Novelc-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentation

Abstract

Mutations in the c-KIT gene have been identified in many sporadic and familial cases of gastrointestinal stromal tumor (GIST). We report a familial case of GIST with cutaneous hyperpigmentation associated with a novel germline mutation in the c-KIT gene. Screening for mutations in exon 11 of the c-KIT gene in genomic DNA from tumors and peripheral blood of the members of a family with GISTs was undertaken by direct genomic sequencing. Tumors from GIST patients were analyzed histologically and immunohistochemically. Clinical examination of GIST patients was also performed to detect other systemic diseases associated with c-KIT mutations. Histological study showed that the tumors were GISTs expressing CD34 and c-KIT protein. This GIST-hyperpigmentation disease was associated in the family with a germline mutation in the c-KIT gene. The mutation is a duplication of the sequence CAACTT located in exon 11 of the c-KIT gene, which introduces two extra glutamine and leucine residues in the encoding protein between positions 576 and 577. This Spanish family was affected with GISTs and cutaneous hyperpigmentation associated with a novel germline mutation Leu576_Pro577insGlnLeu in the juxtamembrane domain of the c-KIT receptor. These types of mutation in the c-KIT gene activate the tyrosine kinase activity of the c-KIT receptor and induce constitutive signaling leading to GISTs, in some cases associated with cutaneous hyperpigmentation.

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

“…The proband showed ICC hyperplasia, which is nearly always observed in patients with familial and multiple GISTs. Although hyperpigmentation is often seen and mast cell tumor is sometimes seen in previously reported patients with exon 11 germline c-kit gene mutation, 30,33,34,[36][37][38]44,48 the present patient and her son, a possible carrier, did not show those phenotypes. Dysphagia is also a symptom that is often seen in exon 17 germline c-kit gene mutation, 35,42 but is rarely seen in exon 11 germline ones.…”

“…30,31,33,34,[36][37][38][39][40]43,44,46,49 KIT-Val559Ala mutation is the most frequent type, which has been detected in five families. 33,34,38,39,49 Recently, we found a germline mutation at exon 11, KIT-Tyr553Cys, in a 68-yearold woman with multiple GISTs.…”

“…30 To our knowledge, B20 families with germline c-kit gene mutations and multiple GISTs have been reported so far. [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] Thirteen families including the first case have the c-kit gene mutation at exon 11, 30,31,33,34,[36][37][38][39][40]43,44,46,49 three families at exon 13, 32,45,48 three families at exon 17 35,42,47 and one family at exon 8. 41 In addition to multiple GISTs, patients of these families have hyperplasia of ICCs in the gut wall.…”

Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor

“…In GIST kindreds, tumor nodules are often contiguous with areas of hyperplastic ICCs on histopathologic analysis 3,4,9,10,12,30,31,36 suggesting that these tumors arise within the hyperplastic ICC. In our study, the tumor nodules appeared to arise from a background of a hyperplastic Auerbach's plexus in the small bowel (Figs.…”

“…Interestingly, GIST kindreds reported to date have been described to have primary GISTs arise from the small intestine 3,9,10,12,13,31,32,37,38 or the small intestine and the stomach 12,13,30,36,39 but not the stomach alone. On the other hand, studies have demonstrated that nearly two-thirds of all sporadic GISTs arise in the stomach.…”