Classification of KIT/PDGFRA wild-type gastrointestinal stromal tumors: implications for therapy

Abstract

Gastrointestinal stromal tumors (GIST) are driven mostly by oncogenic KIT or PDGFRA mutations. However, in 10–15% of all GIST, no such activating mutations can be found and these tumors are classified as ‘wild-type GIST’ (KIT/PDGFRA wt-GIST). Subgroups of KIT/PDGFRA wt-GIST are driven by other sporadic mutations involving the RAS/RAF/MAP-kinase pathway, such as BRAF or KRAS mutations. Furthermore, KIT/PDGFRA wt-GIST are observed in the context of hereditary syndromes, such as neurofibromatosis Type 1, in which the lack of neurofibromin 1 also leads to the activation of the RAS/RAF/MAP-kinase pathway. Finally, the deficiency succinate dehydrogenase seems to play a major role in KIT/PDGFRA wt-GIST. In conclusion, KIT/PDGFRA wt-GIST belong to different subgroups defined by diverse underlying genetic alterations leading to different biological phenotypes. The vast majority of KIT/PDGFRA wt-GIST will not respond to imatinib. Further research to unravel the pathogenesis of KIT/PDGFRA wt-GIST is prerequisite to the development of effective treatment strategies.

Keywords:

• BRAF
• GIST
• imatinib
• KIT
• NF1
• PDGFRA
• SDHA
• SDHB
• wild type

Financial & competing interests disclosure

E Wardelmann has received grants and honorarium from Novartis, Pfizer and PharmaMar. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• In 10–15% of all gastrointestinal stromal tumors (GIST), no oncogenic activating mutations in KIT or PDGFRA can be found and these tumors are classified as ‘KIT/PDGFRA wild type GIST’ (KIT/PDGFRA wt-GIST).

• KIT/PDGFRA wt-GIST represents a very heterogeneous group, subdivided by diverse underlying genetic alterations.

• BRAF or KRAS mutations define a subgroup of KIT/PDGFRA wt-GIST driven by sporadic mutations in the RAS/RAF/MAPK kinase pathway. The same pathway is activated in a hereditary setting, namely in neurofibromatosis type I through loss of neurofibromin.

• A larger number of KIT/PDGFRA wt-GIST present with a succinate dehydrogenase (SDH) subunit deficiency. The complex members SDHA and SDHB can be detected by immunohistochemistry, the latter missing independently of which isoform is altered. The vast majority of cases have a low aggressiveness.

• The group of pediatric and pediatric-type GIST is challenging as the use of tyrosine kinase inhibitor in very young patients is still not well established. The natural history of this subgroup has to be studied more thoroughly.

• The vast majority of KIT/PDGFRA wt-GIST will not respond to imatinib.

• To develop novel treatment strategies, further research is needed to discover the pathogenesis of KIT/PDGFRA wt-GIST.

• Next generation sequencing and further epigenomic characterization will hopefully allow us to understand the natural biology of different subtypes of KIT/PDGFRA wt-GIST.

Notes