Abstract
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.
Highlights
Members of the National Institute for Health Research (NIHR) BioResource are listed in Supplementary information
Histology and immunohistochemistry of both Gastrointestinal stromal tumour (GIST) showed a mixed epithelioid growth pattern and loss of SDHB staining on immunohistochemistry, indicating deficiency of a component of the succinate dehydrogenase (SDH) multiprotein complex (Fig. 1)
We report a rare case of familial dSDH-wild-type GIST (wtGIST) that was associated with germline-predicted truncating variants in both SDHA and PALB2
Summary
DSDH-wtGISTs show phenotypic differences to non-wtGIST including multinodular appearance, lymphovascular invasion, and epitheloid/mixed epitheloid spindle cell histology [5] and are less likely to respond to standard targeted therapy (e.g., imatinib) [2, 6]. They are frequently associated with a germline variants affecting the function of the SDHA, SDHB, SDHC or SDHD (SDHX genes) or. A germline truncating PALB2 variant was found meaning that two cancer predisposition gene variants with implications for genetic counselling were present in the same individual This situation that has previously been termed multilocus inherited neoplasia alleles syndrome (MINAS). Whilst there is little to indicate that the PALB2 variant contributed to GIST tumourigenesis, we speculate that this unusual finding of may have led to increased penetrance in this family
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