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of neurofibromatosis is characterized by genetic alterations on NF1 gene, which had more than 60 exons,
[20]
and encodes neurofibromin, a tumor suppressor that downregulates the RAS/RAF/MEK/ERK pathway .

SDH deficient GISTs
The SDH deficient GISTs’ group includes GIST patients who lost the SDH complex functionality. Indeed,
10%-15% of adult GISTs do not harbor genetic alterations on KIT or PDGFRA but present alterations on
one of the SDH genes. SDH is a mitochondrial enzyme composed by four different subunits, encoded by
[8]
four different genes SDHA, SDHB, SDHC, and SDHD . The SDH loss of expression is often due to germ-
line and/or somatic loss-of-function mutations in any of the SDH subunits. In addition to the canonical
DNA mutations, recently, different papers have showed that SDH inactivation may be due to epigenetic
[21]
mechanisms as hypermethylation of SDHC promoter . The SDH-complex is involved in the Krebs cycle
and is responsible for the conversion of succinate to fumarate. Consequently, SDH deficiency leads to
accumulation of succinate, which in turn promotes HIF1a overexpression and expression of hypoxia-
associated tumorigenic responses and angiogenesis . Considering the clinical features, SDH-deficient GISTs
[22]
show a number of unique characteristics, such as young age at onset, female gender predilection, gastric
localization, frequent lymph node metastatic involvement, and an indolent behavior [7,23] .

TREATMENT OF GIST
GIST management for immunohistologically confirmed GISTs plans: (1) surgical resection for resectable
GISTs without metastasis, or (2) administration of TKIs for unresectable, metastatic, or recurrent GISTs [24-26] .
Currently, the only first-line approved treatment for metastatic and inoperable GIST is imatinib. Imatinib,
introduced in GIST management at the beginning of 2000, deeply changed the prognosis of these patients,
[27]
who were considered irresponsive to the majority of available chemotherapic treatments . Imatinib is a
selective TKI, which targets diverse tyrosine kinase receptors, including ABL, BCR-ABL, KIT, PDGFRA,
PDGFRB and CSF1R. The majority of GISTs respond well to the imatinib standard dose of 400 mg/day, but,
commonly, after 24-36 months, a large proportion of patients develop secondary mutations and the tumor
[28]
progresses . To face the progressive acquisition of resistance, within the last 20 years, a second and a third
line, sunitinib and regorafenib, respectively - have been introduced in GIST management. Sunitinib and
regorafenib are TKIs [29,30] with a wider range of kinase inhibition - compared to imatinib, including KIT,
PDGFR, VEGFR, FLT3, TIE2, RET, FGFR1, RAF [30,31] . However, despite the efficacy of the currently available
three-lines of therapy, patients usually progress even under sunitinib and regorafenib; unfortunately, there
are no other therapeutic options and rechallenge of imatinib or sunitinib may represent a reasonable option
[32]
in advanced GIST patients after failure of previous treatments . In the last years, the research progress
and the advance in deep sequencing techniques promoted the identification of novel potential targets and
different trials are ongoing.

KIT/PDGFRA genotype and clinical outcome
It is well established that tumor genotype play a critical role in GIST clinical outcome. Indeed, among GIST
patients treated with TKIs, it has been observed a wide inter-individual variability and mutational analysis
appear to be critical to make a clinical decision about adjuvant therapy.

Patients may show a primary resistance to the treatment (i.e., fail to respond within the first 6 months of
treatment), or, as often happens in GISTs, stop to respond at some point, after an initial response (secondary
[33]
or acquired resistance during treatment) . It has been reported that about 10%-15% of GISTs treated with
imatinib show primary resistance. Specifically, a meta-analysis of four studies involving 215 GIST patients
evaluated resistance according to KIT and PDGFRA genetic alteration . The authors found that 50% of
[34]
PDGFRA-mutant, ~35% of KIT/PDGFRA wild-type and ~10% of KIT mutant GISTs were irresponsive to
imatinib . Considering the lack of an oncogenic mutation, it is not surprising the low imatinib response
[34]
observed in KIT/PDGFRA WT GIST.