ACC>ATC
ACG>ATG
ACT>ATT
CCA>CTA
CCC>CTC
CCG>CTG
CCT>CTT
GCA>GTA
GCC>GTC
GCG>GTG
GCT>GTT
TCA>TTA
TCC>TTC
TCG>TTG
TCT>TTT
6 mutation classes
Classification of base substitution mutations
![Page 58: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/58.jpg)
C>T
C>A
C>G
T>A
T>C
T>G
ACA>ATA
ACC>ATC
ACG>ATG
ACT>ATT
CCA>CTA
CCC>CTC
CCG>CTG
CCT>CTT
GCA>GTA
GCC>GTC
GCG>GTG
GCT>GTT
TCA>TTA
TCC>TTC
TCG>TTG
TCT>TTT
6 mutation classes
Classification of base substitution mutations
![Page 59: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/59.jpg)
C>T
C>A
C>G
T>A
T>C
T>G
ACA>ATA
ACC>ATC
ACG>ATG
ACT>ATT
CCA>CTA
CCC>CTC
CCG>CTG
CCT>CTT
GCA>GTA
GCC>GTC
GCG>GTG
GCT>GTT
TCA>TTA
TCC>TTC
TCG>TTG
TCT>TTT
6 mutation classes
Classification of base substitution mutations
![Page 60: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/60.jpg)
C>T
C>A
C>G
T>A
T>C
T>G
ACA>ATA
ACC>ATC
ACG>ATG
ACT>ATT
CCA>CTA
CCC>CTC
CCG>CTG
CCT>CTT
GCA>GTA
GCC>GTC
GCG>GTG
GCT>GTT
TCA>TTA
TCC>TTC
TCG>TTG
TCT>TTT
6 mutation classes
Classification of base substitution mutations
![Page 61: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/61.jpg)
C>T
C>A
C>G
T>A
T>C
T>G
ACA>ATA
ACC>ATC
ACG>ATG
ACT>ATT
CCA>CTA
CCC>CTC
CCG>CTG
CCT>CTT
GCA>GTA
GCC>GTC
GCG>GTG
GCT>GTT
TCA>TTA
TCC>TTC
TCG>TTG
TCT>TTT
6 mutation classes
Classification of base substitution mutations
![Page 62: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/62.jpg)
C>T
C>A
C>G
T>A
T>C
T>G
ACA>ATA
ACC>ATC
ACG>ATG
ACT>ATT
CCA>CTA
CCC>CTC
CCG>CTG
CCT>CTT
GCA>GTA
GCC>GTC
GCG>GTG
GCT>GTT
TCA>TTA
TCC>TTC
TCG>TTG
TCT>TTT
6 mutation classesATA>AGA
ATC>AGC
ATG>AGG
ATT>AGT
CTA>CGA
CTC>CGC
CTG>CGG
CTT>CGT
GTA>GGA
GTC>GGC
GTG>GGG
GTT>GGT
TTA>TGA
TTC>TGC
TTG>TGG
TTT>TGT
ATA>ACA
ATC>ACC
ATG>ACG
ATT>ACT
CTA>CCA
CTC>CCC
CTG>CCG
CTT>CCT
GTA>GCA
GTC>GCC
GTG>GCG
GTT>GCT
TTA>TCA
TTC>TCC
TTG>TCG
TTT>TCT
ATA>AAA
ATC>AAC
ATG>AAG
ATT>AAT
CTA>CAA
CTC>CAC
CTG>CAG
CTT>CAT
GTA>GAA
GTC>GAC
GTG>GAG
GTT>GAT
TTA>TAA
TTC>TAC
TTG>TAG
TTT>TAT
ACA>AAA
ACC>AAC
ACG>AAG
ACT>AAT
CCA>CAA
CCC>CAC
CCG>CAG
CCT>CAT
GCA>GAA
GCC>GAC
GCG>GAG
GCT>GAT
TCA>TAA
TCC>TAC
TCG>TAG
TCT>TAT
ACA>AGA
ACC>AGC
ACG>AGG
ACT>AGT
CCA>CGA
CCC>CGC
CCG>CGG
CCT>CGT
GCA>GGA
GCC>GGC
GCG>GGG
GCT>GGT
TCA>TGA
TCC>TGC
TCG>TGG
TCT>TGT
96 mutation classes
Classification of base substitution mutations
![Page 63: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/63.jpg)
Mutational signatures in human cancer
![Page 64: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/64.jpg)
Mutational signatures in human cancer
![Page 65: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/65.jpg)
Mutational signatures in human cancer
ApCpGTpCpG
GpCpG
CpCpG
![Page 66: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/66.jpg)
![Page 67: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/67.jpg)
Mutational signatures in human cancer
![Page 68: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/68.jpg)
Mutational signatures in human cancer
Tobacco
![Page 69: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/69.jpg)
Mutational signatures in human cancer
UV light
![Page 70: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/70.jpg)
associated with exposure to UV light
c
cancer
Mutational signatures in human cancer
![Page 71: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/71.jpg)
associated with exposure to UV light
Simulated sunlight
c
in vitro
cancer
Mutational signatures in human cancer
![Page 72: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/72.jpg)
Mutational signatures in human cancer
Aristolochic acid
![Page 73: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/73.jpg)
Aristolochic acid
c
in vitro
cancer
Mutational signatures in human cancer
![Page 74: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/74.jpg)
Mutational signatures in human cancer
HR deficiency
![Page 75: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/75.jpg)
Mutational signatures in human cancer
MMR deficiency
![Page 76: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/76.jpg)
Mutational signatures in human cancer
Unknown aetiology
![Page 77: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/77.jpg)
![Page 78: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/78.jpg)
It’s early days
• Still in the infancy of understanding mutational signatures
• This is not dogma : mutational signatures will change
• There are improvements in the mathematical frameworks
to be made
![Page 79: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/79.jpg)
DIGGING DEEP INTO DATA:
LOCALIZED MUTATION SIGNATURES
PART II
![Page 80: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/80.jpg)
![Page 81: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/81.jpg)
![Page 82: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/82.jpg)
![Page 83: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/83.jpg)
![Page 84: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/84.jpg)
![Page 85: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/85.jpg)
![Page 86: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/86.jpg)
![Page 87: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/87.jpg)
![Page 88: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/88.jpg)
![Page 89: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/89.jpg)
![Page 90: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/90.jpg)
![Page 91: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/91.jpg)
Panoramic view of whole-genome sequenced cancers
![Page 92: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/92.jpg)
Panoramic view of whole-genome sequenced cancers
![Page 93: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/93.jpg)
p < 0.001Mutation number
Localised hypermutation or kataegis
![Page 94: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/94.jpg)
Coordinate (bp)
Genomic coordinate
(bp)
Localised hypermutation or kataegis
![Page 95: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/95.jpg)
Localised hypermutation or kataegis
![Page 96: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/96.jpg)
Generalised hypermutation of signatures 2/13
PD4120a
ER +ve HER2 -ve
![Page 97: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/97.jpg)
Kataegis and Signatures 2/13 share similar characteristics
![Page 98: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/98.jpg)
TpCpATpCpG
TpCpT
TpCpC
Kataegis and Signatures 2/13 share similar characteristics
![Page 99: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/99.jpg)
TpCpATpCpG
TpCpT
TpCpC
Kataegis and Signatures 2/13 share similar characteristics
![Page 100: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/100.jpg)
What is the biological basis for these mutational
signatures?
![Page 101: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/101.jpg)
• Deamination of cytosine by one of the family
of AID/APOBEC enzymes?
• The family includes AID
APOBEC1
APOBEC2
APOBEC3A-H
APOBEC4
What is the biological basis for these mutational
signatures?
![Page 102: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/102.jpg)
Double strand
break and
rearrangement
DNA editing by the AID/APOBEC family of
cytidine deaminasesWhat is the biological basis for these mutational
signatures?
![Page 103: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/103.jpg)
Double strand
break and
rearrangement
AID /
APOBEC
What is the biological basis for these mutational
signatures?
![Page 104: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/104.jpg)
Double strand
break and
rearrangement
AID /
APOBEC
What is the biological basis for these mutational
signatures?
![Page 105: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/105.jpg)
Double strand
break and
rearrangement
AID /
APOBEC
What is the biological basis for these mutational
signatures?
![Page 106: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/106.jpg)
Double strand
break and
rearrangement
AID /
APOBEC
What is the biological basis for these mutational
signatures?
![Page 107: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/107.jpg)
Double strand
break and
rearrangement
AID /
APOBEC
What is the biological basis for these mutational
signatures?
![Page 108: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/108.jpg)
Double strand
break and
rearrangement
AID /
APOBEC
What is the biological basis for these mutational
signatures?
![Page 109: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/109.jpg)
The AID / APOBEC family of cytidine
deaminases
• AID plays a central role in somatic hypermutation
and class switch recombination at the
immunoglobulin loci
• APOBEC3A-H mutate viruses and restrict
retrotransposon activity
![Page 110: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/110.jpg)
Which member(s) of the family is
responsible for Signature 2/13?
AID
APOBEC1
APOBEC2
APOBEC3A
APOBEC3B
APOBEC3C
APOBEC3DE
APOBEC3F
APOBEC3G
APOBEC3G
APOBEC3H
APOBEC4
![Page 111: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/111.jpg)
A T C G T C G A T G C T C G A T C A T C A G A G T C A A
T A G C A G C T A C G A G C T A G T A G T C T C A G T T
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Kataegis microclusters demonstrate processivityStrand asymmetry
![Page 112: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/112.jpg)
A T C G T C G A T G C T C G A T C A T C A G A G T C A A
T A G C A G C T A C G A G C T A G T A G T C T C A G T T
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Kataegis microclusters demonstrate processivityStrand asymmetry
![Page 113: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/113.jpg)
A T C G T C G A T G C T C G A T C A T C A G A G T C A A
T A G C A G C T A C G A G C T A G T A G T C T C A G T T
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Kataegis microclusters demonstrate processivityStrand asymmetry
![Page 114: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/114.jpg)
A T C G T C G A T G C T C G A T C A T C A G A G T C A A
T A G C A G C T A C G A G C T A G T A G T C T C A G T T
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Kataegis microclusters demonstrate processivityStrand asymmetry
![Page 115: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/115.jpg)
A T C G T C G A T G C T C G A T C A T C A G A G T C A A
T A G C A G C T A C G A G C T A G T A G T C T C A G T T
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Kataegis microclusters demonstrate processivityStrand asymmetry
![Page 116: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/116.jpg)
Kataegis
• Cytosine mutations
• TpC sequence context
• Localised hypermutation
• Co-localising with
rearrangements
• Strand asymmetry about
rearrangement breakpoints
![Page 117: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/117.jpg)
Kataegis
• Cytosine mutations
• TpC sequence context
• Localised hypermutation
• Co-localising with
rearrangements
• Strand asymmetry about
rearrangement breakpoints
Signature 2 & 13
• Cytosine mutations
• TpC sequence context
• Generalised hypermutation
• NOT co-localising with
rearrangements
• Strand asymmetry relating to
replication direction
![Page 118: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/118.jpg)
Kataegis
• Cytosine mutations
• TpC sequence context
• Localised hypermutation
• Co-localising with
rearrangements
• Strand asymmetry about
rearrangement breakpoints
Signature 2 & 13
• Cytosine mutations
• TpC sequence context
• Generalised hypermutation
• NOT co-localising with
rearrangements
• Strand asymmetry relating to
replication direction
Distinct (but related) signatures in human cancers
![Page 119: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/119.jpg)
Distinct (but related) signatures in human cancers
Deep computational analysis paired with experimental work
has started to reveal and validate biological insights into
mechanisms of how the human genome is constantly mutating
![Page 120: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/120.jpg)
![Page 121: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/121.jpg)
Accumulation of mutations in cancer
![Page 122: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/122.jpg)
Accumulation of mutations in cancer
![Page 123: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/123.jpg)
Summary II
• A remarkable phenomenon of localised hypermutation, termed
“kataegis”, was frequently observed in 21 primary breast cancers
and subsequently in many other cancer types including pancreatic
cancer, lung cancer and haematological cancers.
• Regions of kataegis usually co-localized with somatic
rearrangements.
• Base substitutions in these regions were almost exclusively of
cytosine at TpC dinucleotides. This is very similar to the genome-
wide mutagenesis of Signatures 2 and 13.
• A role for the APOBEC family of cytidine deaminases is proposed.
![Page 124: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/124.jpg)
MUTATIONAL PROCESSES:
WHAT DOES IT MEAN FOR PATIENTS?
PART III
![Page 125: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/125.jpg)
Mutational processes in 560 breast cancers
SNZ.2017
Correlated
with age
![Page 126: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/126.jpg)
Mutational processes in 560 breast cancers
SNZ.2017
Associated with
cytosine
deaminases
![Page 127: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/127.jpg)
Mutational processes in 560 breast cancers
SNZ.2017
Mismatch
repair
deficiency
![Page 128: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/128.jpg)
Mutational processes in 560 breast cancers
SNZ.2017
Homologous
recombination
repair deficiency
![Page 129: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/129.jpg)
Mutational processes in 560 breast cancers
SNZ.2017
Uncertain
aetiology
![Page 130: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/130.jpg)
Mutational processes in 560 breast cancers
SNZ.2017
![Page 131: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/131.jpg)
Mutational processes in 560 breast cancers
SNZ.2017
![Page 132: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/132.jpg)
Mutational processes in 560 breast cancers
SNZ.2017
![Page 133: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/133.jpg)
Driver mutations in breast cancer patients
![Page 134: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/134.jpg)
The individuality of each tumour
“No two patients share the same set of drivers or
the same quantities of mutational signatures in
their tumors”
![Page 135: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/135.jpg)
Whole genome profiling
SNZ.2017
![Page 136: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/136.jpg)
Whole genome profiling
SNZ.2017
![Page 137: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/137.jpg)
Whole genome profiling
SNZ.2017
![Page 138: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/138.jpg)
Whole genome profiling
SNZ.2017
![Page 139: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/139.jpg)
Whole genome profiling
SNZ.2017
![Page 140: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/140.jpg)
Whole genome profiling
SNZ.2017
![Page 141: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/141.jpg)
Whole genome profiling
SNZ.2017SNZ.2017
![Page 142: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/142.jpg)
Whole genome profiling
SNZ.2017SNZ.2017
![Page 143: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/143.jpg)
Whole genome profiling
SNZ.2017SNZ.2017
![Page 144: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/144.jpg)
CLINICAL APPLICATIONS OF
MUTATIONAL SIGNATURES
PART IV
Helen
Davies
Dominik Glodzik
![Page 145: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/145.jpg)
Predicting BRCA1/BRCA2 deficiency
![Page 146: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/146.jpg)
HRDetect identifies additional BRCA1/BRCA2 defective tumours
![Page 147: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/147.jpg)
HRDetect identifies additional BRCA1/BRCA2 defective tumours
![Page 148: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/148.jpg)
HRDetect identifies additional BRCA1/BRCA2 defective tumours
![Page 149: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/149.jpg)
HRDetect identifies additional BRCA1/BRCA2 defective tumours
22 known
germline
![Page 150: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/150.jpg)
HRDetect identifies additional BRCA1/BRCA2 defective tumours
22 known
germline
33 new
germline
22 somatic or
promoter
hypermethylation
47 unknown
![Page 151: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/151.jpg)
HRDetect is superior to any individual mutational signature and the HRD index
![Page 152: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/152.jpg)
HRDetect distinguishes clinical outcome
& is robust between samples in the same patient
![Page 153: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/153.jpg)
HRDetect distinguishes clinical outcome
& is robust between samples in the same patient
![Page 154: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/154.jpg)
HRDetect distinguishes clinical outcome
& is robust between samples from the same patient
![Page 155: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/155.jpg)
Summary
• Presented a mutational-signature based algorithm called HRDetect
with excellent sensitivity and specificity for detecting germline
BRCA1/BRCA2 deficient tumours
• Identify a significant proportion of tumours that are BRCA1/BRCA2
deficient that were not previously known (and missed using typical
exome sequencing methods)
• Mutational signatures provides an opportunity to fine-tune genomic
stratification
![Page 156: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/156.jpg)
SNZ.2017
WGS reveals MMR deficient breast cancers
![Page 157: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/157.jpg)
SNZ.2017
WGS reveals MMR deficient breast cancers
![Page 158: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/158.jpg)
SNZ.2017SNZ.2017
WGS reveals MMR deficient breast cancers
![Page 159: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/159.jpg)
MLH1 MSH2
MSH6 PMS2
Immunohistochemistry of MMR proteins : PD23579a
![Page 160: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/160.jpg)
WGS reveals subclonal MMR deficiency
![Page 161: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/161.jpg)
WGS reveals subclonal MMR deficiency
![Page 162: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/162.jpg)
Unpicking cancer evolution
![Page 163: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/163.jpg)
Mutational signatures
Signatures associated with MMR
deficiency
Unpicking cancer evolution
![Page 164: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/164.jpg)
Signatures associated with MMR
deficiency
Acquired mutations in MMR genes
Mutational signatures
Unpicking cancer evolution
![Page 165: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/165.jpg)
Mutational signatures in 560 breast cancer patients
SNZ.2017
![Page 166: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/166.jpg)
SNZ.2017
Mutational signatures in 560 breast cancer patients
![Page 167: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/167.jpg)
The unmet need
SNZ.2017
![Page 168: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/168.jpg)
560 breast cancer genomes
AMC, Netherlands
CRI, UK
DFCI, USA
Erasmus, Netherlands
Institute Curie, France
Bordet, Belgium
Bari, Italy
NCI, Netherlands
ICGC Korea
Lund, Sweden
MD Anderson, USA
MSKCC, USA
NCC, Singapore
Oslo, Norway RUNMC, Netherlands
Synergie, France
TCRU, Belgium
Bergen, Norway
Dundee, Scotland
Reykjavik, Iceland
Brisbane, Australia
![Page 169: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/169.jpg)
acknowledgements
BASIS Consortium & ICGC Breast Cancer Working Group
Mike Stratton
Ewan Birney
Marc van der Vijver
Ake Borg
John Martens
Anne-Lise Borreson-Dale
Henk Stunnenberg
Andrea Richardson
Alastair Thompson
Jorunn Erla Eyfjord
Andy Futreal
Christos Sotiriou
Andy Tutt
Sunil Lakhani
Steven van Laere
Paul Span
Carlos Caldas
Laura van’t Veer
Gilles Thomas
Alain Viari
Gu Kong
![Page 170: Mutational processes in the human genome...DIGGING DEEP INTO DATA: LOCALIZED MUTATION SIGNATURES PART II Panoramic view of whole-genome sequenced cancers Panoramic view of whole-genome](https://reader033.fdocuments.us/reader033/viewer/2022060718/607ea1553077d61b526eee90/html5/thumbnails/170.jpg)
The team
Becky Harris Project Coordinator
Sandro Morganella (industry)
Dominik Glodzik (Lund University)
Hongwei Chen (Group Leader Nanjing Uni )
Xueqing Zou
Helen Davies
Helen Davies
Andrea Degasperi
Tauanne Dias Amarante
Ilias Georgakopoulos-Soares (PhD)
Gene Koh (PhD)
HR
Johan Staaf
WTSI IT/Admin
Keiran Raine
David Jones
Andrew Menzies
Lucy Stebbings
Jon Hinton
Adam Butler
Sancha Martin
MMR
Colin Purdie (Dundee)
Elin Borgen (Oslo)
Hege Russnes (Oslo)
Se Jin Jang (Asan)