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Single Droplet Digital Polymerase Chain Reaction for Comprehensive and Simultaneous Detection of Mutations in Hotspot Regions
Published on: September 25, 2018
Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot?
Alberto Cascón1, Cristina Montero-Conde, Sergio Ruiz-Llorente
1Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncoloógicas, Madrid, Spain.
Abstract:
Pheochromocytoma and paraganglioma are rare neuroendocrine tumors that arise in the adrenal medulla and the extra-adrenal paraganglia, respectively. Inheritance of these tumors is mainly a result of mutations affecting the VHL, RET, NF1, and SDH genes. Germ-line mutations of the SDH genes have been found to account for nearly 10% of apparently sporadic cases. Nevertheless, alterations other than point mutations have not yet been well characterized. In this study, we investigated the frequency of gross SDH deletions in 24 patients who tested negative for point mutations and had at least one of the recommended features for genetic testing. For this purpose, we used a technique that is easy to implement in the lab to specifically detect gross deletions affecting SDHB, SDHC, and SDHD. We identified 3 heterozygous SDHB deletions (3/24) in 3 independent cases with paraganglioma: 1 whole SDHB deletion and 2 deletions exclusively affecting exon 1. These latter mutations match the unique gross deletion previously reported, indicating this region could be a hot spot for gross SDHB deletions. It seems likely that these alterations can account for a considerable number of both familial and apparently sporadic paraganglioma cases. Although this is the first report describing the presence of gross deletions in patients with apparently sporadic paragangliomas, the extra-adrenal location of the tumor seems to constitute a determining factor for whether to include these patients in genetic testing for gross deletions in the SDHB gene.
Insights
Gross deletions in SDHB genes are identified in paraganglioma patients negative for point mutations. This finding suggests a significant role for these alterations in familial and sporadic paraganglioma cases, particularly those with extra-adrenal tumors.
Area of Science:
- Endocrinology
- Genetics
- Oncology
Background:
- Pheochromocytoma and paraganglioma are rare neuroendocrine tumors.
- Germ-line mutations in VHL, RET, NF1, and SDH genes are key inherited causes.
- SDH gene mutations account for ~10% of sporadic cases, but non-point mutation alterations are understudied.
Purpose of the Study:
- Investigate the frequency of gross succinate dehydrogenase (SDH) gene deletions.
- Focus on patients negative for point mutations with features warranting genetic testing.
- Characterize alterations beyond point mutations in SDH genes.
Main Methods:
- Utilized a lab-friendly technique to detect gross deletions in SDHB, SDHC, and SDHD genes.
- Screened 24 patients with paraganglioma who tested negative for point mutations.
- Included patients with at least one recommended feature for genetic testing.
Main Results:
- Identified 3 heterozygous SDHB deletions in 24 patients (3/24).
- Detected 1 whole SDHB deletion and 2 deletions affecting only exon 1.
- The exon 1 deletions matched previously reported unique gross deletions, suggesting a hot spot.
Conclusions:
- Gross SDHB deletions are a notable cause of paraganglioma in patients negative for point mutations.
- These deletions likely contribute significantly to both familial and sporadic paraganglioma cases.
- Extra-adrenal tumor location is a key factor for considering SDHB gross deletion genetic testing.
