Biochemical, molecular, and clinical characterization of succinate dehydrogenase subunit A variants of unknown significance

Amber E. Bannon, Jason Kent, Isaac Forquer, Ajia Town, Lillian R. Klug, Kelly McCann, Carol Beadling, Oliver Harismendy, Jason K. Sicklick, Christopher Corless, Ujwal Shinde, Michael Heinrich

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Purpose: Patients who inherit a pathogenic loss-of-function genetic variant involving one of the four succinate dehydrogenase (SDH) subunit genes have up to an 86% chance of developing one or more cancers by the age of 50. If tumors are identified and removed early in these high-risk patients, they have a higher potential for cure. Unfortunately, many alterations identified in these genes are variants of unknown significance (VUS), confounding the identification of high-risk patients. If we could identify misclassified SDH VUS as benign or pathogenic SDH mutations, we could better select patients for cancer screening procedures and remove tumors at earlier stages. Experimental Design: In this study, we combine data from clinical observations, a functional yeast model, and a computational model to determine the pathogenicity of 22 SDHA VUS. We gathered SDHA VUS from two primary sources: The OHSU Knight Diagnostics Laboratory and the literature. We used a yeast model to identify the functional effect of a VUS on mitochondrial function with a variety of biochemical assays. The computational model was used to visualize variants' effect on protein structure. Results: We were able to draw conclusions on functional effects of variants using our three-prong approach to understanding VUS. We determined that 16 (73%) of the alterations are actually pathogenic, causing loss of SDH function, and six (27%) have no effect upon SDH function. Conclusions: We thus report the reclassification of the majority of the VUS tested as pathogenic, and highlight the need for more thorough functional assessment of inherited SDH variants.

Original languageEnglish (US)
Pages (from-to)6733-6743
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number21
DOIs
StatePublished - Nov 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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