Germline mutations of KIT in gastrointestinal stromal tumor (GIST) and mastocytosis

Abstract

Somatic mutations of KIT are frequently found in mastocytosis and gastrointestinal stromal tumor (GIST), while germline mutations of KIT are rare, and only found in few cases of familial GIST and mastocytosis. Although ligand-independent activation is the common feature of KIT mutations, the phenotypes mediated by various germline KIT mutations are different. Germline KIT mutations affect different tissues such as interstitial cells of Cajal (ICC), mast cells or melanocytes, and thereby lead to GIST, mastocytosis, or abnormal pigmentation. In this review, we summarize germline KIT mutations in familial mastocytosis and GIST and discuss the possible cellular context dependent transforming activity of KIT mutations.

Autosomal dominant progressive hyperpigmentation and lentigines in a Japanese pedigree due to a missense mutation near the C-terminus ofKIT

“…In addition, somatic mutations in KIT cause GIST or mastocytosis. Ten cases of hyperpigmentation and two cases of lentigines were reported in familial mastocytosis or GIST associated with germline KIT mutations …”

“…Finally, the mutation lies on the TK2 activation loop (amino acid residues 810–839) . Many germline mutations within TK2 of KIT have been reported (p.Asp820Tyr and p.Asn822Tyr in GISTs, p.Asn822Ile in mastocytosis and p.Pro832Leu in piebaldism) …”

“…) compared with that in individuals with KIT mutations associated with both hyperpigmentation and GIST . In contrast to somatic mutations, germline mutations of KIT have been found in only a small number of cases of familial mastocytosis and GIST . As of 2016, 37 reports described 21 well‐sequenced germline mutations in KIT .…”

“…Ten cases of hyperpigmentation and two cases of lentigines were reported in familial mastocytosis or GIST associated with germline KIT mutations. 3 We investigated a four-generation Japanese family with progressive hyperpigmentation and lentigines. Physical examination revealed that all six of the living affected individuals in this family manifested pigmentation disorders unassociated with any other familial systemic disease ( Fig.…”

“…1 Many germline mutations within TK2 of KIT have been reported (p.Asp820Tyr and p.Asn822Tyr in GISTs, p.Asn822Ile in mastocytosis and p.Pro832Leu in piebaldism). 1,3 Interestingly, this mutation leads to the unique amino acid sequence 'Pro-Arg-Leu-Pro', which might be an Src homology 3 (SH3) domain-binding motif (Pro-X-X-Pro motif) in KIT (Fig. 1g,h).…”