PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor

doi:10.1053/j.gastro.2003.10.079

Gastroenterology

Volume 126, Issue 1, January 2004, Pages 318-321

https://doi.org/10.1053/j.gastro.2003.10.079 Get rights and content

Abstract

Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder associated with KIT germline mutations. In sporadic forms of the disease, somatic mutations target either KIT or PDGFRA genes. In a kindred in which 5 individuals had GIST, no germline mutation in KIT coding sequence has been detected. We hypothesized that the PDGFRA gene could be a predisposing gene in familial GIST. We sequenced PDGFRA exons 12 and 18 because several somatic mutations were identified within this region. We detected a germline PDGFRA missense mutation, 2675G > T, resulting in a tyrosine substitution for the highly conserved aspartic acid at codon 846. This mutation showed perfect cosegregation with the GIST phenotype among the 7 family members tested. Interestingly, PDGFRA Asp846 is homologous to codon 820, which is located in the KIT tyrosine kinase II domain. In a previous study, a KIT germline Asp820Tyr mutation was detected in a Japanese kindred in which 6 individuals had GIST. Transfection of a KIT820Tyr complementary DNA in nude mice was found to be tumorigenic confirming the oncogenic potential of this mutation. The present study shows that PDGFRA is a second familial GIST predisposing gene. These results indicate a further example of involvement of structurally related genes in familial cancer syndromes.

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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¹: C.K. and M.B. have contributed equally to the present work.

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Case reportsPDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor

Abstract

Section snippets

Case report

Materials and methods

Results and discussion

Acknowledgements

Hum Pathol

Gastroenterology

Gastroenterology

Am J Pathol

Genomics

Genomics

Blood

Trends Genet

Gastrointestinal stromal tumorstheir origin and cause

Int J Clin Oncol

Case reports
PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor