1. Feocromocitoma y Paraganglioma
Taller 8:
Feocromocitoma y Paraganglioma
Mercedes Robledo, PhD
Spanish National Cancer Centre (CNIO), Madrid, Spain

2. International Consortium PCCs/PGLs
Which genes are involved?
NF1
MEN1
VHL
RET
KIF1B
International Consortium PCCs/PGLs
2cen and 16p13:
consistent with recessive inheritance from both regions
Familial forms
???
SDH 2

3. PCC / PGLs. Patients and methods
168 consecutive probandus with PCC and/or PGL (11 to 80 y).
Without antecedents
69 Consecutive probandus PCCs/PGLs
With antecedents
24 PCC/PGL antecedents
35 MEN2 antecedents
10 VHL
Sequencing analysis all coding regions of SDHs and VHL
* RET, exons 10, 11,
Commercial MPLA (VHL)
Multiplex-PCR, SDHs (B, C, D)
Molecular analysis of known genes related
SDHD, SDHB, SDHC, RET*, VHL

4. Without familial antecedents
237 consecutive PCC / PGLs probandus. General results
69 consecutive probandus with familial antecedents
24 PCC/PGL antecedents
35 MEN2 antecedents
10 VHL antecedents
168 consecutive probandus with PCC and/or PGL (11 to 80 y).
Without familial antecedents
19/24 PCC: 79.1%
8 SDHB
7 SDHD
3 VHL
1 RET
5 No mutation (20.8%)**
35/35 MEN2: 100%
10/10 VHL: 100%
Germline mutations in 31 patients: 18.4%
9 VHL/168 (5.4%)
4 SDHD/168 (2.4%)
17 SDHB /168 (10.2%)
1 SDHC/168 (0.6%)
11.6% (Amar L et al. J Clin Oncol 23(34):8812-8, )
24% (Neumman HP et al. Engl J Med 346(19): , 2002.
** Only PCC or PGL, not both

5. PCC / PGLs. Age distribution

6. Genetic test benefits
237 probandus
73.4%
42.3%
19.6%
9.1%

7. Genes involved and age at diagnosis
237 probandus

8. Could we learn from the location?
237 probandus
RET
VHL
SDHD
SDHB

9. P=0.013 1st sign: PCC 31.4% VHL patients 40% MEN2 patients
location and age 10 20 30 40 50 60 70 80 90
VHL
Age of onset
SDHD
SDHB
RET
SDHC
No Mut
26.8
24.9
30.9
36.6
46.8
P=0.013
1st sign: PCC
31.4% VHL patients
40% MEN2 patients

10. 100 80 60 40 20 RET VHL SDHD SDHB SDHC Neg n= 44 cases n= 23 casesu
21.7%
b/m 80
4.3%
b/m u
79.5% b 60
30.4%
80% u m 40 u m
30.4% u 20
0.6% u
2.5% u m
b/m
20.5% b u u
10.8% m b
13.1% u b
5.7%
Non-syndromic
Familial Apparently Sporadic
Syndromic
(MEN2 or VHL)

11. Complete genetic analysis of 237 non-related patients with PCC/PGL
In summary: a PCC/PGL patient should be genetically analized
61%
SPORADIC?
RET
SDHB
SDHD
VHL
8.4%
4.6%
15%
10.5%
0.5%
SDHC
Our series (2008)
Complete genetic analysis of 237 non-related patients with PCC/PGL
93 patients (39%) with germline mutations

12. Could we get some clue in relation to malignancy?
37.5%
20%
4.2%

13. 1 2 3 4 5 6 7 8 c.644delC c.194T>A,C c.166_170delCCTCA (4)
c.278G>A*
c.649C>T
c.167C>T
c.281G>A
c.583_585delAGC
c.653G>A,C
c.141G>A
c.660_661insT
c.286+1G>A
c.136C>G,T
c.661delG
c.286+2T>A
c.137G>A
c.587G>A
c.287G>A
c.683_684delAG
c.24C>T
c.688C>T
c.296G>A
c.594C>A
c.574T>C
c.689G>A (2)
c.127G>C
c.302G>A
c.21delC
c.311delAinsGG
c.575G>A
c.717delT
c.118A>G
c.718_721delCTAT
c.343C>T
c.724C>T
c.112C>T* (Tumor)
c.392delC
c.725G>A
c.780delG*
c.392C>G
c.72+1G>T
c.395A>C
c.747C>A
c.423+1G>A,C
c.758G>A 1 2 3 4 5 6 7 8
Chr. 1
c.765+1G>A
c.1_72del (2)
c.380T>A,C
c.713delT
c.761insC
c.541-3C>G
c.713_716delTCTC
c.79delC
c.623G>A
c.298T>C
-55delC?
c.79C>T
c.292T>C
c.502insC
c.620_621delTG
c.87_88insCAG
c.293G>A
c.591delC
c.87_88insCCAG
c.88delC
c.287-2A>G
c.590C>G
c.157G>A
c.268C>T
c.424-1G>A
c.174_175delinsTT
c.260T>C
c.424-3C>G
c.200+3G >C
c.207_208insC?
c.-134_1100del
2Fe-2S_Iron-sulfur 1 (p.93,98,101,113)
3Fe-4S_Iron-sulfur 3 (p.196,243,249)
Ferredoxin domain (p )
4Fe-4S_Iron-sulfur 2 (p.186,189,192,253)

14. SDHB gene. Other series. Malignant behaviour

15. 15 probandus. Location primary tumour:
Could we learn from the location in relation to malignancy?
15 probandus. Location primary tumour:
12 H&N
3 Abdominal
3 malignant cases:
2 Abdominal
1 H&N

16. In a syndromic presentation Non syndromic presentation**
Different scenarios
In a syndromic presentation
Non syndromic presentation**
Apparently sporadic cases
(only one tumour)
Targeted genetic testing should be offered
100% positive cases
79.1% positive cases
Rational screening
NF1
RET
Familial antecedents
VHL
Tumour location
Bilateral / multiple
malignancy
SDHB
SDHD
SDHC
RET
VHL

17. Abdominal or thoracic PGL
PCC/PGLs apparently sporadic (no fam antecedents, No bilateral, No multiple)
PCC
Abdominal or thoracic PGL
H&N PGL 10 20 30 40 50 60 70 80 90
Age at onset
Neg Pos
1.7%
10%
3.6%
76%
22%
16%
2.1% 94
45.8% 24
26%
4.5%***
20% 15
16/133 (12%) exhibited germline mutations. Most of them affecting SDHB

18. Familial PGL antecedents
Genetic test in PCC / PGLs. Study protocol
Patient
Bilateral/Multiple/Fam. antecedents
Yes No
Bilateral adrenal
VHL, RET
Familial PGL antecedents
SDHD SDHC
Mult H&N
Malignant behavior
SDHB
Mult. Abd / Tho
>50y
<50y
SDHB
Abd/tho
1º SDHB
2º SDHD
H&N
1º SDHD
2º SDHB
3º SDHC
Adrenal
1º VHL
2º RET
3º SDHB