Investigating the genetic background of pheochromocytomas and paragangliomas

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) (PPGLs) are rare tumors that affect children and adults and have an incidence of less than 1 per 300,000 persons per year. PHEOs are located in the adrenal glands, and PGLs are found along the paravertebral axis and may be located everywhere (head, neck, thorax, abdomen). PPGLs can cause hypersecretion of catecholamines (e.g., adrenaline), which may result in severe blood pressure, palpitations, anxiety, diabetes and cardiovascular morbidity and/or mortality. Unfortunately, more than 50% of individuals affected by PPGL are not diagnosed, and the initial presentation of the disease may be sudden death secondary to sudden catecholamine release. 

PPGLs may be metastatic in 10 to 17% of cases, but the prevalence reaches up to 40% in patients carrying mutations. Patients with metastases have a low 5-year survival rate of 40-77%. Currently, no good histopathological criteria predict the potential malignancy or tumoral recurrences of PPGLs. All patients who undergo complete resection of PPGLs are still at risk of metastases and recurrences (6.5-17.4%) and require lifelong follow-up. Importantly, the only efficient treatment for PPGL is surgical resection, and therapeutic options are limited and mainly restricted to palliative management for unresectable/malignant PPGL.  

PPGLs are tumors with the highest heritability in adult patients, with identification of a germline mutation in up to 40% of apparently sporadic cases (no known family history or manifestations of a genetic syndrome). Since 2014, guidelines have recommended germline genetic testing in every patient affected by PPGL. More than 20 susceptibility genes for PPGLs were identified. All described germline mutations have an autosomal dominant transmission with potential impacts on family members of index cases. 

As described previously, early knowledge of germline genetic status has a positive impact on the clinical outcome of patients by impacting surgical approach, intensity of follow-up, and therapeutic approaches. This project offers a unique opportunity to further characterize the genetic background of PPGLs.

While a number of susceptibility genes have been identified, the genetic basis has not been defined for all PPGL cases. Indeed, in our database of 164 PPGL patients,  the number of patients  without a molecular diagnostic despite exhaustive genetic testing is 73,8% in all PPGLs and 62,1% in metastatic PPGL. Therefore, further genetic investigations are needed to identify novel or rare variants of PPGL that may serve as biomarkers to improve early diagnosis or predict metastatic disease.    This project offers a unique opportunity to further characterize the genetic background of PPGLs and may lead to novel precision medicine approaches and treatment strategies in patients with PPGLs.