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 Table of Contents  
Year : 2018  |  Volume : 4  |  Issue : 3  |  Page : 75-82

The “Wild”-type gastrointestinal stromal tumors: Heterogeneity on molecule characteristics and clinical features

1 Division of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
2 Division of Oncology, Xiangya Hospital, Central South University; Institute of Medical Sciences, Changsha, Hunan, China

Date of Submission02-Jun-2018
Date of Acceptance21-Jun-2018
Date of Web Publication29-Jun-2018

Correspondence Address:
Prof. Bin Li
Division of Oncology, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha 410008, Hunan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ctm.ctm_17_18

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KIT and platelet-derived growth factor receptor alpha (PDGFRA) are known as the most driven genes in gastrointestinal stromal tumors (GISTs). However, about 10%–15% of GISTs without KIT and PDGFRA mutation are named “Wild-type” (WT) GISTs. Gene abnormalities and clinical features of WT GISTs are significantly different from KIT/PDGFRA-mutated GISTs. Recently, based on the findings of next-generation sequencing, WT GISTs have been shown to be not a single disease entity, but instead a set of various pathologic and clinical diseases. Nevertheless, although several genetic alterations have been identified in WT GISTs, the exact roles of these molecules have not yet been well defined. We herein summarize the recent progression on KIT/PDGFRA WT GISTs.

Keywords: Clinical features, molecule characteristics, wild-type gastrointestinal stromal tumors

How to cite this article:
Mou Y, Wang Q, Li B. The “Wild”-type gastrointestinal stromal tumors: Heterogeneity on molecule characteristics and clinical features. Cancer Transl Med 2018;4:75-82

How to cite this URL:
Mou Y, Wang Q, Li B. The “Wild”-type gastrointestinal stromal tumors: Heterogeneity on molecule characteristics and clinical features. Cancer Transl Med [serial online] 2018 [cited 2019 Feb 21];4:75-82. Available from: http://www.cancertm.com/text.asp?2018/4/3/75/235601

  Introduction Top

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract, accounting for approximately 14–20 cases per million based on population-studies. However, these incidence rates may underestimate the actual occurrence of GIST, as subclinical GISTs are much more common. c-KIT was reported as the first-driven oncogene associated with GISTs, and soon after platelet-derived growth factor receptor alpha (PDGFRA) was discovered. Subsequently, imatinib (which specifically targets these two oncogenes) was successfully used in the controlling c-KIT and PDGFRA-positive GISTs.

Although the presence of KIT and PDGFRA in GIST provides potentially new avenues to cure this type of disease, there still remains a portion of GIST without KIT or PDG-FRA mutations. These have been classified as KIT/PDGFRA wild-type (WT) GISTs, informally known as WT GISTs.[1] Although WT GISTs only occupy about 10%–15% of total GISTs, they are often considered as a family of disease and not as a single disease entity due to their extreme heterogeneity of gene aberration and clinical features.[2]

Usually, KIT or PDGFRA-mutated GISTs harbor several cytogenetic abnormalities which mainly involved 14q, 22q, and 1p chromosomes. However, WT GISTs scarcely have genomic imbalances.[3],[4] Further, patients with KIT/PDGFRA WT GISTs seem to have a different microRNA expression profile compared to mutated GISTs.[5] Due to the absence of the KIT/PDGFRA mutation, WT GISTs are typically resistant to imatinib treatment. Furthermore, it seems that most WT GISTs behave indolently, not forecasted by traditional risk stratification. Interestingly, KIT/PDGFRA WT GISTs are more prevalent in children (up to 85%) than in adults.[6] Recent studies have gradually revealed various novel gene mutations and their molecular mechanisms that are related to WT GISTs. This review will summarize current research on WT GISTs, and inquire whether or not they could eventually be used as novel therapeutic targets.

  Different Origin and Gene Expression Profile in Wild-Type Gastrointestinal Stromal Tumors Top

Over the past a few years, research studies have demonstrated that KIT/PDGFRA WT GISTs are strikingly different from KIT/PDGFRA-mutant GISTs regarding their genomic expression profile. Regular chromosome banding techniques have shown that several cytogenetic alterations, especially 14q, 22q, and 1p chromosomes, are typically involved in KIT/PDGFRA-mutated GISTs, but not in the WT GISTs, which seems have no genomic imbalance. In addition, KIT/PDGFRA WT GISTs have been shown to be quite different than mutant GIST, regarding gene expression profiling. In a particular study that compared copy number and gene expression data from 21 mutant genes to 4 KIT/PDGFRA WT GISTs, the highest differential expression was the downregulated expression of RTN1, DAAM1, and DACT1 within the mutant subgroup.[4]

Moreover, patients with KIT/PDGFRA WT GISTs seem to have a different microRNA expression profile, relative to the mutated GIST. Recent findings regarding a set of 13 GIST tumor samples (9 mutant vs. 4 WT GIST) disclosed that 56 microRNAs were differentially expressed between WT and mutant samples. Further, the downregulation of hsa-let-7b and hsa-let-7c microRNAs in WT samples, relative to mutated samples, were the most differentially expressed microRNAs. These were shown to be able to target the IGF1R receptor. Immunohistochemical staining revealed that EGFR and IGF1R, but not HER2, were expressed by some WT GISTs. These may become potential therapeutic targets for WT GISTs.

Intriguingly, the following meta-analysis data which was administrated in murine, human, and murine interstitial cells of Cajal (ICCs) (DMP and MY) showed that mutated GIST co-map with ICCs. Conversely, however, the expression profile of KIT/PDGFRA WT GISTs was not allocated by either mutated tumors or putative precursor ICCs. These results indicate that KIT/PDGFRA WT GISTs may have a different cell origin from mutated subgroups, or it may be derived from precursors of ICCs.[7] Although there are more than 20 distinct molecular entities for KIT/PDGFRA WT GISTs, they likely reflect a common molecular pathway similar to pediatric GISTs. In general, overall survival in adults with WT GISTs has been shown to be better than that in mutated GIST subtypes. This is particularly prevalent in succinate dehydrogenase (SDH)-deficiency GISTs and neurofibromatosis type 1 (NF1)-related GISTs, which always show an indolent process.[8]

  Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors Top

Recent studies have indicated that SDH-deficient GISTs represent about one-third to one-half of all KIT/PDGFRA WT GISTs. These are identified by the loss of subunit B (SDHB) protein expression as indicated through immunochemical staining. SDHB protein deficiency is commonly due to germline and/or somatic loss-of-function mutations in any of the four SDH subunits (A, B, C, or D), one of which destabilize the SDH heterotrimer, leading to negative SDHB immunostaining.[9]

SDH deficiency and the resulting accumulation of succinate promote GIST development through different mechanisms, including upregulation of HIF1α and inhibition of DNA demethylation.[10],[11] SDH complex is located in the inner membrane of mitochondria, including four subunits (SDHA, SDHB, SDHC, and SDHD). It is a component of the citric acid cycle and respiratory electron transfer chain and participates in the Krebs cycle by catalyzing succinic acid to fumaric acid. As the loss of SDH complex induces a pseudohypoxic status, several nuclear genes including HIF1α have been shown to be excessively activated, leading to the dysregulation of angiogenesis, erythropoiesis, and apoptosis.[12],[13] Thus, in some sense, SDH-deficient GISTs can be considered a metabolic disease. Further, antiangiogenic treatments may be effective toward this type of SDH-deficiency GIST. Meanwhile, SDH deficiency can cause the accumulation of succinate, which is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases, such as the TET family of 5-methylcytosine hydroxylases.[14] Therefore, blockage of TET activities, which are active DNA demethylases that convert 5-methylcytosine to 5-hydroxymethylcytosine, result in aberrant DNA methylation in GISTs. Indeed, a genome-wide DNA methylation analysis of SDH-deficient GISTs may disclose greater DNA hypermethylation in WT GISTs than in mutated counterparts.[15]

Prominently, the hypermethylation level of SDH in WT GISTs has been shown to be higher than that of the mutated GISTs. In addition, aberrant hypermethylation of SDHC promoter was observed in Carney's triad (GIST, paraganglioma, and chondroma), which is considered an epigenetic mechanism of tumorigenesis.[15] Furthermore, a loss-of-function mutation in any of the four genes encoding the SDH complex is known to cause Carney–Stratakis syndrome (personal or family history of paraganglioma).[16] Therefore, SDH-deficiency GISTs can arise in the context of the Carney–Stratakis Syndrome or Carney's triad and account for a significant proportion of pediatric GISTs cases with lymph node metastases.

Patients with SDH-deficiency GISTs are mostly young-adult women and characterized with some common clinical and pathological traits, such as gastric primary tumor location, multifocal lesions with mixed epithelioid and spindle cell morphology and diffuse KIT and DOG1 IHC positivity. Impressively, these GIST subtypes usually present with lymph node metastases and an indolent course, even if metastatic, which is remarkably different from KIT/PDGFRA-mutated GISTs.[17]

SDHA deficiency, which usually due to SDHA gene mutation, occurred in about 30% of SDHB-negative GISTs. GISTs with SDHA deficiency showed the immunohistochemically negative of SDHA.[18] The SDHA-negative GISTs were predominantly seen in male with older age and apt to liver metastasis. However, there are no difference in the tumor size, mitosis rate, and clinical course between SDHA-positive and SDHA-negative GISTs.[8],[18]

IGF1R was upregulated in all patients with SDH-deficiency, which resulting from SDH gene mutations or DNA hypermethylation, compared with the KIT/PDGFRA WT GISTs without SDH mutations or KIT/PDGFRA mutation subtype.[19] Western blot assay confirmed that all SDH-deficiency patients with an upregulation of IGF1R mRNA had the detectable IGF1R protein expression.[19],[20],[21] High level of IGFR1 protein maybe confer to the pathogenesis of this subtype and endow it insensitive to imatinib. IGFR1 was one of the two receptors in the IGF family and the combination of IGF to IGFR1 triggers the target pathways, such as the MAPK and PI3K/AKT pathways.[22] IGF signal played an important role in the SDH-deficient cases because studies showed that IGFR1 inhibition can cause cells apoptosis and suppress the MAPK and AKT signaling pathways in the GIST cells with SDH-deficiency. These findings pinpointed that IGFR1 overexpression in KIT/PDGFRA WT GISTs could be driven by the loss of function of the SDH mitochondrial complex.[23] Moreover, it also indicated that IGF1R positivity may be an alternative marker to identify SDH-deficient GISTs.[23],[24] Nevertheless, the functional relationship between loss-of-function of SDH and IGF1R overexpression should be clarified to understand if IGF1R could be considered a true target in these patients. Altogether, noticeable clinical features with strong IGF1R-positive, common epigenomic background distinguished by a distinctive hypermethylation and particular miRNA profile, should be warned by clinician to detect SDH gene mutation and protein expression.

  Gastrointestinal Stromal Tumors with the Mutation of Raf or Ras Top

Apart from SDH-deficiency GISTs, some KIT/PDGFRA WT GISTs harbor other sporadic driving mutations, which involve the RAS/RAF/MAPK pathway, such as the BRAF or KRAS mutation.[25] BRAF gene mutation with gain of function has been observed in various cancers, such as malignant melanomas, colorectal carcinomas, and lung cancer.[26] BRAF is located in chromosome 7q34, and the most frequent activation mutation is in exon 15a, where nucleotide substitution is at the position 1799 (A to T) in the kinase, leading to a substitution of valine by glutamic acid at codon 600 (p. V600E). Due to the seemingly important role of BRAF in these cancers, the specific BRAF inhibitors, vemurafenib and dabrafenib, have successfully exploited this addiction to BRAF oncogenic signaling. This causes a disturbance within the RAS-RAF-MEK-ERK pathway. For this reason, vemurafenib and dabrafenib have been approved to treat advanced melanoma with a known BRAF mutation.

The first reports describing the BRAF V600E mutation in GISTs were case studies of three middle-aged females with lesions in the small bowel, which were classified as high risk of recurrence.[27] However, another study found BRAF mutations in two male patients with early-stage GISTs. These were located in the gastric corpus and jejunum, also with spindle cell morphology, but mitotically inactive. In a study of 26 WT GISTs, one patient harboring the V600E mutation was a male patient with a small intestinal involvement.[28]

Huss et al.[29] investigated a cohort of 444 GISTs (272 KIT/PDGFRA-mutant and 172 WT GISTs) and identified BRAF mutations in seven tumors. The BRAF mutation existed in about 1.6% of all GISTs and 3.9% of WT GISTs.[29] In the following studies, the BRAF V600E mutation was determined in 4%–13% KIT/PDGFRA WT GISTs.[30] It was also reported that BRAF-related GISTs can localize in various sites including the small intestine, the stomach, the colon, the rectum, and within extraintestinal locations such as peritoneum.[31] However, many BRAF-mutated GISTs usually occur in the small intestine, tend to show spindle cell morphology, and seem to have a more favorable prognosis. In addition, the BRAF mutation is often found in small GISTs with diameters of 4 mm, and it is considered to be one of the earliest events in GIST development.[32],[33] Very recently, Leonidas reported that concomitant mutations of BRAF and fibroblast growth factor receptor 3 (FGFR3) genes were observed in two patients with the KIT gene mutation.[25] In general, BRAF mutations can be detected in different ways, noticeably in GISTs. In particular, DNA dideoxy sequencing, denaturing high-pressure liquid chromatography (DHPLC), and applied allele-specific polymerase chain reaction (AS-PCR) are clinically recommended for BRAF mutation detection. It is noted that DNA dideoxy is the most frequently used method. However, based on the higher sensitivity and specificity of assay, combination of DHPLC and AS-PCR is typically recommended for mutation identification. Clinically, however, immunohistochemistry with VE1 antibody is usually considered a valuable surrogate marker for a BRAF mutation. In line with the report of Rossi et al.[34] the immunohistochemistry of the VE1 antibody has been shown to have a high specificity (> 95%) and a high sensitivity (81.8%–100%) as reported by Huss et al.[29]

RAS proteins, encoded by RAS genes, usually serve as a molecular shift which toggles between two different status of active GTP-bound and inactive GDP-bound. The conversion from inactive GDP-bound mode to active GTP-bound mode is regulated by GTPase-activating proteins (GAPs). KRAS mutations frequently occur on codon 12 or 13, leading to a substitution of glycine at codon 12 or 13, which resultantly causes RAS constitution activation. Further, the glycine substitution at codon 12 or 13 prohibits RAS inactivation by GAPs, which also keep RAS kinase in sustained active form.[35]

Following earlier reports describing RAS involvement at the protein level in GISTs,[36] it was reported that KRAS mutations were in 5% of naïve GISTs with activating mutations in KIT or PDGFRA.[37] The mutations in codon 12 and/or 13 (G12D, G13D, and G12A/G13D) of KRAS were detected in all reported cases. Intriguingly, these mutations were shown to coexist with KIT exon 11 deletions (Δ570–576 and Δ579) in GIST samples. However, the tumor with the G13D mutation demonstrated a PDGFRA mutation at exon 18 (D842V). Significantly, these KRAS-mutated cases were from a cohort of 74 consecutive patients affected by GISTs registered in the Ticino Cancer Registry database.[37] The author also gave in vitro evidence that KRAS mutations might contribute to imatinib resistance in GISTs. In addition, HRAS and NRAS mutations have been mentioned (as unpublished observations) as possible driver events in these tumors.[38] In accordance with this result, recent reports have shown that the KRAS gain-of-function mutation was found in a naïve GIST case and is the causative factor of primary imatinib resistance. Remarkably, one GIST was shown to have HRAS mutations concomitant with PIK3CA mutation, indicating that coactivation of RAS pathway and PI3K pathway have similar capability as KIT activation causing GISTs occurrence.[39] Very recently, two GIST patients with WT KIT/PDGFRA had mutations in either KRAS or PIK3CA genes.[25]

However, a series of studies have failed to detect KRAS mutations in GISTs based on a relatively small number of cases.[40],[41],[42],[43] Similar results were published in a recent study, which reported that no KRAS mutations were observed in 514 GIST cases (350 gastric, 100 intestinal, and 64 primary disseminated GISTs) using Sanger sequencing and pyrosequencing.[44] The author concluded that KRAS mutations are extremely rare if they exist (< 0.2%) in GISTs. A summary of RAS mutations in GISTs is shown in [Table 1]. The discrepancy between these studies is difficult to explain, and further investigation is necessary to confirm the mutation profile of GISTs based on simultaneous evaluation of many genes from various genes involved in RAS pathways using next-generation sequencing (NGS) methods.
Table 1: RAS mutation in gastrointestinal stromal tumors

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  Quadruple Gastrointestinal Stromal Tumors Top

Although the discovery of KIT/PDGFRA/BRAF/SDH mutations in GISTs promotes the possibility of better prognoses, GIST pathogenesis is still not fully understood.[45] Recently, we have learned that GIST is also caused by mutations in NF1, KRAS, NRAS, and HRAS, the aberrance of one of them leading to the excessive activation of the RAS/MAPK pathway. Eventually, the terminology of “quadruple WT GISTs” emerged which originally referred to GISTs lacking cancer-causing alterations in KIT, PDGFRA, the RAS-pathway (K/N/H-RAS, BRAF, and NF1) or SDH subunits.[46] Different genetic signatures from KIT/PDGFRA-mutant and SDH-mutant GISTs existed in quadruple WT GISTs. Furthermore, quadruple WT GISTs have an enormous molecular heterogeneity, with a variety of mutation events. Recently, NF1-deficiency GISTs, patients with which do not have mutation in the other genes, were reclassified into the quadruple WT GISTs. Beyond NF1 deletion causing GISTs, there are still a few other rare gene abnormalities, such as ETV6-NTRK3, FGFR1, and the other putative drivers including ARID1A,[47] ARID1B, ATR, LTK, PARK2, SUFU, and ZNF217 have been added to the list of causative genes. A recent study displayed that the MEN1 and MAX mutations had a neuroendocrine-like molecular heterogeneity in quadruple WT GISTs based on data from genome-wide analyses.[48] Hence, the discovery of these new molecular abnormalities in the quadruple GISTs will inevitably result in the disappearance of the term “quadruple GISTs” in the future, which was intended to be taken place by their corresponding molecular fingerprint. When taking into account these aforementioned genes, more than 20 GIST subtypes have been identified, and there are still some GISTs with mutations/epimutations waiting to be discovered.

  Neurofibromatosis Type 1-Associated Gastrointestinal Stromal Tumors Top

NF1 is a tumor suppressor gene, which spans a large locus (350 kbp) at chromosome 17q11.2. It encodes neurofibromin protein, a member of the mammalian RAS-GAP-related proteins, which mainly regulates cellular levels of activated RAS proteins. The GAP-related domain region, encoded by exons 20–27a, is the key function part for neurofibromin protein.[49] Most RAS proteins prevail in their inactive GDP-bound form, and only a very small portion stay in their metabolically active GTP-bound form, which are responsible for activating many downstream effectors in the RAS/RAF/MAPK signaling pathway.

Neurofibromin is a vital actor for promoting the changeover of active RAS-GTP into its inactive RAS-GDP statue by provoking the RAS protein's GTPase activity. Therefore, the dysfunction of neurofibromin, resulting from inactivation of the NF1 gene, will lead to persistent activation of RAS-GTPase. Consequently, the RAS/RAF/MAPK signaling pathway is excessively activated and thus brings about uncontrolled cell growth and proliferation.[50]

NF1, also known as von Recklinghausen disease, is an inherited autosomal dominant disease. More than 2600 various mutations in NF1 have been identified in the Human Gene Mutation Database.[51] Most constitutional NF1 mutations (> 80%) are inactive, resulting in the function loss of NF1 transcript or protein.[52] Aside from presenting with multiple café-au-lait spots, Lisch nodules, freckling, and development of neurofibromas, it has been reported that about 7% NF1 cases can develop GISTs.[53],[54] Moreover, Gasparotto et al.[55] reported that a considerable part of apparently sporadic quadruple-negative GISTs actually exist in the background of imperceptible NF-Type 1 syndrome. Actually, up to 60%, GISTs without KIT/PDGFRA/RAS/SDH mutation have been identified that harbor distinct loss-of-function mutations of NF1 gene.

Notably, NF1-active GIST patients have been predominantly female, with a frequent nongastric site and multifocal or with a multinodular growth pattern. The GISTs typically arise in the small intestine, sometimes only in a segment, suggesting some type of mosaic. No other particular genetic mutations have been defined in NF1-related GISTs, neither KIT/PDGFRA mutation nor SDH gene deficiency.[55] That is to say, all GISTs arising in the background of NF1 are SDHB positive. Usually, NF1-associated GIST has a low risk of recurrence, is often clinically indolent and does not differ morphologically or immunophenotypically from sporadic intestinal GISTs.[56] Therefore, the diagnosis of a quadruple-negative GIST, particularly with characteristics of multilesions in a scatter pattern and in a nongastric location, may indicate a potential NF-type 1 syndromic condition.

Data from diverse databases, including TCGA, ICGC, COSMIC, and cBioPortal for Cancer Genomics, have shown that the somatic NF1 mutation was detected in divergent kinds of tumors.[50],[57] Recently, Li et al.[58] reported that the concurrence of RAS/MAPK pathway activation resulting from somatic NF1 mutation and PI3K pathway aberration can lead to GIST formation. Further, with the onset of NGS technology, the somatic mutations of NF1 have been identified in about 1% cases of total GISTs.[59] Although the genetic and somatic mutations of NF1 were found in GISTs, their function in the advancement of GISTs is not fully understood. NF1-deficiency GISTs have been shown to be resistant to the KIT-inhibitor, imatinib, due to extensive RAS/MAPK kinase activation, which is derived from NF1 inactivation, but not from mutated-KIT ignition. Regrettably, to date, therapeutic agents that target the RAS pathway have provided limited response.[60] This situation has prompted further exploration of the underlying mechanism, which will provide new insight for GIST pathogenesis and eventually provide an avenue of target therapy for quadruple GISTs.

  Other Gene Abnormality in Quadruple Gastrointestinal Stromal Tumors Top

Some reports have disclosed the mutation of other oncogenes in GISTs. For example, about 0.93% (3/323) of primary GISTs harbor EGFR mutations, and it was often mutually with a KIT mutation as well as the mutations of PDGFRA, KRAS, or BRAF.[61] The clinical characteristics of GISTs with EGFR mutations are typically in the stomach of female patients and have a low relapse rate. The PIK3CA (p. H1047 L) mutation has also been observed in a GIST case carrying the deletion of KIT exon.[42]

Other putative drivers such as FGFR1 p. N546K, ARID1A, ARID1B, ATR, LTK, PARK2, SUFU, and ZNF217[62],[63],[64] were also put on the list of causative genes based on the results of various studies. Two GISTs hold FGFR1 gene fusions of FGFR1-HOOK3 or FGFR1-TACC1. Another GIST case has the ETV6-NTRK3 fusion,[62],[65] which was detected by a transcriptome sequencing assay.[42] The ETV6-NTRK3 fusion transcript has been defined in breast carcinomas.[66] Likewise, there are still other fusion events including KIT–PDGFRA, MARK2-PPFIA1, and SPRED2-NELFCD happening in quadruple GISTs.[48],[63]

Interestingly, using genome-wide analyses, MEN1 and MAX mutations were found in a few quadruple WT GIST samples,[48],[67] and max inactivation was considered as an early event in GIST development, which was correlated with cell proliferation.[68]

Moreover, a high expression level of genes such as ASCL1 and EPHA4 are known to be involved in the neural commitment process, which indicates a genetic similarity between neuroendocrine tumors and some quadruple WT GISTs. This further supports the hypothesis of a neuroendocrine-like signature in some WT GIST cases.[7] Very recently, with different next sequencing approaches, some quadruple-negative GISTs were found carrying somatic mutations in TP53, CHD4, CTDNN2, CBL, BCOR, NTRK2, COL22A1, and APC genes.[67] The mutations of protein phosphatase 2 regulatory subunit A alpha (PPP2R1A), attributing to protein phosphatase 2A function loss, were found in some portions of GISTs (17/94). Notably, most PPP2R1A- mutant GISTs (16/17) also simultaneously carry the mutations of KIT, PDGFRA, or RAS family genes, while the rest of PPP2R1A- mutant cases are with SDH deficiency.[69] The abnormality of BRCA1 and BRCA2 as tumor suppressor genes may be related to the pathogenesis of GIST. A patient cherishing the germline mutation of BRCA2 8642del3insC may be predisposed to cancer and in particular, prostate cancer, breast cancer, and GIST.[70]

Although the genes mentioned above are involved in GISTs, the importance and exact role of these molecules in GIST pathogenesis are still to be determined. In total, there may be at least more than 20 GIST subtypes. The summary of alternative gene mutations in GISTs is shown in [Table 2]. However, some quadruple GISTs are still left with mutations/epimutations that remain to be discovered. The shortage of knowledge on these genetics prohibits the application of targeted treatments. Therefore, due to their utmost molecular and clinical heterogeneity, quadruple WT GISTs should be considered as a variety of diseases, not only a single disease. These quadruple-negative GISTs are poorly responsive to standard treatments of imatinib and sunitinib. From the EORTC Phase III trial 62005, data showed that treatment efficacy in patients with advanced GISTs lacking KIT or PDGFRA mutations was fairly low, giving evidence for treatment failure in this WT GIST subtype. Correspondingly, the relative risk of death increased by 76% when compared to KIT exon 11 mutants after TKI treatment.
Table 2: Various gene mutations in wild-type gastrointestinal stromal tumors

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  Hypothesis and Clinical Prospective Top

In conclusion, WT GISTs are a series of different diseases preserved by various molecular alterations. Although the morphology and immunohistochemical characteristics yield the same clinic definition as KIT/PDGFRA mutation GISTs, WT GISTs may potentially be a different disease with an impressive molecular heterogeneity. It is plausible that WT GISTs (especially quadruple WT GISTs) are derived from a particular population of pluripotent ICC, or they may share a molecular driver at the epigenomic level.

Currently, it is important to domesticate WT GISTs with their known molecular abnormality. Until there is normal SDHB protein expression and no alterations on whole-genome (i.e., mutation analysis), whole-genome bisulfite (i.e., methylation analysis), and RNA sequencing (i.e., RNA expression analysis), these tumors can be named as WT, in which driver genes and genomic alterations have yet to be determined. Hence, in the future, research must be focused on the biology and underlying mechanism of the different WT GIST subgroups. Large series of patients are needed to define the biological fingerprint of each subtype and integrate it with clinical data. Such studies would allow the transfer of biological information to clinical practice, and its use as an additional tool in the clinic for diagnosis, prognosis, and treatment choices.

Financial support and sponsorship

This work was supported by grants from the Natural Scientific Foundation of China (81200366,81171841) and Province Natural Scientific Foundation of Hunan (No. 14JJ6004) and the Key Subject Education Department of Hunan ((2012)594).

Conflicts of interest

There are no conflicts of interest.

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