Abstract:Quadruple wild-type (WT) gastrointestinal stromal tumor (GIST) is a genomic subgroup lacking KIT/PDGFRA/RAS pathway mutations, with an intact succinate dehydrogenase (SDH) complex. The aim of this work is to perform a wide comprehensive genomic study on quadruple WT GIST to improve the characterization of these patients. We selected 14 clinical cases of quadruple WT GIST, of which nine cases showed sufficient DNA quality for whole exome sequencing (WES). NF1 alterations were identified directly by WES. Gene ex… Show more
“…Recently, we and others reported a handful of gene fusions in GIST 4–7 (Table 1). However, here we report a novel, previously unreported PRKAR1B-BRAF gene fusion in a patient with GIST (Figure 2).…”
Section: Discussionmentioning
confidence: 97%
“…3 We and others recently reported that a small subset of GISTs also occur due to kinase fusions (eg, ETV6-NTRK3 , FGFR1-TACC1 , FGFR1-HOOK3 ), a previously unappreciated mechanism for GIST tumorigenesis. 4–7 …”
Gastrointestinal stromal tumors (GISTs) are rare in pregnancy, with only 11 reported cases. Adjuvant imatinib therapy, which targets the most common driver mutations in GIST (KIT and PDGFRA), is recommended for patients with high-risk GIST, but it has known teratogenicity in the first trimester. A 34-year-old G3P2 woman underwent exploratory laparotomy at 16 weeks’ gestation for a presumed adnexal mass. Surgical findings included normal adnexa and a 14-cm solid small bowel mass. The mass was resected en bloc with a segment of jejunum followed by a primary anastomosis. Histopathology and genomic analyses demonstrated a GIST with high-risk features but lack of KIT/PDG-FRA mutations and identified the presence of a previously unreported, pathogenic PRKAR1B-BRAF gene fusion. Given her tumor profile, adjuvant therapy with imatinib was not recommended. GIST is rare in pregnancy, but can masquerade as an adnexal mass in women of childbearing age. Because neoadjuvant/adjuvant imatinib has risks of teratogenicity, tumor molecular profiling is critical as we identified a previously unreported gene fusion of PRKAR1B with BRAF that is predicted to be imatinib-resistant. In this case, testing provided the rationale for not offering adjuvant imatinib to avoid unnecessary toxicity to the patient and fetus.
“…Recently, we and others reported a handful of gene fusions in GIST 4–7 (Table 1). However, here we report a novel, previously unreported PRKAR1B-BRAF gene fusion in a patient with GIST (Figure 2).…”
Section: Discussionmentioning
confidence: 97%
“…3 We and others recently reported that a small subset of GISTs also occur due to kinase fusions (eg, ETV6-NTRK3 , FGFR1-TACC1 , FGFR1-HOOK3 ), a previously unappreciated mechanism for GIST tumorigenesis. 4–7 …”
Gastrointestinal stromal tumors (GISTs) are rare in pregnancy, with only 11 reported cases. Adjuvant imatinib therapy, which targets the most common driver mutations in GIST (KIT and PDGFRA), is recommended for patients with high-risk GIST, but it has known teratogenicity in the first trimester. A 34-year-old G3P2 woman underwent exploratory laparotomy at 16 weeks’ gestation for a presumed adnexal mass. Surgical findings included normal adnexa and a 14-cm solid small bowel mass. The mass was resected en bloc with a segment of jejunum followed by a primary anastomosis. Histopathology and genomic analyses demonstrated a GIST with high-risk features but lack of KIT/PDG-FRA mutations and identified the presence of a previously unreported, pathogenic PRKAR1B-BRAF gene fusion. Given her tumor profile, adjuvant therapy with imatinib was not recommended. GIST is rare in pregnancy, but can masquerade as an adnexal mass in women of childbearing age. Because neoadjuvant/adjuvant imatinib has risks of teratogenicity, tumor molecular profiling is critical as we identified a previously unreported gene fusion of PRKAR1B with BRAF that is predicted to be imatinib-resistant. In this case, testing provided the rationale for not offering adjuvant imatinib to avoid unnecessary toxicity to the patient and fetus.
“…Interestingly, MEN1 and MAX mutations, along with NF1 and SDH, further extend the list of genes detected in KIT/PDGFRA WT GIST, genes which are characteristic for neuroendocrine tumors. Moreover, detection of high expression level of genes involved in the neural commitment process, such ASCL1 and EPHA4, further support the hypothesis of a neuroendocrine like signature for some quadruple WT GIST [32]. Fig.…”
mentioning
confidence: 56%
“…Moreover, two fusion genes involving FGFR1 were reported in three cases of quadruple WT GIST (FGFR1–HOOK3 and FGFR1–TACC1) [30]. Recently, other fusion events (KIT–PDGFRA, MARK2-PPFIA1 and SPRED2-NELFCD) have also been detected [31, 32]. Finally, relevant somatic mutations, including TP53, MEN1, MAX, CHD4, FGFR1, CTDNN2, CBL, ARID1A, BCOR and APC were also identified [30–33].…”
Recent advances in molecular biology have revolutionized the concept of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumors (GIST) than the past. Indeed, from being defined as GIST without KIT or PDGFRA mutations, we are now faced with the opposite scenario, where KIT/PDGFRA WT GIST are “positively” defined according to their specific molecular alterations. In particular, if until recently KIT/PDGFRA GIST without abnormalities of KIT, PDGFRA, SDH, and the RAS signaling pathway were referred as quadruple WT GIST, today also this small subset of GIST is emerging out as a group of heterogeneous distinct entities with multiple different molecular alterations. Therefore, given this still growing and rapidly evolving scenario, the progressive molecular fragmentation may inevitably lead over the time to the disappearance of KIT/PDGFRA WT GIST, destined to be singularly defined by their molecular fingerprint.
“…Most KIT/PDGFRA mutated GISTs respond to the RTK inhibitor imatinib; however, treatment response is mainly depending on tumor genotype. [10][11][12] In contrast, the SDH-deficient GIST group includes the majority of pediatric GISTs, some sporadic adult/young adult cases, and rare syndromic GISTs developing in association with the Carney-Stratakis-Syndrome and the Carney triad. Over the last years, it became apparent that the so-called "WT-GIST group" is quite heterogeneous with regards to clinical phenotype and molecular characteristics.…”
Up to 85% of gastrointestinal stromal tumors (GIST) harbor mutually exclusive mutations in the KIT or the PDGFRA gene. Among others, known as wild type GIST, succinate dehydrogenase (SDH)‐deficient tumors develop due to genetic or epigenetic alterations in any of four SDH genes. Herein, we present a unique case of SDH‐deficient GIST with an unusual heterogeneous SDHA and SDHB staining pattern and mutations detected in the SDHA and KIT gene. A 50‐year‐old patient presented with a 5 cm large gastric tumor with a multinodular/plexiform growth pattern, mixed epithelioid and spindle cell morphology, and focal pronounced nuclear atypia with hyperchromasia and high mitotic activity. Immunohistochemically, CD117 and DOG‐1 were positive. SDHB and SDHA stains showed loss of expression in some of the nodules, whereas others presented with an unusually weak patchy positivity. Molecular analysis revealed a point mutation in exon 5 of the SDHA gene and a mutation in exon 11 of the KIT gene. We hypothesize that based on the allele frequency of SDHA and KIT mutations the tumor is best regarded as SDH‐deficient GIST in which the SDHA mutation represents the most likely driver mutation. The identified KIT mutation raises the distinct possibility that the KIT mutation is a secondary event reflecting clonal evolution. This is the first case of a treatment naïve GIST harboring a somatic SDHA and a KIT mutation, challenging the dogma that oncogenic mutations in treatment naïve GIST are mutually exclusive.
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