Familial wild-type gastrointestinal stromal tumour in association with germline truncating variants in both SDHA and PALB2.

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Casey, Ruth T 
Giger, Olivier 
Martin, Jose Ezequiel 

Gastrointestinal stromal tumour (GIST) is a mesenchymal neoplasm arising in the gastrointestinal tract. A rare subset of GISTs are classified as wild-type GIST (wtGIST) and these are frequently associated with germline variants that affect the function of cancer predisposition genes such as the succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC, SDHD) or NF1. However, despite this high heritability, familial clustering of wtGIST is extremely rare. Here, we report a mother-son diad who developed wtGIST at age 66 and 34 years, respectively. Comprehensive genetic testing revealed germline truncating variants in both SDHA (c.1534C>T (p.Arg512*)) and PALB2 (c.3113G>A (p.Trp1038*)) in both affected individuals. The mother also developed breast ductal carcinoma in-situ at age 70 years. Immunohistochemistry and molecular analysis of the wtGISTs revealed loss of SDHB expression and loss of the wild-type SDHA allele in tumour material. No allele loss was detected at PALB2 suggesting that wtGIST tumourigenesis was principally driven by succinate dehydrogenase deficiency. However, we speculate that the presence of multilocus inherited neoplasia alleles syndrome (MINAS) in this family might have contributed to the highly unusual occurrence of familial wtGIST. Systematic reporting of tumour risks and phenotypes in individuals with MINAS will facilitate the clinical interpretation of the significance of this diagnosis, which is becoming more frequent as strategies for genetic testing for hereditary cancer becomes more comprehensive.


Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272

Funder: National Health Service

Funder: European Research Council (Advanced Researcher Award) Cancer Research UK Cambridge Cancer Centre Medical Research Council (Infrastructure Award) National Health Service

Adult, Aged, Alleles, Databases, Genetic, Family, Fanconi Anemia Complementation Group N Protein, Female, Gastrointestinal Stromal Tumors, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation, Humans, Immunohistochemistry, Male, Middle Aged, Sequence Analysis, DNA, Succinate Dehydrogenase, Symptom Assessment, Whole Genome Sequencing
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Eur J Hum Genet
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Springer Science and Business Media LLC
National Institute for Health and Care Research (IS-BRC-1215-20014)