A Novel Kindred with Familial Gastrointestinal Stromal Tumors Caused by a Rare KIT Germline Mutation (N655K): Clinico-Pathological Presentation and TKI Sensitivity
Open Access
- 17 November 2020
- journal article
- case report
- Published by MDPI AG in Journal of Personalized Medicine
- Vol. 10 (4), 234
- https://doi.org/10.3390/jpm10040234
Abstract
Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are characterized by activating mutations in KIT or PDGFRA genes. The vast majority of GISTs are sporadic, but rare hereditary forms have been reported, often featuring multifocality and younger age of onset. We here report the identification of a novel kindred affected by familial GIST caused by a KIT germline mutation in exon 13 (N655K). No family affected by hereditary GIST due to this KIT variant has been reported in literature so far. We were able to track the mutation in three members of the family (proband, mother, and second-degree cousin), all affected by multiple GISTs. Due to its rarity, the N655K variant is poorly characterized. We conducted in vitro drug sensitivity assays that indicated that most tyrosine kinase inhibitors (TKIs) currently included in the therapeutic armamentarium for GISTs have a limited inhibitory activity toward this mutation. However, when compared to a classical imatinib-resistant KIT mutation (T670I), N655K was slightly more sensitive to imatinib, and encouraging responses were observed with last-generation TKIs.This publication has 58 references indexed in Scilit:
- Rare, Germline Mutation of KIT With Imatinib-Resistant Multiple GI Stromal Tumors and MastocytosisJournal of Clinical Oncology, 2013
- A Novel Germline KIT Mutation (p.L576P) in a Family Presenting With Juvenile Onset of Multiple Gastrointestinal Stromal Tumors, Skin Hyperpigmentations, and Esophageal StenosisThe American Journal of Surgical Pathology, 2013
- Can a familial gastrointestinal tumour syndrome be allelic with Waardenburg syndrome?Clinical Genetics, 2010
- Hereditary gastrointestinal stromal tumors sharing the KIT Exon 17 germline mutation p.Asp820Tyr develop through different cytogenetic progression pathwaysGenes, Chromosomes and Cancer, 2009
- Stromal, Fibrous, and Fatty Gastrointestinal Tumors in a Patient With a PDGFRA Gene MutationThe American Journal of Surgical Pathology, 2008
- Rectal gastrointestinal stromal tumors associated with a novel germline KIT mutationInternational Journal of Cancer, 2008
- Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumorInternational Journal of Cancer, 2007
- Intestinal Neurofibromatosis Is a Subtype of Familial GIST and Results From a Dominant Activating Mutation in PDGFRAGastroenterology, 2006
- Multiple gastrointestinal stromal tumors with a germline c‐kit mutationPathology International, 2005
- Novelc-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentationAmerican Journal of Medical Genetics Part A, 2004