Feocromocitoma y Paraganglioma

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

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 http://cgap.nci.nih.gov/Pathways/Kegg/ 2

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, 13 -16 Commercial MPLA (VHL) Multiplex-PCR, SDHs (B, C, D) Molecular analysis of known genes related SDHD, SDHB, SDHC, RET*, VHL

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, 2005. ) 24% (Neumman HP et al. Engl J Med 346(19):1459-66, 2002. ** Only PCC or PGL, not both

PCC / PGLs. Age distribution

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

Genes involved and age at diagnosis 237 probandus

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

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

100 80 60 40 20 RET VHL SDHD SDHB SDHC Neg n= 44 cases n= 23 cases u 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)

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

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

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.40-133) 4Fe-4S_Iron-sulfur 2 (p.186,189,192,253)

SDHB gene. Other series. Malignant behaviour

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

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

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

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