The p53 MUTATION HANDBOOK

(1)

The p53 MUTATION HANDBOOK

Version 1.0 02/2007

Thierry Soussi

Christophe Béroud,

Dalil Hamroun

Jean Michel Rubio Nevado

http://p53/free.fr

(2)

The p53 Mutation HandBook

By T Soussi, J.M. Rubio-Nevado, D. Hamroun and C. Béroud

What is the p53 Mutation HandBook?

The p53 Mutation Handbook is a compilation of multiple analyses

performed using information from the UMD p53 Mutation database

Which release of the UMD TP53 database was used for these

analyses?

Except when otherwise specified, the curated version of the 2007_R1

release of the UMD p53 mutation database was used.

What is the difference between the curated and uncurated version

of the p53 database?

The curated version of the UMD TP53 database has been purged from

artefactual data known to affect p53 mutation analysis. More information

can

be

found

on

our

website

(

http://p53.free.fr/Database/p53_database.html

) or in our recent

publication (

Soussi, T., Asselain, B., Hamroun, D., Kato, S., Ishioka, C.,

Claustres, M. and Beroud, C. (2006) Meta-analysis of the p53 mutation

database for mutant p53 biological activity reveals a methodological

bias in mutation detection. Clin Cancer Res, 12, 62-69.)

How were the various analyses performed?

Using novel software, the entire UMD TP53 mutation database was

automatically analyzed resulting in the p53 Mutation Handbook as output.

What type of information can be found in the p53 Mutation

HandBook?

(3)

be used and reproduced freely by anyone as long as the reference to the

p53 mutation handbook is indicated.

What is the reference of the p53 Mutation HandBook?

T Soussi, J.M. Rubio-Nevado, D. Hamroun and C. Béroud. The p53

Mutation handbook, available online; http://p53.free.fr

What is the audience for this handBook?

Every scientist interested in p53 mutations or more globally in mutation

analysis in human cancer.

What if I need a specific analysis which is not included in this p53

Mutation handbook?

Just send us an email and, if your request is feasible, the analysis will be

performed and added to the handbook.

You can also make suggestions via our Forum (http://p53.free.fr/Forum)

What is the future of the p53 Mutation HandBook?

More analyses and novel information will be added to the next version.

Stay tuned!

Version History

1.1 March 2007

Modification of the CpG mutation analysis page 68 and 69

1.0

(4)

p53 mutational events

GC->AT AT->GC GC->CG GC->TA AT->CG AT->TA Fr.

0

10

20

30

40

50 FREQUENCY (%)

MUTATIONAL EVENTS

DNA substitution mutations are of two

types. Transitions are interchanges of

purines (A G) or of pyrimdines (C T),

which therefore involve bases of similar

shape. Transversions are interchanges

between purine and pyrmidine bases,

which therefore involve exchange of

one-ring and two-one-ring structures. Although

there are twice as many possible

transversions, because of the molecular

mechanisms by which they are generated,

transition mutations occur at higher

frequency than transversions

mutation at CpG

mutation outside CpG

Ts

Tv

Ts: transition

Tv: transversion

Fr: frameshift mutation

Spectrum of p53 mutations in various types of tumors.

A predominance of the GC->AT transition at the CpG dinucleotide (colon, ovary brain,

or leukemia) is the consequence of spontaneous deamination of 5-methylcytosine.

(5)

1

30

60

90

120

150

180

210

240

270

300

330

360

390

0

2

4

6

8 FREQUENCY (%)

p53 CODON

175

248

273 The human p53 protein consists of 393 amino acids with 5 evolutionarily conserved

domains (I to V). Domains II to V correspond to the DNA binding domain which is the

target for p53 mutations.

90 % of p53 mutations occur in the central region which harbors four of the five

highly conserved evolutionary domains. X-ray crystallography of p53-DNA

complexes shows that this region is essential for the p53-DNA interaction [Cho,

1994, #3218]. However, this distribution might be slightly biased since most

investigations have focused exclusively on this region of the p53 gene.

More recent studies on all the coding exons (exons 2 through 11) show that a

considerable number of mutations are found in exons 4 and 10. Mutations in exons

5-8 are significantly different from those found in exons 4, 9 (see exon distribution).

(6)

Distribution of p53 mutations in the various functional domains of p53.

The higher frequency of frameshift mutations between exon 2-4 and exon 5-8

domains is statistically significant (p<0.0001).

I

II

III

IV

V

Human p53 protein (Hp53) can be divided into five domains, each corresponding

to specific functions:

i) The amino-terminus part 1-42 contains the acidic transactivation domain and the

mdm2 protein binding site. It also contains the Highly Conserved Domain I (HCD I)

(7)

19268 1906 2603 23777 998 81% 8% 11% 100% 4% Number of missense mutations

Number of nonsense mutations Number of frameshift mutations

Total number of mutations Number of polymorphisms 1512 86 473 2071 203 73% 4% 23% 100% 10% Number of missense mutations

Number of nonsense mutations Number of frameshift mutations

Total number of mutations Number of polymorphisms

10%

7%

83%

31%

13%

56%

23%

26%

51%

p53 MUTATION DATABASE ANALYSIS

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

175 248 273 248 273 282 245 249 220 213 CGC CGG CGT CGG CGT CGG GGC AGG TAT CGA CAC CAG CAT TGG TGT TGG AGC AGC TGT TGA Arg Arg Arg Arg Arg Arg Gly Arg Tyr Arg His Gln His Trp Cys Trp Ser Ser Cys Stop Ts Ts Ts Ts Ts Ts Ts Tv Ts Ts Yes Yes Yes Yes Yes Yes Yes No No Yes 1102 846 759 701 648 572 420 390 322 280 Codon WT Codon Mutant Codon WT AA Mutant AA Type CpG File Qty

I

II

III

IV

V

Frameshift

Nonsense

Missense

Exon 2-4

Exon 5-8

Exon 9-11

FREQUENCY

(%)

FREQUENCY

(8)

1

30

60

90

120

150

180

210

240

270

300

330

360

390

0

2

4

6

8 FREQUENCY

(%)

I

II

III

IV

V

p53 MUTATION DATABASE ANALYSIS

p53 CODON

p53 mutation distribution

p53 mutational events

20

30

40

50 (%)

175

248

273 mutation at CpG

mutation outside CpG

(9)

All

hepatocellular carcinoma

lung (sclc) lung (nsclc)esophageal adc

esophageal scc

skin squamous cell carcinoma

head and neck scc

endometrial tumor

bladder carcinoma

ovarian carcinoma

glioblastomaprostate ca.rectal ca. b-chronic lymphocytic leukemia

gastric carcinoma

pancreatic cancer

breast carcinoma

none

b-cell lymphoma

colorectal carcinoma

osteosarcomabasal cell carcinoma

gliomas astrocytomali-fraumeni synd.

0

5

10

15

20

25

30

35

40

45 CANCER

all

colorectal carcinoma

breast carcinoma

lung (nsclc)head and neck scc

ovarian carcinoma

esophageal scc

bladder carcinoma

hepatocellular carcinoma

gastric carcinoma

glioblastoma

astrocytoma

pancreatic cancer

esophageal adc

basal cell carcinoma

prostate ca.b-cell lymphoma

lung (sclc)skin squamous cell carcinoma

gliomas endometrial tumor

osteosarcoma

rectal ca.li-fraumeni synd.

none b-chronic lymphocytic leukemia

0

10

20

30

40

50

60

70 FREQUENCY OF GC->AT TRANSITION

FREQUENCY OF GC->TA TRANSVERSION

p53 MUTATION DATABASE ANALYSIS

CANCER

FREQUENCY (%)

mutation at CpG

(10)

Skin tumours

Internal tumours

0

5

10

15

20

25 FREQUENCY

(%)

Skin tumours

Internal Tumours

0

20

40

60

80

100 FREQUENCY

(%)

40

60

80

100 (%)

MUTATIONS AT DI-PYRIMIDINE SITES IN VARIOUS CANCER

TANDEM MUTATIONS

MUTATIONS AT Py-Py SITES

p53 MUTATION DATABASE ANALYSIS

(11)

1652

200

389 2241

57 74%

9%

17%

100%

3%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

465

49

224

738

48 63%

7%

30%

100%

7%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

15%

8%

77%

63%

6%

31%

30%

34%

36%

BREAST CANCER

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

175

248

273

248

245

220

273

213

237

282 CGC

CGG

CGT

CGG

GGC

TAT

CGT

CGA

ATG

CGG

CAC

CAG

CAT

TGG

AGC

TGT

TGA

ATA

TGG

Arg

Gly

Tyr

Arg

Met

Arg

His

Gln

His

Trp

Ser

Cys

Stop

Ile

Trp

Ts

Yes

No

Yes

No

Yes

103

92

87

62

36

35

33

31

29

27

Codon WT Codon Mutant Codon WT AA Mutant AA Type

CpG

File Qty

FREQUENCY

(%)

FREQUENCY

(%)

(12)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

1

2

3

4

5

6

7

8 FREQUENCY

(%)

BREAST CANCER

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

30

40

50 (%)

mutation at CpG

mutation outside CpG

248

175

273

(13)

2529

277

313 3119

53 81%

9%

10%

100%

2%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

472

45

161

678

38 70%

7%

24%

100%

6%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

9%

82%

46%

14%

41%

36%

20%

44%

CRC CANCER

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

175

248

273

282

245

273

196

213

245 CGC

CGG

CGT

CGG

GGC

CGT

CGA

GGC

CAC

CAG

TGG

CAT

TGG

AGC

TGT

TGA

GAC

Arg

Gly

Arg

Gly

His

Gln

Trp

His

Trp

Ser

Cys

Stop

Asp

Ts

Yes

No

318

192

178

177

155

117

111

62

61

38 CpG

File Qty

10

12

14 FREQUENCY

(%)

FREQUENCY

(%)

I

II

III

IV

V

(14)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

2

4

6

8

10

12

14 FREQUENCY

(%)

CRC CANCER

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

40

50

60

70 (%)

mutation at CpG

mutation outside CpG

248

175

273

(15)

477

22

45

544

4 88%

4%

8%

100%

1%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

165

11

41

217

3 76%

5%

19%

100%

1%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

8%

3%

89%

8%

17%

75%

0%

80%

20%

ASTROCYTOMA

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

Frameshift

Nonsense

Missense

273

175

248

273

282

248

234

179

163

245 CGT

CGC

CGG

CGT

CGG

TAC

CAT

TAC

GGC

TGT

CAC

CAG

CAT

TGG

TGC

CGT

TGC

AGC

Arg

Tyr

His

Tyr

Gly

Cys

His

Gln

His

Trp

Cys

Arg

Cys

Ser

Ts

Yes

No

Yes

89

47

30

23

17

13

8

7

6

6 CpG

File Qty

10

15

20

25 FREQUENCY

(%)

FREQUENCY

(%)

I

II

III

IV

V

(16)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

5

10

15

20

25 FREQUENCY

(%)

ASTROCYTOMA

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

40

50

60 (%)

mutation at CpG

mutation outside CpG

248

175

273

(17)

571

21

50

642

7 89%

3%

8%

100%

1%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

213

9

41

263

7 81%

3%

16%

100%

3%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

8%

3%

89%

7%

0%

93%

GLIOBLASTOMA

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

273

175

248

273

248

282

245

237

158

220 CGT

CGC

CGG

CGT

CGG

GGC

ATG

CGC

TAT

TGT

CAC

CAG

CAT

TGG

AGC

ATA

CAC

TGT

Arg

Gly

Met

Arg

Tyr

Cys

His

Gln

His

Trp

Ser

Ile

His

Cys

Ts

Yes

No

Yes

No

61

43

27

23

22

17

14

10

8

8 CpG

File Qty

10

12

14 FREQUENCY

(%)

FREQUENCY

(%)

I

II

III

IV

V

(18)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

2

4

6

8

10

12

14 FREQUENCY

(%)

GLIOBLASTOMA

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

40

50

60 (%)

mutation at CpG

mutation outside CpG

248

175

273

(19)

1711

203

237 2151

55 80%

9%

11%

100%

3%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

483

50

151

684

43 71%

7%

22%

100%

6%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

10%

9%

81%

27%

20%

53%

16%

29%

56%

LUNG (NSCLC )

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

158

273

249

157

220

248

245

248

273

175 CGC

CGT

AGG

GTC

TAT

CGG

GGC

CGG

CGT

CGC

CTC

CTT

AGT

TTC

TGT

CTG

TGC

TGG

CAT

CAC

Arg

Val

Tyr

Arg

Gly

Arg

Leu

Ser

Phe

Cys

Leu

Cys

Trp

His

Tv

Ts

Tv

Ts

No

Yes

51

47

46

45

38

37

36

34

33 CpG

File Qty

FREQUENCY

(%)

FREQUENCY

(%)

(20)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

1

2

3

4

5

6 FREQUENCY

(%)

LUNG (NSCLC )

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

30

40 (%)

mutation at CpG

mutation outside CpG

248

175

273

158

157

(21)

181

28

17

226

9 80%

12%

8%

100%

4%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

105

13

16

134

8 78%

10%

12%

100%

6%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

6%

11%

84%

40%

20%

38%

25%

LUNG (SCLC )

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

Frameshift

Nonsense

Missense

248

157

298

249

158

171

175

242

244 CGG

GTC

GAG

AGG

CGC

GAG

CGC

TGC

GGC

CTG

TTC

TAG

AGT

CTC

TAG

CAC

TGC

TTC

TGC

Arg

Val

Glu

Arg

Glu

Arg

Cys

Gly

Leu

Phe

Stop

Ser

Leu

Stop

His

Cys

Phe

Cys

Tv

Ts

Tv

No

Yes

No

13

8

7

6

5

4

4 CpG

File Qty

FREQUENCY

(%)

FREQUENCY

(%)

(22)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

1

2

3

4

5

6

7

8 FREQUENCY

(%)

LUNG (SCLC )

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

30

40 (%)

mutation at CpG

mutation outside CpG

248

175

298

157

(23)

933

94

65 1092

66 85%

9%

6%

100%

6%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

352

36

59

447

49 79%

8%

13%

100%

11%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

5%

8%

87%

12%

15%

73%

14%

23%

64%

BLADDER CANCER

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

Frameshift

Nonsense

Missense

285

280

248

175

273

280

248

220

271

245 GAG

AGA

CGG

CGC

CGT

AGA

CGG

TAT

GAG

GGC

AAG

ACA

CAG

CAC

CAT

AAA

TGG

TGT

AAG

AGC

Glu

Arg

Tyr

Glu

Gly

Lys

Thr

Gln

His

Lys

Trp

Cys

Lys

Ser

Ts

Tv

Ts

No

Yes

No

Yes

No

Yes

56

35

30

27

24

22

21

19

18

15 CpG

File Qty

FREQUENCY

(%)

FREQUENCY

(%)

(24)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

1

2

3

4

5

6 FREQUENCY

(%)

BLADDER CANCER

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

40

50

60 (%)

mutation at CpG

mutation outside CpG

248

175

285

280

273

(25)

142

15

20

177

1 80%

8%

11%

100%

1%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

86

9

16

111

1 77%

8%

14%

100%

1%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

11%

8%

81%

67%

0%

33%

0%

33%

67%

ENDOMETRIAL CANCER

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

Frameshift

Nonsense

Missense

248

175

273

242

213

245

282

157

163 CGG

CGG

CGC

CGT

TGC

CGA

GGC

CGG

GTC

TAC

TGG

CAG

CAC

CAT

TTC

TGA

AGC

TGG

TTC

TGC

Arg

Cys

Arg

Gly

Arg

Val

Tyr

Trp

Gln

His

Phe

Stop

Ser

Trp

Phe

Cys

Ts

Tv

Ts

Tv

Ts

Yes

No

Yes

No

10

8

6

5

4

3

3 CpG

File Qty

10

12 FREQUENCY

(%)

FREQUENCY

(%)

I

II

III

IV

V

(26)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

2

4

6

8

10

12 FREQUENCY

(%)

ENDOMETRIAL CANCER

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

30

40

50 (%)

mutation at CpG

mutation outside CpG

248

175

273

(27)

182

23

32

237

7 77%

10%

14%

100%

3%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

78

9

28

115

5 68%

8%

24%

100%

4%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

13%

10%

78%

40%

20%

40%

ESOPHAGEAL ADC

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

175

248

245

273

248

213

273

282

196

278 CGC

CGG

GGC

CGT

CGG

CGA

CGT

CGG

CGA

CCT

CAC

TGG

AGC

CAT

CAG

TGA

TGT

TGG

TGA

TCT

Arg

Gly

Arg

Pro

His

Trp

Ser

His

Gln

Stop

Cys

Trp

Stop

Ser

Ts

Yes

No

22

14

12

8

7

6

5

4 CpG

File Qty

10 FREQUENCY

(%)

FREQUENCY

(%)

I

II

III

IV

V

(28)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

1

2

3

4

5

6

7

8

9

10 FREQUENCY

(%)

ESOPHAGEAL ADC

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

40

50

60 (%)

mutation at CpG

mutation outside CpG

248

175

273

(29)

897

124

168 1189

38 75%

10%

14%

100%

3%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

288

46

114

448

29 64%

10%

25%

100%

6%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

14%

10%

77%

43%

14%

43%

24%

48%

29%

ESOPHAGEAL SCC

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

175

282

273

220

248

179

273

176

157 CGC

CGG

CGT

TAT

CGG

CAT

CGT

TGC

GTC

CAC

TGG

CAT

TGT

CAG

TGG

CGT

TGT

TTC

Arg

Tyr

Arg

His

Arg

Cys

Val

His

Trp

His

Cys

Gln

Trp

Arg

Cys

Phe

Ts

Tv

Yes

No

Yes

No

Yes

No

68

41

26

25

23

18

17

14

11 CpG

File Qty

FREQUENCY

(%)

FREQUENCY

(%)

(30)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

1

2

3

4

5

6 FREQUENCY

(%)

ESOPHAGEAL SCC

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

30

40

50 (%)

mutation at CpG

mutation outside CpG

248

175

273

(31)

689

60

76

825

51 84%

7%

9%

100%

6%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

260

21

59

340

35 76%

6%

17%

100%

10%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

9%

7%

84%

25%

33%

42%

GASTRIC CANCER

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

Frameshift

Nonsense

Missense

175

282

273

248

245

273

196

213

220 CGC

CGG

CGT

CGG

GGC

CGT

CGA

TAT

CAC

TGG

CAT

CAG

TGG

AGC

TGT

TGA

TGT

Arg

Gly

Arg

Tyr

His

Trp

His

Gln

Trp

Ser

Cys

Stop

Cys

Ts

Yes

No

59

43

32

30

29

23

13

12 CpG

File Qty

FREQUENCY

(%)

FREQUENCY

(%)

(32)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

1

2

3

4

5

6

7

8 FREQUENCY

(%)

GASTRIC CANCER

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

40

50

60 (%)

mutation at CpG

mutation outside CpG

248

175

273

282

245

(33)

759

52

863

25 88%

6%

100%

3%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

264

31

42

337

21 78%

9%

12%

100%

6%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

5%

90%

18%

14%

68%

20%

40%

HCC

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

Frameshift

Nonsense

Missense

249

273

157

251

220

249

159

175

248

214 AGG

CGT

GTC

ATC

TAT

AGG

GCC

CGC

CGG

CAT

AGT

TGT

TTC

AAC

TGT

ATG

CCC

CAC

CAG

CGT

Arg

Val

Ile

Tyr

Arg

Ala

Arg

His

Ser

Cys

Phe

Asn

Cys

Met

Pro

His

Gln

Arg

Tv

Ts

Tv

Ts

Tv

Ts

No

Yes

No

Yes

No

263

19

15

12

9

7

6 CpG

File Qty

10

15

20

25

30

35 FREQUENCY

(%)

FREQUENCY

(%)

I

II

III

IV

V

(34)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

5

10

15

20

25

30

35 FREQUENCY

(%)

HCC

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

30

40

50 (%)

mutation at CpG

mutation outside CpG

249

(35)

1433

200

285 1918

66 75%

10%

15%

100%

3%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

442

52

173

667

47 66%

8%

26%

100%

7%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

14%

9%

77%

31%

22%

47%

36%

31%

33%

HEAD AND NECK SCC

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

Frameshift

Nonsense

Missense

248

175

273

282

248

220

176

273

205

157 CGG

CGC

CGT

CGG

TAT

TGC

CGT

TAT

GTC

CAG

CAC

CAT

TGG

TGT

TTC

TGT

TTC

Arg

Tyr

Cys

Arg

Tyr

Val

Gln

His

Trp

Cys

Phe

Cys

Phe

Ts

Tv

Ts

Tv

Yes

No

Yes

No

58

55

50

46

41

33

31

30

27

22 CpG

File Qty

FREQUENCY

(%)

FREQUENCY

(%)

(36)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

1

2

3

4

5

6

7 FREQUENCY

(%)

HEAD AND NECK SCC

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

30

40 (%)

mutation at CpG

mutation outside CpG

248

175

273

(37)

148

19

16

183

0 81%

10%

9%

100%

0%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

53

9

13

75

0 71%

12%

17%

100%

0%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

8%

10%

82%

LI-FRAUMENI SYNDROME

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

Frameshift

Nonsense

Missense

175

248

245

273

282

213

290

306 CGC

CGG

GGC

CGT

CGG

CGA

CGC

CGA

CAC

CAG

TGG

AGC

CAT

TGT

TGG

TGA

CAC

TGA

Arg

Gly

Arg

His

Gln

Trp

Ser

His

Cys

Trp

Stop

His

Stop

Ts

Yes

15

12

11

7

6

5

5 CpG

File Qty

10

12

14

16 FREQUENCY

(%)

FREQUENCY

(%)

I

II

III

IV

V

(38)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

2

4

6

8

10

12

14

16 FREQUENCY

(%)

LI-FRAUMENI SYNDROME

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

40

50

60

70 (%)

mutation at CpG

mutation outside CpG

248

175

273

(39)

231

35

13

279

24 83%

13%

5%

100%

9%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

105

11

12

128

16 82%

9%

100%

13%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

3%

10%

87%

46%

23%

31%

0%

71%

29%

SKIN BCC

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

Frameshift

Nonsense

Missense

196

248

241

177

282

179

248

127

152

213 CGA

CGG

TCC

CCC

CGG

CAT

CGG

TCC

CCG

CGA

TGA

TGG

TTC

CTC

TGG

TAT

CAA

TTC

TCG

TGA

Arg

Ser

Pro

Arg

His

Arg

Ser

Pro

Arg

Stop

Trp

Phe

Leu

Trp

Tyr

Gln

Phe

Ser

Stop

Ts

Yes

No

Yes

No

Yes

14

13

11

9

8

5

5 CpG

File Qty

FREQUENCY

(%)

FREQUENCY

(%)

(40)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

1

2

3

4

5

6

7

8

9 FREQUENCY

(%)

SKIN BCC

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

50

60

70

80 (%)

mutation at CpG

mutation outside CpG

248

196

177

241

(41)

150

20

10

180

18 83%

11%

6%

100%

10%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

99

13

7

119

13 83%

11%

6%

100%

11%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

4%

7%

89%

33%

0%

56%

44%

SKIN SCC

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

Frameshift

Nonsense

Missense

282

248

179

281

286

196

317

104

245

248 CGG

CGG

CAT

GAC

GAA

CGA

CAG

GGC

CGG

TGG

TAT

GAT

AAA

TGA

TAG

INS1B

AGC

CAG

Arg

His

Asp

Glu

Arg

Gln

Gly

Arg

Trp

Tyr

Asp

Lys

Stop

Fs.

Ser

Gln

Ts

Fr

Ts

Yes

No

Yes

No

Yes

9

8

6

5

4

3

3 CpG

File Qty

FREQUENCY

(%)

FREQUENCY

(%)

(42)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

1

2

3

4

5

6

7

8 FREQUENCY

(%)

SKIN SCC

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

40

50

60 (%)

mutation at CpG

mutation outside CpG

248

175

273

(43)

84

5

94

15 89%

5%

100%

16%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

74

5

84

15 88%

6%

100%

18%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

4%

_5%

92%

0%

13%

88%

67%

0%

33%

MELANOMA

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

177

248

290

127

187

258

266

46

47

59 CCC

CGG

CGC

TCC

GGT

GAA

GGA

TCC

CCG

GGT

TCC

TGG

CAC

TTC

AGT

AAA

GAA

CCC

TCG

GAT

Pro

Arg

Ser

Gly

Glu

Gly

Ser

Pro

Gly

Ser

Trp

His

Phe

Ser

Lys

Glu

Pro

Ser

Asp

Ts

No

Yes

No

3

2

1

1 CpG

File Qty

FREQUENCY

(%)

FREQUENCY

(%)

(44)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

1

2

3

4

5 FREQUENCY

(%)

MELANOMA

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

40

50

60

70 (%)

mutation at CpG

mutation outside CpG

248

177 ₂₉₀

(45)

294

19

57

370

14 79%

5%

15%

100%

4%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

142

11

45

198

12 72%

6%

23%

100%

6%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

15%

5%

80%

60%

0%

40%

PANCREAS CARCINOMA

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

Frameshift

Nonsense

Missense

273

175

248

273

282

220

248

213

132

151 CGT

CGC

CGG

CGT

CGG

TAT

CGG

CGA

AAG

CCC

CAT

CAC

TGG

TGT

TGG

TGT

CAG

CTA

AGG

TCC

Arg

Tyr

Arg

Lys

Pro

His

Trp

Cys

Trp

Cys

Gln

Leu

Arg

Ser

Ts

Tv

Ts

Yes

No

Yes

No

30

16

11

10

8

6

4

4 CpG

File Qty

10

12

14 FREQUENCY

(%)

FREQUENCY

(%)

I

II

III

IV

V

(46)

1

31

61

91

121

151

181

211

241

271

301

331

361

391

0

2

4

6

8

10

12

14 FREQUENCY

(%)

PANCREAS CARCINOMA

p53 mutation distribution

p53 mutational events

I

II

III

IV

V

p53 CODON

30

40

50 (%)

mutation at CpG

mutation outside CpG

248

175

273

(47)

233

17

22

272

18 86%

6%

8%

100%

7%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

133

12

16

161

13 83%

7%

10%

100%

8%

Number of missense mutations

Number of nonsense mutations

Number of frameshift mutations

Total number of mutations

Number of polymorphisms

7%

6%

87%

36%

9%

55%

11%

78%

PROSTATE CANCER

p53 mutation frequency

p53 mutant frequency

Hot spot mutations

Exon distribution

EXON 9-11

EXON 2-4

EXON 5-8

Frameshift

Nonsense

Missense

273

175

138

251

273

214

248

274

126

152 CGT

CGC

GCC

ATC

CGT

CAT

CGG

GTT

TAC

CCG

TGT

CAC

DEL1A

AGC

CAT

CGT

TGG

TTT

TGC

CCA

Arg

Ala

Ile

Arg

His

Arg

Val

Tyr

Pro

Cys

His

Fs.

Ser

His

Arg

Trp

Phe

Cys

Pro

Ts

Fr

Tv

Ts

Tv

Ts

Yes

No

Yes

No

Yes

No

Yes

13

7

6

5

4

4 CpG

File Qty

FREQUENCY

(%)

FREQUENCY

(%)