Abstract
Pheochromocytoma (PCC) is a rare, mostly benign tumour of the adrenal medulla. Hereditary PCC accounts for ~35% of cases and has been associated with germline mutations in several cancer susceptibility genes (e.g., KIF1B, SDHB, VHL, SDHD, RET). We performed whole-exome sequencing in a family with four PCC-affected patients in two consecutive generations and identified a potential novel candidate pathogenic variant in the REXO2 gene that affects splicing (c.531-1G>T (NM 015523.3)), which co-segregated with the phenotype in the family. REXO2 encodes for RNA exonuclease 2 protein and localizes to 11q23, a chromosomal region displaying allelic imbalance in PCC. REXO2 protein has been associated with DNA repair, replication and recombination processes and thus its inactivation may contribute to tumorigenesis. While the study suggests that this novel REXO2 gene variant underlies PCC in this family, additional functional studies are required in order to establish the putative role of the REXO2 gene in PCC predisposition.
Highlights
Pheochromocytoma (PCC; OMIM #171300) is a rare neuroendocrine tumour of the adrenal medulla
It is still possible that the coverage was insufficient to detect existing mutations or that there were major gene rearrangements affecting any of these known PCC predisposition genes that were not detected
A potential pathogenic sequence variants (PSVs) in the RNA exonuclease 2 (REXO2) gene was identified as a novel candidate for PCC predisposition
Summary
Pheochromocytoma (PCC; OMIM #171300) is a rare neuroendocrine tumour of the adrenal medulla. PCCs are mostly benign tumours that exhibit variable prevalence rates across populations. As is the prevailing paradigm for all tumours, PCC development is associated with and driven by the accumulation of somatic mutations (Burnichon et al, 2011). Inherited predisposition to PCC, implying germline mutations that increase PCC risk, are detected in ∼35% of incident PCC cases (Neumann et al, 2002, 2018). In nearly 60% of all hereditary PCC cases, driver germline mutations have been detected in up to 20 genes, including MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, TMEM127, FH, VHL and others (Rattenberry et al, 2013, Martucci & Pacak, 2014, Buffet et al, 2018)
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