Kym Spencer Liverpool Women’s Hospital

High resolution mapping of the X chromosome pseudoautosomal region in two siblings with Hodgkin Lymphoma and Leri-Weill Dyschondrosteosis

Kym Spencer

Liverpool Women’s Hospital

Reed-Sternberg cells & Hodgkin cells

Clinical Features

Incidence

Cancer Research UK figures for 2004:1,519 new cases - 0.5% of all cancers

diagnosed.Incidence of 2.4/100,000 individuals

2.7/100,000 males2.1/100,000 females

Bimodal age of incidence15-40 years>55 years

A genetic cause of HL

Several familial cases of HL reported.Risk of HL higher in individuals with a family history of

the condition.Higher in siblings.Highest in gender concordant siblings.Combination of inherited susceptibility with shared

environment?

Male predominance of HL Horwitz & Weirnik (1999 & 2007) suggest pseudoautosomal

link due to recombination mechanism of pseudoautosomal regions.

Family L

2 (PL) 3 (JW) 1 (ML)

1 (RL)

2 (GW)

2 (GL) 3 (RW)

4 (GW)

4 (NW)

LWD

HL

I

II

III

Leri-Weill Dyschondrosteosis (LWD)

Hodgkin Lymphoma (HL)

LWD - Madelung Deformity

Pseudoautosomal Regions

X Y

PAR1

PAR2

p

p

q

q

Map of PAR1

Tel

omere

100 300 200

PLCXD1

GTPBP6 (PGPL)

PPP2R3B

LLNOYCO3’M’2E2

LLNOYCO3’M’56G10

Not deleted (Shears et al 2003)

Deleted – (Shears et al.2003)

Not deleted – (present study)

Deleted – (present study)

100

Distance from telomere (kb)

Gene

FISH probe (approx. location)

Direction of transcription

DXYS

Microsatellite markers

2726

-L1588

MLPA probes

* Deleted in IC - (present study)

RP13-465B17

RP13-391G2

Microarray probes:

Not deleted Deleted

Family L

LWD

HL

2 (PL) 3 (JW) 1 (ML)

1 (RL) 2 (GL) 3 (RW)

4 (GW)

4 (NW)

I

II

III

Leri-Weill Dyschondrosteosis (LWD)

Hodgkin Lymphoma (HL)2 (GW)

Methods

MLPA for SHOX copy number using P018B MLPA kit from MRC Holland

Fluorescent microsatellite analysisAddition of custom probes into existing

MLPA kitSNP analysisMicroarray analysis

SHOX MLPA

DE

L

C1

5q31

C2

16p1

3

C3

20q1

1

C4

9q34

C5

13q1

4

C6

8q24

C7

18q2

1

C8

13q1

2

C9

2p22

C10

10p

14

PP

P2R

3B

LOC

1590

15

SH

OX

Ex1

SH

OX

Ex2

SH

OX

Ex3

SH

OX

Ex4

SH

OX

Ex5

SH

OX

Ex6

SH

OX

Ex7

SH

OX

Ex8 PA

R 5

642-

L509

6

PA

R 5

643-

L509

7

PA

R 5

644-

L509

8

PA

R 5

645-

L509

9

PA

R 5

646-

L510

0

PA

R 5

647-

L510

1

PA

R 6

291-

L622

2

PA

R 6

292-

L580

1

PA

R 6

293-

L621

9

PA

R 5

648-

L621

8

PA

R 5

649-

L510

3

PA

R 5

650-

L510

4

PA

R 5

651-

L510

5

CS

F2R

A

IL3R

A

PA

R 5

652-

L510

6

AS

MT

AR

SF

GP

R14

3

GP

R14

3(ii)

Xq2

5

SY

BL1

SM

CY

SR

Y

DB

Y

0.00

0.20

0.40

0.60

0.80

1.00

1.20

RL

C1

5q31

C2

16p1

3C

3 20

q11

C4

9q34

C5

13q1

4C

6 8q

24C

7 18

q21

C8

13q1

2

C9

2p22

C10

10p

14P

PP

2R3B

LOC

1590

15

SH

OX

Ex1

SH

OX

Ex2

SH

OX

Ex3

SH

OX

Ex4

SH

OX

Ex5

SH

OX

Ex6

SH

OX

Ex7

SH

OX

Ex8

PA

R 5

642-

L5096

PA

R 5

643-

L5097

PA

R 5

644-

L5098

PA

R 5

645-

L5099

PA

R 5

646-

L5100

PA

R 5

647-

L5101

PA

R 6

291-

L6222

PA

R 6

292-

L5801

PA

R 6

293-

L6219

PA

R 5

648-

L6218

PA

R 5

649-

L5103

PA

R 5

650-

L5104

PA

R 5

651-

L5105

CS

F2R

AIL

3RA

PA

R 5

652-

L5106

AS

MT

AR

SF

GP

R14

3G

PR

143(ii

)

Xq25

SY

BL1

SM

CY

SR

YD

BY

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

ML

C1 5

q31

C2 1

6p13

C3 2

0q11

C4 9

q34

C5 1

3q14

C6 8

q24

C7 1

8q21

C8 1

3q12

C9 2

p22

C10 1

0p14

PP

P2R

3B

LO

C159015

SH

OX

Ex1

SH

OX

Ex2

SH

OX

Ex3

SH

OX

Ex4

SH

OX

Ex5

SH

OX

Ex6

SH

OX

Ex7

SH

OX

Ex8

PA

R 5

642-L

5096

PA

R 5

643-L

5097

PA

R 5

644-L

5098

PA

R 5

645-L

5099

PA

R 5

646-L

5100

PA

R 5

647-L

5101

PA

R 6

291-L

6222

PA

R 6

292-L

5801

PA

R 6

293-L

6219

PA

R 5

648-L

6218

PA

R 5

649-L

5103

PA

R 5

650-L

5104

PA

R 5

651-L

5105

CS

F2R

A

IL3R

A

PA

R 5

652-L

5106

AS

MT

AR

SF

GP

R143

GP

R143(ii)

Xq25

SY

BL1

SM

CY

SR

Y

DB

Y

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

SHOX MLPA

Tel

omere

100 200

PLCXD1

GTPBP6 (PGPL)

PPP2R3B

2726

-L1588 (PPP2R3B exon 5)

LLNOYCO3’M’2E2


Key Not deleted (Shears et al 2003)




100


Gene



DXYS


2726

-L1588

MLPA probes


RP13-465B17

RP13-391G2

Microarray probes:

Not deleted Deleted

PPP2R3B

PPP2R3B encodes PR48. B subunit of the PP2A holoenzyme. Involved in cell cycle regulation - binds to Cdc6 in mammalian

cells and restricts DNA replication.

PP2A is a cell cycle regulator and tumour suppressor. Consists of A, B and C subunits. B subunits confer substrate specificity.

A

B

C

B’

B’’

B’’’

PR65α or β

PP2A

PR55α, β, γ or δ

PR61α, β, γ, δ or ε

PR72/PR130 or PR48

PR93/SG2NA or PR110/striatin

α or β

Microsatellite Analysis

111+23

--- ∆ --

--- ∆ --

RL GL

221+12

221+11

221+12

111+23

221+11

331+24

--- ∆ --

ML PL

GW

DXYS10037 DXYS10038 DXYS10039 SHOX DXYS10180 DXYS10181

LWD

HL

Microsatellite Analysis

Tel

omer

e

100 300 200 400

PLCXD1

GTPBP6 (PGPL)

PPP2R3B

2726-L1588 (P

PP

2R3B

exon 5)

LLNOYCO3’M’2E2






100


Gene



D

XY

S


2726-L1588

MLPA probes


RP13-465B17

RP13-391G2

Microarray probes:

Not deleted Deleted

Custom MLPA

DE

L

C1

5q

31

C2

16

p1

3C

3 2

0q

11

C4

9q

34

C5

13

q1

4C

6 8

q2

4C

7 1

8q

21

C8

13

q1

2C

9 2

p2

2C

10

10

p1

4P

PP

2R

3B

Ex

5P

PP

2R

3B

Ex

4P

PP

2R

3B

Ex

1L

OC

15

90

15

SH

OX

Ex1

SH

OX

Ex2

SH

OX

Ex3

SH

OX

Ex4

SH

OX

Ex5

SH

OX

Ex6

SH

OX

Ex7

SH

OX

Ex8

PA

R 5

64

2-L

50

96

PA

R 5

64

3-L

50

97

PA

R 5

64

4-L

50

98

PA

R 5

64

5-L

50

99

PA

R 5

64

6-L

51

00

PA

R 5

64

7-L

51

01

PA

R 6

29

1-L

62

22

PA

R 6

29

2-L

58

01

PA

R 6

29

3-L

62

19

PA

R 5

64

8-L

62

18

PA

R 5

64

9-L

51

03

PA

R 5

65

0-L

51

04

PA

R 5

65

1-L

51

05

CS

F2

RA

IL3

RA

PA

R 5

65

2-L

51

06

AS

MT

AR

SF

GP

R1

43

GP

R1

43

(ii)

Xq

25

SY

BL

1S

MC

YS

RY

DB

Y

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

RL

C1

5q

31

C2

16

p1

3C

3 2

0q

11

C4

9q

34

C5

13

q1

4C

6 8

q2

4C

7 1

8q

21

C8

13

q1

2C

9 2

p2

2C

10

10

p1

4P

PP

2R

3B

Ex

5P

PP

2R

3B

Ex

4P

PP

2R

3B

Ex

1L

OC

15

90

15

SH

OX

Ex1

SH

OX

Ex2

SH

OX

Ex3

SH

OX

Ex4

SH

OX

Ex5

SH

OX

Ex6

SH

OX

Ex7

SH

OX

Ex8

PA

R 5

64

2-L

50

96

PA

R 5

64

3-L

50

97

PA

R 5

64

4-L

50

98

PA

R 5

64

5-L

50

99

PA

R 5

64

6-L

51

00

PA

R 5

64

7-L

51

01

PA

R 6

29

1-L

62

22

PA

R 6

29

2-L

58

01

PA

R 6

29

3-L

62

19

PA

R 5

64

8-L

62

18

PA

R 5

64

9-L

51

03

PA

R 5

65

0-L

51

04

PA

R 5

65

1-L

51

05

CS

F2

RA

IL3

RA

PA

R 5

65

2-L

51

06

AS

MT

AR

SF

GP

R1

43

GP

R1

43

(ii)

Xq

25

SY

BL

1S

MC

YS

RY

DB

Y

0.00

0.20

0.40

0.60

0.80

1.00

1.20

ML

C1

5q

31

C2

16

p1

3C

3 2

0q

11

C4

9q

34

C5

13

q1

4C

6 8

q2

4C

7 1

8q

21

C8

13

q1

2C

9 2

p2

2C

10

10

p1

4P

PP

2R

3B

Ex

5P

PP

2R

3B

Ex

4P

PP

2R

3B

Ex

1L

OC

15

90

15

SH

OX

Ex1

SH

OX

Ex2

SH

OX

Ex3

SH

OX

Ex4

SH

OX

Ex5

SH

OX

Ex6

SH

OX

Ex7

SH

OX

Ex8

PA

R 5

64

2-L

50

96

PA

R 5

64

3-L

50

97

PA

R 5

64

4-L

50

98

PA

R 5

64

5-L

50

99

PA

R 5

64

6-L

51

00

PA

R 5

64

7-L

51

01

PA

R 6

29

1-L

62

22

PA

R 6

29

2-L

58

01

PA

R 6

29

3-L

62

19

PA

R 5

64

8-L

62

18

PA

R 5

64

9-L

51

03

PA

R 5

65

0-L

51

04

PA

R 5

65

1-L

51

05

CS

F2

RA

IL3

RA

PA

R 5

65

2-L

51

06

AS

MT

AR

SF

GP

R1

43

GP

R1

43

(ii)

Xq

25

SY

BL

1S

MC

YS

RY

DB

Y

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

Custom MLPA

Tel

omer

e

100 300 200 400

PLCXD1

GTPBP6 (PGPL)

PPP2R3B

2726-L1588 (PP

P2R3B

exon 5)

PP

P2R

3B exon 1 C

ustom

PP

P2R

3B exon 4 C

ustom

LLNOYCO3’M’2E2






100


Gene



D

XY

S


2726-L1588

MLPA probes


RP13-465B17

RP13-391G2

Microarray probes:

Not deleted Deleted

SNP Analysis

ML

RL

PL

GW

GL

PPP2R3B + +rs4986484 G/T G Grs5991323 G/A G Grs4986485 A/G A Ars4986486 C/T C Crs4131267 G/A G Grs6645040 C/T C Crs4986487 A/T A Ars6645077 G/A G -rs6644996 A/G A -rs28715562 A/G A -rs28418955 G/A G -rs6644997 T/C T -rs6645078 C/T C -rs28491143 G/T G -rs28393142 T/C T -rs35933458 C/T C -rs35741392 C/G C -rs6645016 G/A A -rs6645017 G/C C -rs28430679 C/T C -SHOX + -

LWD

HL

PPP2R3B + +rs4986484 G/T G Trs5991323 G/A G Grs4986485 A/G A Grs4986486 C/T C Trs4131267 G/A G Ars6645040 C/T C Trs4986487 A/T A Trs6645077 G/A G Grs6644996 A/G A Ars28715562 A/G G Ars28418955 G/A A Grs6644997 T/C C Trs6645078 C/T C Crs28491143 G/T T Grs28393142 T/C C Trs35933458 C/T C Crs35741392 C/G C Crs6645016 G/A A Grs6645017 G/C C Grs28430679 C/T C CSHOX + +

PPP2R3B + +rs4986484 G/T G Grs5991323 G/A G Grs4986485 A/G A Ars4986486 C/T C Crs4131267 G/A G Grs6645040 C/T C Crs4986487 A/T A Ars6645077 G/A G -rs6644996 A/G A -rs28715562 A/G G -rs28418955 G/A A -rs6644997 T/C C -rs6645078 C/T C -rs28491143 G/T T -rs28393142 T/C C -rs35933458 C/T C -rs35741392 C/G C -rs6645016 G/A A -rs6645017 G/C C -rs28430679 C/T C -SHOX + -

PPP2R3B + +rs4986484 G/T T Grs5991323 G/A G Grs4986485 A/G G Ars4986486 C/T T Crs4131267 G/A A Grs6645040 C/T T Crs4986487 A/T T Ars6645077 G/A G -rs6644996 A/G A -rs28715562 A/G A -rs28418955 G/A G -rs6644997 T/C T -rs6645078 C/T C -rs28491143 G/T G -rs28393142 T/C T -rs35933458 C/T C -rs35741392 C/G C -rs6645016 G/A G -rs6645017 G/C G -rs28430679 C/T C -SHOX + -

PPP2R3B + +rs4986484 G/T G Grs5991323 G/A G Grs4986485 A/G A Ars4986486 C/T C Crs4131267 G/A G Grs6645040 C/T C Crs4986487 A/T A Ars6645077 G/A G Grs6644996 A/G A Ars28715562 A/G A Grs28418955 G/A G Ars6644997 T/C T Crs6645078 C/T C Crs28491143 G/T G Trs28393142 T/C T Crs35933458 C/T C Crs35741392 C/G C Crs6645016 G/A A Grs6645017 G/C C Grs28430679 C/T C CSHOX + +

SNP Analysis

Tel

omer

e

100 300 200 400

PLCXD1

GTPBP6 (PGPL)

PPP2R3B

2726-L1588 (P

PP

2R3B

exon 5)

PP

P2R

3B exon 1 C

ustom

PP

P2R

3B exon 4 C

ustom

282kb – 7 SNP

s

355kb – 8 SNP

s

445kb – 6 SNP

s

LLNOYCO3’M’2E2






100


Gene



D

XY

S


2726-L1588

MLPA probes


RP13-465B17

RP13-391G2

Microarray probes:

Not deleted Deleted

CTCF

Tel

omer

e

100 300 200 400

PLCXD1

GTPBP6 (PGPL)

PPP2R3B

2726-L1588 (P

PP

2R3B

exon 5)

PP

P2R

3B exon 1 C

ustom

PP

P2R

3B exon 4 C

ustom

282kb – 7 SNP

s

355kb – 8 SNP

s

445kb – 6 SNP

s

LLNOYCO3’M’2E2






100


Gene



D

XY

S


2726-L1588

MLPA probes


RP13-465B17

RP13-391G2

Microarray probes:

Not deleted Deleted CTCF

Binding site

CTCF CTCF (CCCTC - binding factor) Transcriptional regulator through

chromatin remodelling epigenetic modification control of transcriptional machinery insulating promoter interaction with enhancers /silencers

Can bind to a diverse array of DNA sequences using different combinations of its 11 zinc finger domains

CTCF zinc finger domain

More SNP analysis

ML

RL

PL

GW

GL

LWD

HL

PPP2R3B + +SNPs @ 282kb + +rs7060857 C/G G Grs7060861 A/G G Grs7060992 C/G G Grs7061128 G/T G Grs35803036 A/G G Grs34424779 G/T G Grs7061154 A/G G Grs6603263 C/T C Trs28536695 C/G C Crs5950823 G/T T Trs5950824 C/T T Crs5950825 C/G C Crs5950826 A/G G G

CTCF + +rs28421260 G/A A Ars5991174 G/C G Grs5950684 G/A A Ars5950685 C/T T Trs34943375 A/G A Ars5950834 G/A G Grs5950686 C/G G Grs5950835 A/G G Grs7473428 A/G A A

SNPs @ 355kb + +SNPs @ 445kb + +SHOX + +

PPP2R3B + +SNPs @ 282kb + +rs7060857 C/G G Grs7060861 A/G G Grs7060992 C/G G Grs7061128 G/T G Grs35803036 A/G G Grs34424779 G/T G Grs7061154 A/G G Grs6603263 C/T C T

rs28536695 C/G C -rs5950823 G/T T -rs5950824 C/T T -rs5950825 C/G C -rs5950826 A/G G -CTCF + -rs28421260 G/A A -rs5991174 G/C G -rs5950684 G/A A -rs5950685 C/T T -rs34943375 A/G A -rs5950834 G/A G -rs5950686 C/G G -rs5950835 A/G G -rs7473428 A/G A -SNPs @ 355kb + -SNPs @ 445kb + -SHOX + -


rs28536695 C/G C C

rs5950823 G/T G T

rs5950824 C/T C T

rs5950825 C/G C C

rs5950826 A/G G A

CTCF + +rs28421260 G/A A G

rs5991174 G/C G G

rs5950684 G/A A G

rs5950685 C/T T C

rs34943375 A/G A G

rs5950834 G/A G A

rs5950686 C/G G Crs5950835 A/G G A

rs7473428 A/G A G

SNPs @ 355kb + +SNPs @ 445kb + +SHOX + +


rs28536695 C/G C -rs5950823 G/T G -rs5950824 C/T C -rs5950825 C/G C -rs5950826 A/G G -CTCF + -rs28421260 G/A A -rs5991174 G/C G -rs5950684 G/A A -rs5950685 C/T T -rs34943375 A/G A -rs5950834 G/A G -rs5950686 C/G G -rs5950835 A/G G -rs7473428 A/G A -SNPs @ 355kb + -SNPs @ 445kb + -SHOX + -

PPP2R3B + +SNPs @ 282kb + +rs7060857 C/G G Grs7060861 A/G G Grs7060992 C/G G Grs7061128 G/T G Grs35803036 A/G G Grs34424779 G/T G Grs7061154 A/G G Grs6603263 C/T T T

rs28536695 C/G C -rs5950823 G/T T -rs5950824 C/T T -rs5950825 C/G C -rs5950826 A/G A -CTCF + -rs28421260 G/A G -rs5991174 G/C G -rs5950684 G/A G -rs5950685 C/T C -rs34943375 A/G G -rs5950834 G/A A -rs5950686 C/G C -rs5950835 A/G A -rs7473428 A/G G -SNPs @ 355kb + -SNPs @ 445kb + -SHOX + -

Microarray analysis

Tel

omer

e

100 300 200 400

PLCXD1

GTPBP6 (PGPL)

PPP2R3B

2726-L1588 (PP

P2R

3B exon 5)

PP

P2R

3B exon 1 C

ustom

PP

P2R

3B exon 4 C

ustom

282kb – 7 SNP

s

355kb – 8 SNP

s

LLNOYCO3’M’2E2


RP13-465B17





100


Gene



D

XY

S


2726-L1588

MLPA probes


RP13-465B17

RP13-391G2

Microarray probes:

Not deleted Deleted

309kb – 9 SN

Ps

CTCF Binding site

305kb – 5 SN

Ps

300kb – 9 SN

Ps

Conclusions

Deletion of this CTCF binding site could affect regulation of its target gene.

Could the target be PPP2R3B?Deregulation of PPP2R3B could result in

deregulation of the cell cycleAnother B subunit of PP2A is present at 4p16.1, a

region linked to HL in a study by Goldin et al. (2006).

The CTCF binding site could regulate another, more distant gene.

Further studies required.

Map of PAR1

Tel

omere

100 300 200

PLCXD1

GTPBP6 (PGPL)

PPP2R3B

LLNOYCO3’M’2E2


Not deleted (Shears et al 2003)




100


Gene



DXYS


2726

-L1588

MLPA probes


RP13-465B17

RP13-391G2

Microarray probes:

Not deleted Deleted

Conclusions

Deletion of this CTCF binding site could affect regulation of its target gene.

Could the target be PPP2R3B?Deregulation of PPP2R3B could result in

deregulation of the cell cycleAnother B subunit of PP2A is present at 4p16.1, a

region linked to HL in a study by Goldin et al. (2006).

The CTCF binding site could regulate another, more distant gene.

Further studies required.

AcknowledgementsThanks to the following people for their help: David Gokhale Vicky Stinton G Malcolm Taylor Ciaron McAnulty Frances White Una Maye Julie Sibbring Emma McCarthy Roger Mountford Andrew Wallace Simon Thomas Kevin Baker Gareth Evans John Radford All at Liverpool Molecular Genetics Laboratory for their help, advice, interest

and patience.

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Kym Spencer Liverpool Women’s Hospital

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