Genetics

Members

Anne-Paule Gimenez-Roqueplo, MD, PhD
Full Professor in Genetics
Service de Génétique
Hôpital européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France
Tel : 33 (0)1 56 09 38 81
Email : anne-paule.gimenez-roqueplo@egp.aphp.fr

Head of the academic research team ‘Pheochromocytomas and paragangliomas from Genetics to molecular targeted therapies’
INSERM UMR970, Paris cardiovascular research center, team 13
56 rue Leblanc, 75015 Paris, France
Tel : 33 (0)1 53 98 80 14
Email : anne-paule.gimenez-roqueplo@inserm.fr

Mercedes Robledo, PhD
Professor in Genetics
Hereditary Endocrine Cancer Group Leader
Human Cancer Genetics Programme
Spanish National Cancer Center
C/ Melchor Fernández Almagro 3
28029 Madrid, Spain
Phone: +34 91 732 8000 Ext 3320
Email: mrobledo@cnio.es

Patricia Dahia
Associate Professor of Medicine
Division of Hematology and Medical Oncology, Dept.Medicine
Cancer Therapy and Research Center
University of Texas Health Science Center at San Antonio
7703 Floyd Curl Drive MC7880
San Antonio-TX 78229
Tel : +1 (210)567 4866
Email : dahia@uthscsa.edu

Diana Benn
Senior Research Fellow
Cancer Genetics
Kolling Institute of Medical Research
Royal North Shore Hospital
St Leonards NSW 2065
Australia
Tel : +61 2 9926 4767
Email : diana.benn@sydney.edu.au

Goals

  1. To provide patients and clinicians with information on recent advances on new genes involved in pheochromocytoma and paraganglioma development.
  2. To provide patients and clinicians with information on other diseases associated with the PCC and PGL susceptibility genes.
  3. To provide patients and clinicians with genetic markers of malignant behavior.
  4. To provide researchers with a platform for collaborations and exchange of scientific resources and ideas in the area of pheochromocytoma and paraganglioma.

Background

Nowadays genetic testing and genetic counselling occupy a central position in the patient’s management because one of the important recent changes in pheochromocytoma/ paraganglioma has been the understanding of the major role of the genetics in their development. Most of 10 different susceptibility genes were identified and numerous international genotyping studies showed that germline mutations of one of these genes are present in the genome of around 40% of the affected patients. The identification of a mutation is a clue for patient management and offers the opportunity of familial genetic counselling for their families.

1. Diseases and genes
Neurofibromatosis type 1 (gene NF1), multiple endocrine neoplasia type 2 (RET), von Hippel-Lindau disease (VHL), hereditary paraganglioma (SDHA, SDHB, SDHC, SDHD, SDHAF2), familial pheochromocytoma (TMEM127, MAX), polycythemia-paraganglioma syndrome (HIF2A), Reed’s syndrome (FH) should be considered. Eighty per cent of the germline mutations are in VHL, SDHB, SDHD or SDHC genes. Family history, clinical presentation, biological phenotype and immunohistochemical characteristics of the tumor when available, should be taken account for thediagnosis. The main genotype-phenotype correlations are indicated in Table 1. A mutation can be found in a patient with an apparently sporadic pheochromocytoma/paraganglioma (PPGL) especially in SDHB, VHL, MAX and TMEM127 genes. Mutation in SDHB gene is a biomarker of unfavourable outcome and an indicator of a strict follow-up after first surgery.

2. PPGL decisional algorithms for genetic testing, from Sanger to NGS
To decrease results delay and analyses cost, decisional algorithms for PPGL genetic testing ‘from the patient to the candidate genes’ are routinely used to order the series of the tests based on clinical (Figure 1A) or pathological phenotype (Figure 1B). The up-coming next generation sequencing (NGS) methods, able to screen multiple genes in a single assay, produce large amount of sequences and find new mutations or variants of unknown significance (VUS). The biological interpretation of these VUS will still based on the clinical features of the patient and the tumor and on decisional algorithms ‘from the mutated genes to the affected patient’ (Figure 2A & Figure 2 B).

3. From ‘Omics’ studies to a personalized medicine
Integrative genomics studies demonstrated that germline and/or somatic mutations in PPGL susceptibility genes, which are present in more than 60% of the cases, act as main cancer drivers in triggering specific tumorigenesis pathways. NF1 gene is the first mutated gene at the somatic level. Transcriptomic studies showed that PPGL are remarkably classified into two different clusters according their genotype. The VHL, SDHx and FH tumors are classifed in a cluster characterized by the high-expression of genes involved in the hypoxia-angiogenesis pathway. The second is characterized by the activation of the MAP kinase/mTOR pathway and contained the RET, NF1, TMEM127, MAX and sporadic tumors. Epigenomic studies demonstrated that SDHx and FH tumors are characterized by an hypermethylator phenotype. All these pathways could be targeted for therapy (Figure 3).

Conclusion
It is likely that in the near future, omics-based tests would move from research to clinics for a personalized medicine with the goal to improve the care (targeted therapies and targeted imaging) and the outcome of the patients.

Table 1

Genes Year Main clinical presentation Biological phenotype Main associated lesions Specific immunohistochemistry Mutation rate
NF1 1990 Single or bilateral PH Adr & NAdr Café-au-lait spots, neurofibromas, lentiginosis, Lisch nodules Rare (<3%)
RET 1993 Single or bilateral PH Adr & NAdr Medullary thyroid carcinoma, hyperparathyroidism <10%
VHL 1993 Single or bilateral PH NAdr >Adr Hemangioblastomas, renal and pancreatic tumors Frequent (>10%)
SDHD 2000 Multiple PPGL NAdr >>Adr SDHB Frequent (>10%)
SDHC 2000 PPGL NAdr >>Adr SDHB <10%
SDHB 2001 PPGL NAdr >>Adr Metastases SDHB Frequent (>10%)
SDHAF2 2009 PGL NAdr >>Adr SDHB Rare (<3%)
TMEM127 2010 Single or bilateral PH Adr & NAdr Rare (<3%)
SDHA 2010 PPGL NAdr >>Adr SDHB & SDHA Rare (<3%)
MAX 2011 Single or bilateral PH NAdr >Adr MAX Rare (<3%)
HIF2A 2012 PPGL NAdr >Adr Polycythemiae Rare (<3%)
FH 2013 PPGL NAdr >>Adr Renal cancer (papillary type 2), skin & uterine leiomyomas 2SC Rare (<3%)

Figure 1A

Figure 1B

Figure 2A

Figure 2B

Figure 3