Endocrine Abstracts (2016) 40 L15 | DOI: 10.1530/endoabs.40.L15

Meet-the-expert: from genetics to the bedside

Mercedes Robledo


Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, CNIO, Madrid, Spain.


Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine tumours, located in the adrenal medulla (PCC) and in the intra-abdominal, thoracic or head and neck paraganglia (PGL). They have the highest heritability of all human neoplasms being a good example of diseases with underlying genetic heterogeneity. In this regard, at least 40% of PCC/PGL (PPGL) patients carry a germline mutation in one of the 22 genes described so far as related to the disease. In addition to the complexity of the genetics of PCC/PGL (from now on, PPGL), we need to consider the role of somatic mutations, which to date, have been identified at least in 20–30% of tumours. The latter have been observed to occur not only in the same genes involved in heritable susceptibility, but also in new ones, which have thus recently emerged as key players in the sporadic presentation of these diseases.

Other remarkable feature is the clinical heterogeneity among patients diagnosed with PPGL. Part of them develops additional tumours or disorders that serve as clues for deciding the most appropriated genetic test to perform. However, the main proportion of patients develops non-syndromic PPGLs, being necessary to use other information (such as biochemical secretion, tumour location, immunostaining data, etc.) that helps to address the genetic screening. In this regard, several algorithms have been proposed, but they usually exclude sporadic-PPGLs and none include somatic testing. Our group aimed to genetically characterize S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritizing also the DNA source.

Nowadays, new approaches based on targeted next generation sequencing (NGS) are allowing to simultaneously analyze all genes related to a disease, but interpretation of variants found is a new challenge to deal with, which must catch our attention in order to offer genetic counseling.

In addition, despite of the increasing proportion of patients already explained by germline or somatic genetic defects, there are still patients with clinical indicators of hereditary disease (i.e. familial antecedents, multiple tumors and/or young age) without a molecular diagnosis. In this regard, the genomic characterization has demonstrated to be an efficient tool for identifying not only diagnostic and prognostic markers, but also for discovering new genes related to the disease, after applying whole-exome sequencing to candidate patients clustered according to their genomic features.

The talk will review algorithms to apply in the genetic screening of patients diagnosed with PPGLs.

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