Characterization of novel germline c-kit gene mutation, KIT-Tyr553Cys, observed in a family with multiple gastrointestinal stromal tumors

Abstract

We found a novel type germline mutation at exon 11 of the c-kit gene, which results in a substitution of Tyr to Cys at codon 553 of the c-kit gene product (KIT-Tyr553Cys), in a 68-year-old female patient with multiple gastrointestinal stromal tumors (GISTs). In the present study, we carried out mutational analysis in her family members to determine the carriers and characterized the mutation by introducing the corresponding mutation (murine KIT-Tyr552Cys) into expression vector possessing murine c-kit cDNA. Mutational analysis of peripheral blood leukocytes of her family members revealed that a 44-year-old son had the same mutation, but at present he had neither apparent symptoms nor images of multiple GISTs. By transfection with the expression vector possessing the murine mutant c-kit cDNA, interleukin-3-dependent Ba/F3 murine lymphoid cells started growing autonomously without any growth factors, indicating that the mutation was considered to be of gain-of-function. Imatinib, a small molecule of tyrosine kinase inhibitor, effectively inhibited autophosphorylation of KIT-Tyr552Cys. Nilotinib, another small molecule of the KIT inhibitor, also effectively inhibited autophosphorylation of KIT-Tyr552Cys. In fact, proliferation of Ba/F3 cells expressing KIT-Tyr552Cys was effectively inhibited by both imatinib and nilotinib. These findings indicate that the novel type human KIT-Tyr553Cys mutation is the cause of the present familial and multiple GISTs, and that both imatinib and nilotinib might effectively inhibit the growth of GISTs developing in the patients of this family.

Familial Gastrointestinal Stromal Tumor Syndrome: Report of 2 Cases with KIT Exon 11 Mutation

“…Twenty families with familial GIST have arisen from exon 11 of KIT as described by Neuhann et al, 4 Nakai et al, 5 Adela et al, 7 and the cases presented here. KIT and PDGFRA are members of the family of class 3 tyrosine kinase receptors.…”

Detection of germinoma cells in cerebrospinal fluid using Oct4 immunocytochemistry: a case report

“…As the present case showed a relatively weak response to conventional chemotherapy, we performed Sanger sequencing for the c‐kit gene and found a point mutation (Y553C, c.A1658G) in exon 11 (Figure f). A recent experimental study has revealed that KIT Y553C is a gain‐of‐function mutation, and that proliferation of murine lymphocytes expressing this mutant is effectively inhibited by imatinib and nilotinib, which are known ATP‐competitive tyrosine kinase inhibitors that can affect KIT with juxtamembrane domain mutation . Although these molecular drugs targeting intracranial germinomas have yet to be applied, it is speculated that the present case may have been sensitive to these tyrosine kinase inhibitors.…”

Familial gastrointestinal stromal tumors, lentigines, and café‐au‐lait macules associated with germline c‐kit mutation treated with imatinib

“…Out of the 35 familial GIST, including the present kindred, described so far, 22 carry mutations in exon 11 (encoding the juxtamembrane domain), seven in exon 13 (kinase I domain), four in exon 17 (kinase II domain), one single family, and one single patient in exons 8 and 9 (extracellular juxtamembrane domain), respectively …”

“…Familial GISTs, associated with germline c‐kit mutation, are a very rare inherited condition described so far in 34 different families . The KIT receptor is expressed on erythrocytes, melanocytes, germ cells, mast cells, and interstitial cells of Cajal (ICC).…”

“…Familial GISTs, caused by germline gain‐of‐function c‐ kit mutations, represent a rare autosomal dominant condition characterized by multiple primary neoplasms, involvement of several family members, early presentation, and additional clinical features, including hyperpigmentation, mast cell disease, and dysphagia . Gain‐of‐function mutations of c‐kit produce a constitutive, ligand independent activation of the receptor and downstream pathways .…”