Case reportsPDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor
Section snippets
Case report
A French family with 5 GIST cases was referred to the Institut Gustave Roussy Oncogenetic Clinic (Figure 1A). All GISTs cases were confirmed by pathological records. Written informed consent was obtained for all family subjects before participation in the study under a protocol approved by the internal institutional review board.
The index case III-5 developed several submucosal gastric nodules typical of GIST, diagnosed in 1998 at the age of 42; these nodules were removed with gastric
Materials and methods
Peripheral blood samples were obtained from 7 family members: 4 affected and 3 unaffected. Genomic DNA was extracted from peripheral blood lymphocytes by using the QIAamp DNA blood mini kit (Qiagen, Chatsworth, CA) according to the manufacturer’s instructions.
Both exons 12 and 18 of the PDGFRA gene were screened for mutations by direct sequencing. Specific PCR primers were designed to amplify each exon and its 50–100 bp corresponding flanking intronic sequences. Primers design was assisted by
Results and discussion
Previous studies identified several somatic mutations within regions encoding PDGFRA exons 12 and 18, which contain both juxtamembrane and activation loop domains, respectively.12 DNA sequencing of these latter regions revealed the presence of a germline PDGFRA missense mutation, 2675G>T, resulting into substitution of a tyrosine residue for the highly conserved aspartic acid at codon 846, D846Y (Figure 1C). This mutation showed perfect cosegregation with GIST phenotypes among all 7 family
Acknowledgements
The authors thank Alexandre Valent for cytogenetic analysis, Dr. Sylvie Bonvalot for referring the index case to the Oncogenetics Clinic, Dr. Bernard Guigui and Dr. Pierre Duvillard for pathological expertise, Pr. Jean Feunteun and Pr. Christer Betsholtz for useful discussion, and Lorna Saint Ange for editing.
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2020, Cancer GeneticsCitation Excerpt :However, in spite of the overwhelming prevalence of WT genotype, pediatric GIST tumors consistently overexpress KIT protein, as evidenced by the strong immunostaining for CD117 and as observed also in our patients [13]. GISTs can occur sporadically or in association with specific predisposing conditions: familial GIST with a germline KIT [14] or PDGFRA mutation [15,16], GIST and neurofibromatosis type 1 [17], the Carney triad, characterized by the development of GISTs, extra-adrenal paragangliomas and pulmonary chondromas [18] and Carney-Stratakis syndrome (CSS), that lacks the pulmonary chondromas [19]. Pediatric GISTs have been linked to the latter two syndromes.
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C.K. and M.B. have contributed equally to the present work.